bluuebunny/crossref_metadata_2025 huggingface dataset:
PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression
Authors: Deng Shuo , Leong Hin Chong , Datta Arpita , Gopal Vennila , Kumar Alan Prem , Yap Celestial T.
Published: March 2022

The PI3K/AKT signaling pathway plays essential roles in multiple cellular processes, which include cell growth, survival, metabolism, and motility. In response to internal and external stimuli, the PI3K/AKT signaling pathway co-opts other signaling pathways, cellular components, and cytoskeletal proteins to reshape individual cells. The cytoskeletal network comprises three main components, which are namely the microfilaments, microtubules, and intermediate filaments. Collectively, they are essential for many fundamental structures and cellular processes. In cancer, aberrant activation of the PI3K/AKT signaling cascade and alteration of cytoskeletal structures have been observed to be highly prevalent, and eventually contribute to many cancer hallmarks. Due to their critical roles in tumor progression, pharmacological agents targeting PI3K/AKT, along with cytoskeletal components, have been developed for better intervention strategies against cancer. In our review, we first discuss existing evidence in-depth and then build on recent advances to propose new directions for therapeutic intervention.
TERT Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC
Authors: Jablonowski Carolyn M. , Gil Hyea Jin , Pinto Emilia M. , Pichavaram Prahalathan , Fleming Andrew M. , Clay Michael R. , Hu Dongli , Morton Christopher L. , Pruett-Miller Shondra M. , Hansen Baranda S. , Chen Xiang , Jones Karissa M. Dieseldorff , Liu Yanling , Ma Xiaotu , Yang Jun , Davidoff Andrew M. , Zambetti Gerard P. , Murphy Andrew J.
Published: March 2022

Increased TERT mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased TERT expression by determining the association between TERT and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate TERT expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the TERT promoter. This study identified near ubiquitous hypermethylation of the TERT promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in WT1 (7/45, 15.6%) were found to have lower TERT expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher TERT expression and telomerase activity. In vitro shRNA knockdown of WT1 resulted in decreased expression of TERT, reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type WT1. CRISPR-Cas9-mediated knockout of WT1 resulted in decreased expression of telomere-related gene pathways. However, an inducible Wt1-knockout mouse model showed no relationship between Wt1 knockout and Tert expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased TERT promoter activity and TERT transcription. Thus, multiple mechanisms of TERT activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of TERT activation in Wilms tumor that could be of therapeutic interests.
Multimodality Treatment including Surgery Related to the Type of N2 Involvement in Locally Advanced Non-Small Cell Lung Cancer
Authors: Allaeys Toon , Berzenji Lawek , Lauwers Patrick , Yogeswaran Suresh Krishan , Hendriks Jeroen M. H. , Billiet Charlotte , De Bondt Charlotte , Van Schil Paul E.
Published: March 2022

For patients with locally advanced non-small cell lung cancer (NSCLC) or positive N1 nodes, multimodality treatment is indicated. However, the optimal management of patients presenting with ipsilateral positive mediastinal nodes (N2 disease) has not been determined yet. Different treatment regimens consisting of chemotherapy, radiation therapy, and surgery have been proposed and implemented previously. In more recent years, immunotherapy and targeted therapies have been added as therapeutic options. The role of surgery is currently redefined. Recent studies have shown that surgical resection after induction immunotherapy or targeted therapy is feasible and yields good short-term results. In this review, we summarize the latest data on multimodality treatment options for stage IIIA-N2 locally advanced NSCLC, depending on the extent of nodal involvement.
BDP1 Alterations Correlate with Clinical Outcomes in Breast Cancer
Authors: Cabarcas-Petroski Stephanie , Schramm Laura
Published: March 2022

TFIIIB is deregulated in a variety of cancers. However, few studies investigate the TFIIIB subunit BDP1 in cancer. BDP1 has not been studied in breast cancer patients. Herein, we analyzed clinical breast cancer datasets to determine if BDP1 alterations correlate with clinical outcomes. BDP1 copy number (n = 1602; p = 8.03 × 10−9) and mRNA expression (n = 130; p = 0.002) are specifically decreased in patients with invasive ductal carcinoma (IDC). In IDC, BDP1 copy number negatively correlates with high grade (n = 1992; p = 2.62 × 10−19) and advanced stage (n = 1992; p = 0.005). BDP1 mRNA expression also negatively correlated with high grade (n = 55; p = 6.81 × 10−4) and advanced stage (n = 593; p = 4.66 × 10−4) IDC. Decreased BDP1 expression correlated with poor clinical outcomes (n = 295 samples): a metastatic event at three years (p = 7.79 × 10−7) and cancer reoccurrence at three years (p = 4.81 × 10−7) in IDC. Decreased BDP1 mRNA correlates with patient death at three (p = 9.90 × 10−6) and five (p = 1.02 × 10−6) years. Both BDP1 copy number (n = 3785; p = 1.0 × 10−14) and mRNA expression (n = 2434; p = 5.23 × 10−6) are altered in triple-negative invasive breast cancer (TNBC). Together, these data suggest a role for BDP1 as potential biomarker in breast cancer and additional studies are warranted.
HPV8 Reverses the Transcriptional Output in Lrig1 Positive Cells to Drive Skin Tumorigenesis
Authors: Syed Adnan Shahzad , Marcuzzi Gian Paolo , Miller-Lazic Daliborka , Hess Jochen , Hufbauer Martin , Akgül Baki
Published: March 2022

K14-HPV8-CER transgenic mice express the complete early genome region of human papillomavirus type 8 (HPV8) and develop skin tumours attributed to the expansion of the Lrig1+ stem cell population. The correlation between HPV8-induced changes in transcriptional output in the stem cell compartment remains poorly understood. To further understand the oncogenic pathways underlying skin tumour formation we examined the gene expression network in skin tumours of K14-HPV8-CER mice and compared the differentially expressed genes (DEG) with those of the Lrig1-EGFP-ires-CreERT2 mice. Here, we report 397 DEGs in skin tumours of K14-HPV8-CER mice, of which 181 genes were up- and 216 were down-regulated. Gene ontology and KEGG pathway enrichment analyses suggest that the 397 DEGs are acting in signalling pathways known to be involved in skin homeostasis. Interestingly, we found that HPV8 early gene expression subverts the expression pattern of 23 cellular genes known to be expressed in Lrig1+ keratinocytes. Furthermore, we identified putative upstream regulating transcription factors as well as miRNAs in the control of these genes. These data provide strong evidence that HPV8 mediated transcriptional changes may contribute to skin tumorigenesis, offering new insights into the mechanism of HPV8 driven oncogenesis.
In Silico Bioinformatics Followed by Molecular Validation Using Archival FFPE Tissue Biopsies Identifies a Panel of Transcripts Associated with Severe Asthma and Lung Cancer
Authors: Salameh Laila , Bhamidimarri Poorna Manasa , Saheb Sharif-Askari Narjes , Dairi Youssef , Hammoudeh Sarah Musa , Mahdami Amena , Alsharhan Mouza , Tirmazy Syed Hammad , Rawat Surendra Singh , Busch Hauke , Hamid Qutayba , Al Heialy Saba , Hamoudi Rifat , Mahboub Bassam
Published: March 2022

Severe asthma and lung cancer are both heterogeneous pathological diseases affecting the lung tissue. Whilst there are a few studies that suggest an association between asthma and lung cancer, to the best of our knowledge, this is the first study to identify common genes involved in both severe asthma and lung cancer. Publicly available transcriptomic data for 23 epithelial brushings from severe asthmatics and 55 samples of formalin-fixed paraffin-embedded (FFPE) lung cancer tissue at relatively early stages were analyzed by absolute gene set enrichment analysis (GSEA) in comparison to 37 healthy bronchial tissue samples. The key pathways enriched in asthmatic patients included adhesion, extracellular matrix, and epithelial cell proliferation, which contribute to tissue remodeling. In the lung cancer dataset, the main pathways identified were receptor tyrosine kinase signaling, wound healing, and growth factor response, representing the early cancer pathways. Analysis of the enriched genes derived from the pathway analysis identified seven genes expressed in both the asthma and lung cancer sets: BCL3, POSTN, PPARD, STAT1, MYC, CD44, and FOSB. The differential expression of these genes was validated in vitro in the cell lines retrieved from different lung cancer and severe asthma patients using real-time PCR. The effect of the expression of the seven genes identified in the study on the overall survival of lung cancer patients (n = 1925) was assessed using a Kaplan–Meier plot. In vivo validation performed in the archival biopsies obtained from patients diagnosed with both the disease conditions provided interesting insights into the pathogenesis of severe asthma and lung cancer, as indicated by the differential expression pattern of the seven transcripts in the mixed group as compared to the asthmatics and lung cancer samples alone.
Do We Need TNM for Tracheal Cancers? Analysis of a Large Retrospective Series of Tracheal Tumors
Authors: Piórek Aleksandra , Płużański Adam , Teterycz Paweł , Kowalski Dariusz Mirosław , Krzakowski Maciej
Published: March 2022

Due to the low incidence of primary tracheal neoplasms, there is no uniform system for staging of this disease. Our retrospective analysis based on registry data included 89 patients diagnosed with primary tracheal cancer at the National Research Institute of Oncology in Warsaw, Poland, between January 2000 and December 2016. We analyzed demographic, clinical, pathological, therapeutic, and survival data. The staging—for the purpose of our analysis—was performed retrospectively on the basis of imaging results. Tumor (T) category was defined as a disease confined to the trachea or lesion derived from the trachea and spreading to adjacent structures and organs. Node (N) and metastases (M) categories were divided into absence/presence of metastasis in regional lymph nodes and the absence/presence of distant metastasis. Survival analysis was performed depending on the clinical presentation of these features. There was a significant difference in overall survival depending on the T, N, M categories in the entire group. In the group of patients undergoing radical treatment, the T and N categories had a statistically significant impact on overall survival. In the group of patients treated with palliative aim, only the T category had an impact on overall survival. Multivariate analysis showed statistical significance for the T category in patients undergoing radical and those receiving palliative treatment. The assessment of the anatomical extent of lesions may help decide about treatment options and prognosis.
A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer
Authors: Cetraro Pierina , Plaza-Diaz Julio , MacKenzie Alex , Abadía-Molina Francisco
Published: March 2022

The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), have been implicated in mediating its effects. As a result, abnormal expression of inhibitor apoptosis proteins (IAPs) can lead to dysregulated apoptosis promoting the development of different pathologies. In several cancer types IAPs are overexpressed, while their natural antagonist, the second mitochondrial-derived activator of caspases (Smac), appears to be downregulated, potentially contributing to the acquisition of resistance to traditional therapy. Recently developed Smac mimetics counteract IAP activity and show promise in the re-sensitization to apoptosis in cancer cells. Given the modest impact of Smac mimetics when used as a monotherapy, pairing of these compounds with other treatment modalities is increasingly being explored. Modulation of molecules such as tumor necrosis factor-α (TNF-α) present in the tumor microenvironment have been suggested to contribute to putative therapeutic efficacy of IAP inhibition, although published results do not show this consistently underlining the complex interaction between IAPs and cancer.
TGF-β/SMAD Pathway Is Modulated by miR-26b-5p: Another Piece in the Puzzle of Chronic Lymphocytic Leukemia Progression
Authors: Marquez Maria Elena , Sernbo Sandra , Payque Eugenia , Uria Rita , Tosar Juan Pablo , Querol Juliana , Berca Catalina , Uriepero Angimar , Prieto Daniel , Alvarez-Saravia Diego , Oliver Carolina , Irigoin Victoria , Dos Santos Gimena , Guillermo Cecilia , Landoni Ana Inés , Navarrete Marcelo , Palacios Florencia , Oppezzo Pablo
Published: March 2022

Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes. Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is well established that unmutated CLLs (U-CLLs) have worse evolution than mutated cases. Nevertheless, progression and treatment requirement of patients can evolve independently from the mutational status. Microenvironment signaling or epigenetic changes partially explain this different behavior. Thus, we think that detailed characterization of the miRNAs landscape from patients with different clinical evolution could facilitate the understanding of this heterogeneity. Since miRNAs are key players in leukemia pathogenesis and evolution, we aim to better characterize different CLL behaviors by comparing the miRNome of clinically progressive U-CLLs vs. stable U-CLLs. Our data show up-regulation of miR-26b-5p, miR-106b-5p, and miR-142-5p in progressive cases and indicate a key role for miR-26b-5p during CLL progression. Specifically, up-regulation of miR-26b-5p in CLL cells blocks TGF-β/SMAD pathway by down-modulation of SMAD-4, resulting in lower expression of p21−Cip1 kinase inhibitor and higher expression of c-Myc oncogene. This work describes a new molecular mechanism linking CLL progression with TGF-β modulation and proposes an alternative strategy to explore in CLL therapy.
Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue
Authors: AlZaim Ibrahim , Al-Saidi Aya , Hammoud Safaa H. , Darwiche Nadine , Al-Dhaheri Yusra , Eid Ali H. , El-Yazbi Ahmed F.
Published: March 2022

The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
Research Progress in Semiconductor Materials with Application in the Photocatalytic Reduction of CO2
Authors: Cui Yan , Ge Pengxiang , Chen Mindong , Xu Leilei
Published: March 2022

The large-scale burning of non-renewable fossil fuels leads to the gradual increase of the CO2 concentration in the atmosphere, which is associated with negative impacts on the environment. The consequent need to reduce the emission of CO2 resulting from fossil fuel combustion has led to a serious energy crisis. Research reports indicate that the photocatalytic reduction of CO2 is one of the most effective methods to control CO2 pollution. Therefore, the development of novel high-efficiency semiconductor materials has become an important research field. Semiconductor materials need to have a structure with abundant catalytic sites, among other conditions, which is of great significance for the practical application of highly active catalysts for CO2 reduction. This review systematically describes various types of semiconductor materials, as well as adjustments to the physical, chemical and electronic characteristics of semiconductor catalysts to improve the performance of photocatalytic reduction of CO2. The principle of photocatalytic CO2 reduction is also provided in this review. The reaction types and conditions of photocatalytic CO2 reduction are further discussed. We believe that this review will provide a good basis and reference point for future design and development in this field.
Overexpression of HLH4 Inhibits Cell Elongation and Anthocyanin Biosynthesis in Arabidopsis thaliana
Authors: Hou Quancan , Zhao Wei , Lu Lu , Wang Linlin , Zhang Tianye , Hu Binbin , Yan Tingwei , Qi Yuchen , Zhang Fan , Chao Nan , Bartels Dorothea , Wan Xiangyuan
Published: March 2022

In plants, many basic helix-loop-helix (bHLH) transcription factors are involved in controlling cell elongation. Three bHLH proteins, PACLOBTRAZOL RESISTANCE1 (PRE1), Cryptochrome Interacting Basic Helix-loop-helix 5 (CIB5), and Arabidopsis ILI1 binding bHLH1 (IBH1) form a triantagonistic system that antagonistically regulates cell elongation in a competitive manner. In this study, we identified a new player, HLH4, related to IBH1, that negatively regulates cell elongation in Arabidopsis thaliana. Overexpression of HLH4 causes dwarf and dark green phenotypes and results in the downregulation of many key regulatory and enzymatic genes that participate in the anthocyanin biosynthetic pathway. HLH4 interacts with CIB5 and PRE1. By interacting with CIB5, HLH4 interferes with the activity of CIB5, and thus inhibiting the transcription of cell elongation-related genes regulated by CIB5, including EXPANSINS8 and 11 (EXP8 and EXP11) and indole-3-acetic acid 7 and 17 (IAA7 and IAA17). The interference of HLH4 on CIB5 is counteracted by PRE1, in which these bHLH proteins form a new tri-antagonistic system.
Cardiac Remodeling in the Absence of Cardiac Contractile Dysfunction Is Sufficient to Promote Cancer Progression
Authors: Awwad Lama , Goldenberg Tomer , Langier-Goncalves Irina , Aronheim Ami
Published: March 2022

Cardiovascular diseases and cancer are the leading cause of death worldwide. The two diseases share high co-prevalence and affect each other’s outcomes. Recent studies suggest that heart failure promotes cancer progression, although the question of whether cardiac remodeling in the absence of cardiac contractile dysfunction promotes cancer progression remains unanswered. Here, we aimed to examine whether mild cardiac remodeling can promote tumor growth. We used low-phenylephrine (PE)-dose-infused in mice, together with breast cancer cells (polyoma middle T, PyMT), implanted in the mammary fat pad. Although cardiac remodeling, hypertrophy and fibrosis gene hallmarks were identified, echocardiography indicated no apparent loss of cardiac function. Nevertheless, in PE-infused mouse models, PyMT-cell-derived tumors grew larger and displayed increased cell proliferation. Consistently, serum derived from PE-infused mice resulted in increased cancer cell proliferation in vitro. ELISA and gene expression analysis identified periostin, fibronectin and CTGF as cardiac- and tumor-secreted factors that are highly abundant in PE-infused mice serum as compared with non-infused mice. Collectively, a low dose of PE infusion without the deterioration of cardiac function is sufficient to promote cancer progression. Hence, early detection and treatment of hypertension in healthy and cancer patients would be beneficial for improved outcomes.
Mechanisms of Action of Extracorporeal Photopheresis in the Control of Bronchiolitis Obliterans Syndrome (BOS): Involvement of Circulating miRNAs
Authors: Bozzini Sara , Del Fante Claudia , Morosini Monica , Berezhinskiy Hatice Oya , Auner Sophia , Cattaneo Elena , Della Zoppa Matteo , Pandolfi Laura , Cacciatore Rosalia , Perotti Cesare , Hoetzenecker Konrad , Jaksch Peter , Benazzo Alberto , Meloni Federica
Published: March 2022

Clinical evidence suggests an improvement or stabilization of lung function in a fraction of patients with bronchiolitis obliterans syndrome (BOS) treated by extracorporeal photopheresis (ECP); however, few studies have explored the epigenetic and molecular regulation of this therapy. The aim of present study was to evaluate whether a specific set of miRNAs were significantly regulated by ECP. Total RNA was isolated from serum of patients with established BOS grade 1–2 prior to the start and after 6 months of ECP treatment. We observed a significant downregulation of circulating hsa-miR-155-5p, hsa-miR-146a-5p and hsa-miR-31-5p in BOS patients at the start of ECP when compared to healthy subjects. In responders, increased miR-155-5p and decreased miR-23b-3p expression levels at 6 months were found. SMAD4 mRNA was found to be a common target of these two miRNAs in prediction pathways analysis, and a significant downregulation was found at 6 months in PBMCs of a subgroup of ECP-treated patients. According to previous evidence, the upregulation of miR-155 might be correlated with a pro-tolerogenic modulation of the immune system. Our analysis also suggests that SMAD4 might be a possible target for miR-155-5p. Further longitudinal studies are needed to address the possible role of miR-155 and its downstream targets.
Brain and Retinal Organoids for Disease Modeling: The Importance of In Vitro Blood–Brain and Retinal Barriers Studies
Authors: Martinelli Ilenia , Tayebati Seyed Khosrow , Tomassoni Daniele , Nittari Giulio , Roy Proshanta , Amenta Francesco
Published: March 2022

Brain and retinal organoids are functional and dynamic in vitro three-dimensional (3D) structures derived from pluripotent stem cells that spontaneously organize themselves to their in vivo counterparts. Here, we review the main literature data of how these organoids have been developed through different protocols and how they have been technically analyzed. Moreover, this paper reviews recent advances in using organoids to model neurological and retinal diseases, considering their potential for translational applications but also pointing out their limitations. Since the blood–brain barrier (BBB) and blood–retinal barrier (BRB) are understood to play a fundamental role respectively in brain and eye functions, both in health and in disease, we provide an overview of the progress in the development techniques of in vitro models as reliable and predictive screening tools for BBB and BRB-penetrating compounds. Furthermore, we propose potential future directions for brain and retinal organoids, in which dedicated biobanks will represent a novel tool for neuroscience and ophthalmology research.
Use of Musical Intervention in the Pediatric Intensive Care Unit of a Developing Country: A Pilot Pre–Post Study
Authors: Buzzi Federica , Yahya Nizar Bakir , Gambazza Simone , Binda Filippo , Galazzi Alessandro , Ferrari Antonella , Crespan Stefano , Al-Atroushy Hevan Adel , Cantoni Barbara Maria , Laquintana Dario ,   Collaborative Group
Published: March 2022

Music is frequently used in different clinical settings, and it is implemented as a complementary, low-cost and useful intervention to reduce pain, anxiety and to improve relaxation. This pilot pre–post study aimed to examine the feasibility and preliminary effectiveness of a specific musical intervention in patients ≤16 years admitted to the Pediatric Intensive Care Unit (PICU) of an Iraqi hospital. The COMFORT Behavior Scale (CBS) was used by nurses to assess the level of sedation. Fifty-nine children were enrolled during the study period (March 2020–August 2021). CBS was lowered by 2.2 (95% CI: 1.9 to 2.6) points after 30 min, and by 3.3 (95% CI: 2.9 to 3.6) points after 60 min from music initiation. Thirty minutes after music initiation, heart rate decreased by 6.3 (95% CI: 4.5 to 8.1) beats per minute, whereas at 60 min, heart rate decreased by 9.1 (95% CI: 7.2 to 10.9) beats per minute. No clinically significant variations were detected in the other vital signs (blood pressure, respiratory rate and oxygen saturation). These findings support the feasibility of musical intervention in a developing country. CBS and heart rate variation may be worth following up in larger and conclusive studies.
Health Economic Aspects of Childhood Excess Weight: A Structured Review
Authors: Onyimadu Olu , Violato Mara , Astbury Nerys M. , Jebb Susan A. , Petrou Stavros
Published: March 2022

An economic perspective is crucial to understand the broad consequences of childhood excess weight (CEW). These can manifest in the form of elevated health care and societal costs, impaired health status, or inefficiencies in the allocation of resources targeted at its prevention, management, or treatment. Although existing systematic reviews provide summaries of distinct economic research strands covering CEW, they have a restricted focus that overlooks relevant evidence. The overarching aim of this structured review was to update and enhance recent key reviews of four strands of economic evidence in this area, namely, (1) economic costs associated with CEW, (2) health utilities associated with CEW, (3) economic evaluations of interventions targeting CEW, and (4) economic determinants and broader consequences of CEW. Our de novo searches identified six additional studies for the first research strand, five studies for the second, thirty-one for the third, and two for the fourth. Most studies were conducted in a small number of high-income countries. Our review highlights knowledge gaps across all the research strands. Evidence from this structured review can act as data input into future economic evaluations in this area and highlights areas where future economic research should be targeted.
In-Brace versus Out-of-Brace Protocol for Radiographic Follow-Up of Patients with Idiopathic Scoliosis: A Retrospective Study
Authors: Peeters Charles M. M. , van Hasselt Arthur J. , Wapstra Frits-Hein , Jutte Paulus C. , Kempen Diederik H. R. , Faber Christopher
Published: March 2022

The purpose of this retrospective study was to compare two standardized protocols for radiological follow-up (in-brace versus out-of-brace radiographs) to study the rate of curve progression over time in surgically treated idiopathic scoliosis (IS) patients after failed brace treatment. In-brace radiographs have the advantage that proper fit of the brace and in-brace correction can be evaluated. However, detection of progression might theoretically be more difficult. Fifty-one IS patients that underwent surgical treatment after failed brace treatment were included. For 25 patients, follow-up radiographs were taken in-brace. For the other 26 patients, brace treatment was temporarily stopped before out-of-brace follow-up radiographs were taken. Both groups showed significant curve progression compared to baseline after a mean follow-up period of 3.4 years. The protocol with in-brace radiographs was noninferior regarding curve progression rate over time. The estimated monthly Cobb angle progression based on the mixed-effect model was 0.5 degrees in both groups. No interaction effect was found for time, and patients’ baseline Cobb angle (p = 0.98), and for time and patients’ initial in-brace correction (p = 0.32). The results of this study indicate that with both in-brace and out-of-brace protocols for radiographic follow-up, a similar rate of curve progression can be expected over time in IS patients with failed brace treatment.
Serum Allergen-Specific IgE among Pediatric Patients with Primary Immunodeficiency
Authors: Pieniawska-Śmiech Karolina , Lewandowicz-Uszyńska Aleksandra , Zemelka-Wiacek Magdalena , Jutel Marek
Published: March 2022

Background: Allergy is a clinical condition that reflects a deviated function of the immune system. The purpose of this study was to evaluate serum allergen-specific IgE (sIgE) along with clinical manifestations of allergy in patients with diagnosed primary immunodeficiency (PID). Methods: 72 patients, aged 1–17 years, diagnosed with PID and hospitalized between July 2020 and February 2021 were included in the study. Blood samples were obtained by venipuncture. sIgE (30 allergens), blood eosinophil count, as well as total IgE and IgG were measured and assessed in relation to a detailed medical examination. Results: Serum sIgE was detected in the blood of 50% of the patients in the study group, which significantly correlated (p < 0.0001) with clinical symptoms of allergy. During the period of the study, 61.1% of the patients showed symptoms of allergy, with 77.27% of them having tested positive for sIgE. The total IgE level was elevated in 18.06% of the patients and correlated with clinical symptoms of allergy (p = 0.004). An elevated total IgE level was not observed in children receiving immunoglobulin replacement therapy. Conclusion: The study showed that serum sIgE and total IgE together might be a plausible diagnostic tool for PID patients. However, for patients receiving immunoglobulin replacement therapy, the assessment of total IgE is not useful.
Multiple Imputation of Missing Data in Educational Production Functions
Authors: Elasra Amira
Published: March 2022

Educational production functions rely mostly on longitudinal data that almost always exhibit missing data. This paper contributes to a number of avenues in the literature on the economics of education and applied statistics by reviewing the theoretical foundation of missing data analysis with a special focus on the application of multiple imputation to educational longitudinal studies. Multiple imputation is one of the most prominent methods to surmount this problem. Not only does it account for all available information in the predictors, but it also takes into account the uncertainty generated by the missing data themselves. This paper applies a multiple imputation technique using a fully conditional specification method based on an iterative Markov chain Monte Carlo (MCMC) simulation using a Gibbs sampler algorithm. Previous attempts to use MCMC simulation were applied on relatively small datasets with small numbers of variables. Therefore, another contribution of this paper is its application and comparison of the imputation technique on a large longitudinal English educational study for three iteration specifications. The results of the simulation proved the convergence of the algorithm.
Mapping in the Topic of Mathematical Model in Paddy Agricultural Insurance Based on Bibliometric Analysis: A Systematic Review Approach
Authors: Riaman  , Sukono  , Supian Sudradjat , Ismail Noriszura
Published: March 2022

Bibliometric analysis is the quantitative study of bibliographic material. In this paper, a systematic review of papers, authors, and journals is carried out. This is necessary to determine and set targets to be achieved in further research. The main objective of this study is to identify some of the most relevant research and the latest trends according to the information found in the Google Scholar, Publish or Perish, Science Direct, and Dimension databases. The methods used are classification, analysis of the most cited journals of all time, and the most prolific and influential authors. The results are information on the number of papers, citations, researchers, h-index, g-index, major reference journals, and visualization of research roadmaps for the topic of agricultural insurance mathematical models. The research findings identify the core themes, which are used as research gaps for future research.
Spatial Shifts in Species Richness in Response to Climate and Environmental Change: An Adaption of the EUROMOVE Model in the Czech Republic
Authors: Tangwa Elvis , Pechanec Vilem , Brus Jan , Vyvlecka Pavel
Published: March 2022

Climate change has greatly altered plant habitats, resulting in greater biodiversity loss at different scales. Therefore, it is important to quantify such changes for better monitoring and conservation. In this study, we adapt the EUROMOVE model and its mean stable area indicator (MSAi) to the conditions in the Czech Republic. Our objective was to predict change in species richness from a representative pool of 687 species from 1990 to 2100 under the RCP 8.5 climate scenario, focusing on the current period (2018). Another objective was to assess the effectiveness of the MSAi as a tool for quantifying landscape vulnerability. Our result shows that species habitat expanded between 1990 and 2018, although about 2 per cent of species were lost. The average MSAi of the most favourable highland habitats may decrease from 0.85 to 0.65 by 2100 as >20% of baseline species may be lost. Indicator species of Alnus (alder) and Festuca (fescue), typical of lowland habitats, are among the most vulnerable, already showing a net loss of their current habitat extent. The MSAi can be applied as a comprehensive tool to quantify the impact of climate change on landscape vulnerability as more survey data becomes available.
Using DNA Metabarcoding to Identify Floral Visitation by Pollinators
Authors: Lowe Abigail , Jones Laura , Witter Lucy , Creer Simon , de Vere Natasha
Published: March 2022

The identification of floral visitation by pollinators provides an opportunity to improve our understanding of the fine-scale ecological interactions between plants and pollinators, contributing to biodiversity conservation and promoting ecosystem health. In this review, we outline the various methods which can be used to identify floral visitation, including plant-focused and insect-focused methods. We reviewed the literature covering the ways in which DNA metabarcoding has been used to answer ecological questions relating to plant use by pollinators and discuss the findings of this research. We present detailed methodological considerations for each step of the metabarcoding workflow, from sampling through to amplification, and finally bioinformatic analysis. Detailed guidance is provided to researchers for utilisation of these techniques, emphasising the importance of standardisation of methods and improving the reliability of results. Future opportunities and directions of using molecular methods to analyse plant–pollinator interactions are then discussed.
Whole System Data Integration for Condition Assessments of Climate Change Impacts: An Example in High-Mountain Ecosystems in Rila (Bulgaria)
Authors: Katrandzhiev Kostadin , Gocheva Kremena , Bratanova-Doncheva Svetla
Published: March 2022

To study climate impacts, data integration from heterogeneous sources is imperative for long-term monitoring in data sparse areas such as the High Mountain Ecosystems in the Rila Mountain, Bulgaria—difficult to both access and observe remotely due to frequent clouds. This task is especially challenging because discerning trends in vegetation location, condition and functioning requires observing over decades. To integrate the existing sparse data, we apply the Whole System framework adapted nationally in the Bulgarian Methodological Framework for Mapping and Assessment of ecosystem services. As the framework mainly relies on field data, we complement it with remote sensing vegetation indices (NDVI, NDWI and NDGI) for 42 years, together with Copernicus High Resolution Layer products and climate change reanalysis data for 40 years. We confirmed that the Whole System framework is extensible and semantically, ontologically and methodologically well suited for heterogeneous data fusion, co-analysis, reanalysis and joint interpretation. We found trends in ecosystem extent and functioning, in particular species composition, in line with climate change trends since around 1990 and exclusively attributable to climate change since 2015. Furthermore, we specified a data crosswalk between habitats and ecosystems at Level 3 (ecosystem subtype), and define new candidate indicators suitable for remotely monitoring climate change’s effects on the ecosystems’ extent and condition, as candidates for inclusion in the methodological framework.
Polyamine Metabolites as Biomarkers in Head and Neck Cancer Biofluids
Authors: DeFelice Brian C. , Fiehn Oliver , Belafsky Peter , Ditterich Constanze , Moore Michael , Abouyared Marianne , Beliveau Angela M. , Farwell D. Gregory , Bewley Arnaud F. , Clayton Shannon M. , Archard Joehleen A. , Pavlic Jordan , Rao Shyam , Kuhn Maggie , Deng Peter , Halmai Julian , Fink Kyle D. , Birkeland Andrew C. , Anderson Johnathon D.
Published: March 2022

Background: Novel, non-invasive diagnostic biomarkers that facilitate early intervention in head and neck cancer are urgently needed. Polyamine metabolites have been observed to be elevated in numerous cancer types and correlated with poor prognosis. The aim of this study was to assess the concentration of polyamines in the saliva and urine from head and neck cancer (HNC) patients, compared to healthy controls. Methods: Targeted metabolomic analysis was performed on saliva and urine from 39 HNC patient samples and compared to 89 healthy controls using a quantitative, targeted liquid chromatography mass spectrometry approach. Results: The metabolites N1-acetylspermine (ASP), N8-acetylspermidine (ASD) and N1,N12-diacetylspermine (DAS) were detected at significantly different concentrations in the urine of HNC patients as compared to healthy controls. Only ASP was detected at elevated levels in HNC saliva as compared to healthy controls. Conclusion: These data suggest that assessment of polyamine-based metabolite biomarkers within the saliva and urine warrants further investigation as a potential diagnostic in HNC patients.
Comparison of Linear and Convex-Array Transducers in Assessing the Enhancement Characteristics of Suspicious Breast Lesions at Contrast-Enhanced Ultrasound (CEUS)
Authors: Boca (Bene) Ioana , Ciurea Anca , Ciortea Cristiana , Vesa Ștefan , Dudea Sorin
Published: March 2022

The purpose of this study was to determine the observer agreement in assessing the enhancement pattern of suspicious breast lesions with contrast-enhanced ultrasound (CEUS) using high and low frequency transducers. Methods: This prospective study included 70 patients with suspicious breast lesions detected at mammography and/or ultrasound and classified according to the American College of Radiology (ACR) Breast Imaging-Reporting and Data System (BI-RADS) in 4A, 4B, 4C, or 5, who underwent CEUS examinations between October 2020 and August 2021. Results: Participants’ ages ranged from 28 to 83 years (48.5 + 6.36, mean age + SD). We obtained a substantial agreement for the first reader (kappa = 0.614, p < 0.001) and a perfect agreement for the second and third reader (kappa = 1, p < 0.001) between the two transducers for the uptake pattern. A moderate agreement for the second and third reader (kappa = 0.517 and 0.538, respectively, p < 0.001) and only a fair agreement (kappa = 0.320, p < 0.001) in the case of the first reader for the perilesional enhancement was observed. We obtained an excellent inter-observer agreement (Cronbach’s Alpha coefficient = 0.960, p < 0.001) for the degree of enhancement, a good inter-observer agreement for the uptake pattern and perilesional enhancement (Cronbach’s Alpha coefficient = 0.831 and 0.853, respectively, p < 0.001), and a good and acceptable inter-observer agreement for internal homogeneity, perfusion defects and margins of the lesions (Cronbach’s Alpha coefficient = 0.703, 0.703 and 0.792, respectively, p < 0.001) concerning the evaluation of breast lesions with the linear-array transducer. Conclusions: The evaluation of suspicious breast lesions by three experts with high-frequency linear-array transducer and low-frequency convex-array transducer was comparable in terms of uptake pattern and perilesional enhancement. The agreement regarding the evaluation of the degree of enhancement, the internal homogeneity, and the perfusion defects varied between fair and substantial. For all CEUS characteristics, the inter-observer agreement was superior for linear-array transducer, which leads to more a homogeneous and reproducible interpretation.
Are Electrocochleographic Changes an Early Sign of Cochlear Synaptopathy? A Prospective Study in Tinnitus Patients with Normal Hearing
Authors: Ting Kuan-Chung , Chang Chia-Chen , Huang Chii-Yuan , Chen Yu-Fu , Cheng Yen-Fu
Published: March 2022

The mechanism of tinnitus accompanied by a normal audiogram remains elusive. This study aimed to investigate evidence of primary neural degeneration, also known as cochlear synaptopathy, in tinnitus patients with normal hearing thresholds. We analyzed the differences in electrocochleography (ECochG) measurements between normal-hearing subjects with and without tinnitus. Forty-five subjects were enrolled in this study: 21 were in the tinnitus group, defined by chronic tinnitus of over two months’ duration with normal audiometric thresholds, and 24 were in the control group, defined by a lack of tinnitus complaints. Electrocochleograms were evoked by 1, 4, 6, and 8 kHz alternating-polarity tone bursts at sound pressure levels (SPLs) of 90–110 dB. The tinnitus group had smaller action potential (AP) amplitudes than the control group for 1, 4, 6, and 8 kHz tone bursts and showed significant amplitude reduction at 1 kHz 110 dB SPL (p < 0.01), 1 kHz 90 dB SPL (p < 0.05), and 4 kHz 110 dB SPL (p < 0.05). There were no significant differences in the summating potential/action potential (SP/AP) amplitude ratios across the four tested frequencies. A trend of reduced AP amplitudes was found in the tinnitus group, supporting the hypothesis that tinnitus might be associated with primary neural degeneration.
Clinical Spectrum and CSF Findings in Patients with West-Nile Virus Infection, a Retrospective Cohort Review
Authors: Bakos Imre , Mahdi Mohamed , Kardos László , Nagy Anna , Várkonyi István
Published: March 2022

West Nile Virus (WNV) infection is a world-wide zoonotic disease transmitted by mosquitoes. The infection is usually self-limiting; however, elderly patients or those with comorbidities are predisposed to developing severe, and sometimes fatal complications of the infection. Recently, the incidence of WNV infection in Europe had seen a sharp increase, as compared to previous years. We are currently reporting on the clinical presentation and laboratory findings in 23 cases of WNV infection, of which one resulted in a fatal outcome. The clinical picture was predominantly that of meningitis/meningoencephalitis of varying severity. One patient suffered a fatal outcome, and a rare manifestation of chorioretinal lesions and iridocyclitis was also reported as a result of WNV infection. Cerebrospinal fluid analysis predominantly showed lymphocytic pleocytosis, and total protein levels were increased in all but three of the patients. Levels of total protein in CSF samples were found to show a positive correlation with age. Given the ever-increasing incidence of WNV infection in Europe, a high index of clinical suspicion should always accompany cases of meningitis, especially during the summer period, as a similar epidemic pattern is predicted to recur.
Deep Learning–Based Brain Computed Tomography Image Classification with Hyperparameter Optimization through Transfer Learning for Stroke
Authors: Chen Yung-Ting , Chen Yao-Liang , Chen Yi-Yun , Huang Yu-Ting , Wong Ho-Fai , Yan Jiun-Lin , Wang Jiun-Jie
Published: March 2022

Brain computed tomography (CT) is commonly used for evaluating the cerebral condition, but immediately and accurately interpreting emergent brain CT images is tedious, even for skilled neuroradiologists. Deep learning networks are commonly employed for medical image analysis because they enable efficient computer-aided diagnosis. This study proposed the use of convolutional neural network (CNN)-based deep learning models for efficient classification of strokes based on unenhanced brain CT image findings into normal, hemorrhage, infarction, and other categories. The included CNN models were CNN-2, VGG-16, and ResNet-50, all of which were pretrained through transfer learning with various data sizes, mini-batch sizes, and optimizers. Their performance in classifying unenhanced brain CT images was tested thereafter. This performance was then compared with the outcomes in other studies on deep learning–based hemorrhagic or ischemic stroke diagnoses. The results revealed that among our CNN-2, VGG-16, and ResNet-50 analyzed by considering several hyperparameters and environments, the CNN-2 and ResNet-50 outperformed the VGG-16, with an accuracy of 0.9872; however, ResNet-50 required a longer time to present the outcome than did the other networks. Moreover, our models performed much better than those reported previously. In conclusion, after appropriate hyperparameter optimization, our deep learning–based models can be applied to clinical scenarios where neurologist or radiologist may need to verify whether their patients have a hemorrhage stroke, an infarction, and any other symptom.
Genetic Testing for Rare Diseases
Authors: Millán José M. , García-García Gema
Published: March 2022

The term rare disease was coined in the 1970s to refer to diseases that have a low prevalence [...]