bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Quadratus Lumborum Block as Part of an Opioid-Free Anaesthesia for Canine Ovariohysterectomy
Authors: Viscasillas Jaime , Sanchis-Mora Sandra , Burillo Paula , Esteve Vicente , Del Romero Ayla , Lafuente Pilar , Redondo Jose Ignacio
Published: December 2021

Quadratus lumborum block (QLB) is used to provide analgesia for abdominal surgery in humans. The aim of this study was to assess an anaesthetic protocol involving the QLB for canine ovariohysterectomy. Ten dogs were included. Anaesthetic protocol consisted of premedication with IM medetomidine (20 μg kg−1) and SC meloxicam (0.1 mg kg−1), induction with propofol to effect, and maintenance with sevoflurane in oxygen/medical air. QLB was performed injecting 0.4 mL kg−1 of 0.25% bupivacaine/iohexol per side. Computed Tomography (CT) was performed before and after surgery. Fentanyl was administered as rescue analgesia during surgery. The Short Form of The Glasgow Composite Pain Scale and thermal threshold (TT) at the level of the elbow, T10, T13 and L3 were assessed before premedication and every hour postoperatively. Methadone was given as rescue analgesia postoperatively when pain score was >3. A Yuen’s test on trimmed means for dependent samples was used to analyse the data (p < 0.05). CT images showed spreading of the contrast/block for a median (range) of 3 (2–5) vertebrae, without differences between preoperative and postoperative images. One dog needed rescue analgesia during surgery. Pain score was less than 4/24 in all the animals during the first 4 h after surgery. TT showed a significant increased signal in all the areas tested, apart from the humerus, 30 min after surgery. The QLB may provide additional analgesia for canine ovariohysterectomy. Further studies are needed to assess the specific contribution of the QLB in abdominal analgesia.
Error Correction of Water Vapor Radiometers for VLBI Observations in Deep-Space Networks
Authors: Chen Houcai , Ge Junxiang , Kong Qingde , Zhao Zhenwei , Zhu Qinglin
Published: December 2021

In this paper, we present the design and implementation tests of a water vapor radiometer (WVR) suitable for very long baseline interferometry (VLBI) observation. We describe the calibration method with an analysis of the sources of measurement errors. The experimental results show that the long-term measurement accuracy of the brightness temperature of the water vapor radiometer can reach 0.2 K under arbitrary ambient conditions by absolute calibration, receiver gain error calibration, and antenna feeder system temperature noise error calibration. Furthermore, we present a method for measurements of the calibration error of the oblique path measurement. This results in an oblique path wet delay measurement accuracy of the water vapor radiometer reaching 20 mm (within one month).
Avoided Mortality Associated with Improved Air Quality from an Increase in Renewable Energy in the Spanish Transport Sector: Use of Biofuels and the Adoption of the Electric Car
Authors: Gamarra Ana R. , Lechón Yolanda , Vivanco Marta G. , Theobald Mark Richard , Lago Carmen , Sánchez Eugenio , Santiago José Luis , Garrido Juan Luis , Martín Fernando , Gil Victoria , Rodríguez-Sánchez Alejandro
Published: December 2021

This paper assesses the health impact, in terms of the reduction of premature deaths associated with changes in air pollutant exposure, resulting from double-aim strategies for reducing emissions of greenhouse gases and air pollutants from the transport sector for the year 2030 in Spain. The impact on air quality of selected measures for reducing emissions from the transport sector (increased penetration of biofuel and electric car use) was assessed by air quality modeling. The estimation of population exposure to NO2, particulate matter (PM) and O3 allows for estimation of associated mortality and external costs in comparison with the baseline scenario with no measures. The results show that the penetration of the electric vehicle provided the largest benefits, even when the emissions due to the additional electricity demand were considered.
Effect of Air Purifier Use in the Classrooms on Indoor Air Quality—Case Study
Authors: Basińska Małgorzata , Michałkiewicz Michał , Ratajczak Katarzyna
Published: December 2021

Dissatisfaction with indoor air quality is common even in relatively new or renovated Polish school buildings. To improve air quality in educational buildings, portable devices have seen increased use, for which manufacturers guarantee a high level of indoor air purification. However, their optimized operation largely depends on their correct use. The aim of this article was to determine the effectiveness of air purification in a primary school using an air purification device with an analysis of the classroom indoor air quality (IAQ). Two criteria were used, microbiological and particulate matter concentration. Measurements were made before device installation and during its continuous operation, and before and after lessons on chosen days. Measurements related to IAQ did not detect clear differences in the analyzed measurement periods. For microbiological contamination, in the morning before lessons, the total count for all bacteria and microscopic fungi was definitely lower than after lessons. Comparing the periods before and after device installation, no clear tendency for reducing the bacteria count or microscopic fungi occurred during air purifier operation, nor was there any noticeable trend in the reduction of particulate matter. There was no improvement in air quality in the classrooms during the operation of the purification devices.
Biocompatible Customized 3D Bone Scaffolds Treated with CRFP, an Osteogenic Peptide
Authors: Mustahsan Vamiq M. , Anugu Amith , Komatsu David E. , Kao Imin , Pentyala Srinivas
Published: December 2021

Background: Currently used synthetic bone graft substitutes (BGS) are either too weak to bear the principal load or if metallic, they can support loading, but can lead to stress shielding and are unable to integrate fully. In this study, we developed biocompatible, 3D printed scaffolds derived from µCT images of the bone that can overcome these issues and support the growth of osteoblasts. Methods: Cylindrical scaffolds were fabricated with acrylonitrile butadiene styrene (ABS) and Stratasys® MED 610 (MED610) materials. The 3D-printed scaffolds were seeded with Mus musculus calvaria cells (MC3T3). After the cells attained confluence, osteogenesis was induced with and without the addition of calcitonin receptor fragment peptide (CRFP) and the bone matrix production was analyzed. Mechanical compression testing was carried out to measure compressive strength, stiffness, and elastic modulus. Results: For the ABS scaffolds, there was a 9.8% increase in compressive strength (p < 0.05) in the scaffolds with no pre-coating and the treatment with CRFP, compared to non-treated scaffolds. Similarly, MED610 scaffolds treated with CRFP showed an 11.9% (polylysine pre-coating) and a 20% (no pre-coating) increase (p < 0.01) in compressive strength compared to non-treated scaffolds. Conclusions: MED610 scaffolds are excellent BGS as they support osteoblast growth and show enhanced bone growth with enhanced compressive strength when augmented with CRFP.
Novel Insights into the Prognosis and Immunological Value of the SLC35A (Solute Carrier 35A) Family Genes in Human Breast Cancer
Authors: Ta Hoang Dang Khoa , Minh Xuan Do Thi , Tang Wan-Chun , Anuraga Gangga , Ni Yi-Chun , Pan Syu-Ruei , Wu Yung-Fu , Fitriani Fenny , Putri Hermanto Elvira Mustikawati , Athoillah Muhammad , Andriani Vivin , Ajiningrum Purity Sabila , Wang Chih-Yang , Lee Kuen-Haur
Published: December 2021

According to statistics 2020, female breast cancer (BRCA) became the most commonly diagnosed malignancy worldwide. Prognosis of BRCA patients is still poor, especially in population with advanced or metastatic. Particular functions of each members of the solute carrier 35A (SLC35A) gene family in human BRCA are still unknown regardless of awareness that they play critical roles in tumorigenesis and progression. Using integrated bioinformatics analyses to identify therapeutic targets for specific cancers based on transcriptomics, proteomics, and high-throughput sequencing, we obtained new information and a better understanding of potential underlying molecular mechanisms. Leveraging BRCA dataset that belongs to The Cancer Genome Atlas (TCGA), which were employed to clarify SLC35A gene expression levels. Then we used a bioinformatics approach to investigate biological processes connected to SLC35A family genes in BRCA development. Beside that, the Kaplan–Meier estimator was leveraged to explore predictive values of SLC35A family genes in BCRA patients. Among individuals of this family gene, expression levels of SLC35A2 were substantially related to poor prognostic values, result from a hazard ratio of 1.3 (with 95 percent confidence interval (95% CI: 1.18–1.44), the p for trend (ptrend) is 3.1 × 10−7). Furthermore, a functional enrichment analysis showed that SLC35A2 was correlated with hypoxia-inducible factor 1A (HIF1A), heat shock protein (HSP), E2 transcription factor (E2F), DNA damage, and cell cycle-related signaling. Infiltration levels observed in specific types of immune cell, especially the cluster of differentiation found on macrophages and neutrophils, were positively linked with SLC35A2 expression in multiple BRCA subclasses (luminal A, luminal B, basal, and human epidermal growth factor receptor 2). Collectively, SLC35A2 expression was associated with a lower recurrence-free survival rate, suggesting that it could be used as a biomarker in treating BRCA.
Tilted Arch; Implementation of Additive Manufacturing and Bio-Welding of Mycelium-Based Composites
Authors: Modanloo Behzad , Ghazvinian Ali , Matini Mohammadreza , Andaroodi Elham
Published: December 2021

Bio-based materials have found their way to the design and fabrication in the architectural context in recent years. Fungi-based materials, especially mycelium-based composites, are a group of these materials of growing interest among scholars due to their light weight, compostable and regenerative features. However, after about a decade of introducing this material to the architectural community, the proper ways of design and fabrication with this material are still under investigation. In this paper, we tried to integrate the material properties of mycelium-based composites with computational design and digital fabrication methods to offer a promising method of construction. Regarding different characteristics of the material, we found additive manufacturing parallel to bio-welding is an appropriate fabrication method. To show the feasibility of the proposed method, we manufactured a small-scale prototype, a tilted arch, made of extruded biomass bound with bio-welding. The project is described in the paper.
Diotic and Dichotic Mechanisms of Discrimination Threshold in Musicians and Non-Musicians
Authors: Inabinet Devin , De La Cruz Jan , Cha Justin , Ng Kevin , Musacchia Gabriella
Published: December 2021

The perception of harmonic complexes provides important information for musical and vocal communication. Numerous studies have shown that musical training and expertise are associated with better processing of harmonic complexes, however, it is unclear whether the perceptual improvement associated with musical training is universal to different pitch models. The current study addresses this issue by measuring discrimination thresholds of musicians (n = 20) and non-musicians (n = 18) to diotic (same sound to both ears) and dichotic (different sounds to each ear) sounds of four stimulus types: (1) pure sinusoidal tones, PT; (2) four-harmonic complex tones, CT; (3) iterated rippled noise, IRN; and (4) interaurally correlated broadband noise, called the “Huggins” or “dichotic” pitch, DP. Frequency difference limens (DLF) for each stimulus type were obtained via a three-alternative-forced-choice adaptive task requiring selection of the interval with the highest pitch, yielding the smallest perceptible fundamental frequency (F0) distance (in Hz) between two sounds. Music skill was measured by an online test of musical pitch, melody and timing maintained by the International Laboratory for Brain Music and Sound Research. Musicianship, length of music experience and self-evaluation of musical skill were assessed by questionnaire. Results showed musicians had smaller DLFs in all four conditions with the largest group difference in the dichotic condition. DLF thresholds were related to both subjective and objective musical ability. In addition, subjective self-report of musical ability was shown to be a significant variable in group classification. Taken together, the results suggest that music-related plasticity benefits multiple mechanisms of pitch encoding and that self-evaluation of musicality can be reliably associated with objective measures of perception.
Reading Fluency in Children and Adolescents Who Stutter
Authors: Franke Mona , Hoole Philip , Schreier Ramona , Falk Simone
Published: December 2021

Speech fluency is a major challenge for young persons who stutter. Reading aloud, in particular, puts high demands on fluency, not only regarding online text decoding and articulation, but also in terms of prosodic performance. A written text has to be segmented into a number of prosodic phrases with appropriate breaks. The present study examines to what extent reading fluency (decoding ability, articulation rate, and prosodic phrasing) may be altered in children (9–12 years) and adolescents (13–17 years) who stutter compared to matched control participants. Read speech of 52 children and adolescents who do and do not stutter was analyzed. Children and adolescents who stutter did not differ from their matched control groups regarding reading accuracy and articulation rate. However, children who stutter produced shorter pauses than their matched peers. Results on prosodic phrasing showed that children who stutter produced more major phrases than the control group and more intermediate phrases than adolescents who stutter. Participants who stutter also displayed a higher number of breath pauses. Generally, the number of disfluencies during reading was related to slower articulation rates and more prosodic boundaries. Furthermore, we found age-related changes in general measures of reading fluency (decoding ability and articulation rate), as well as the overall strength of prosodic boundaries and number of breath pauses. This study provides evidence for developmental stages in prosodic phrasing as well as for alterations in reading fluency in children who stutter.
Discussing Personalized Prognosis Empowers Patients with Amyotrophic Lateral Sclerosis to Regain Control over Their Future: A Qualitative Study
Authors: van Eenennaam Remko M. , Koppenol Loulou S. , Kruithof Willeke J. , Kruitwagen-van Reenen Esther T. , Pieters Sotice , van Es Michael A. , van den Berg Leonard H. , Visser-Meily Johanna M. A. , Beelen Anita
Published: December 2021

The ENCALS survival prediction model offers patients with amyotrophic lateral sclerosis (ALS) the opportunity to receive a personalized prognosis of survival at the time of diagnosis. We explored experiences of patients with ALS, caregivers, and physicians with discussing personalized prognosis through interviews with patients and their caregivers, and in a focus group of physicians. Thematic analysis revealed four themes with seven subthemes; these were recognized by the focus group. First, tailored communication: physician’s communication style and information provision mediated emotional impact and increased satisfaction with communication. Second, personal factors: coping style, illness experiences, and information needs affected patient and caregiver coping with the prognosis. Third, emotional impact ranged from happy and reassuring to regret. Fourth, regaining control over the future: participants found it helpful in looking towards the future, and emphasized the importance of quality over quantity of life. Personalized prognosis can be discussed with minimal adverse emotional impact. How it is communicated—i.e., tailored to individual needs—is as important as what is communicated—i.e., a good or poor prognosis. Discussing personalized prognosis may help patients with ALS and their caregivers regain control over the future and facilitate planning of the future (care). For many patients, quality of life matters more than quantity of time remaining.
Prevalence of Central Compartment Lymph Node Metastases in Papillary Thyroid Micro-Carcinoma: A Retrospective Evaluation of Predictive Preoperative Features
Authors: Tagliabue Marta , Giugliano Gioacchino , Mariani Maria Cecilia , Rubino Manila , Grosso Enrica , Chu Francesco , Calastri Anna , Maffini Fausto Antonio , Mauri Giovanni , De Fiori Elvio , Manzoni Marco Federico , Ansarin Mohssen
Published: December 2021

Papillary thyroid micro-carcinomas are considered relatively indolent carcinomas, often occult and incidental, with good prognosis and favorable outcomes. Despite these findings, central lymph node metastases are common, and are related to a poor prognosis for the patient. We performed a retrospective analysis on patients treated with surgery for stage pT1a papillary thyroid micro-carcinomas. One hundred ninety-five patients were included in the analyses. The presence of central lymph node metastases was identified and studied. A multivariate analysis employing binary logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals of possible central lymph node metastases risk factors. In the performed multivariate analysis, male gender, younger age, and histopathological characteristics, such as a tumor sub-capsular localization, were significantly associated with central lymph node metastases in pT1a patients. Central compartment lymph node metastases are present in a non-negligible number of cases in patients with papillary thyroid micro-carcinoma undergoing surgical resection. Studying these factors could be an effective tool for predicting patients’ central lymph node metastases in papillary thyroid micro-carcinomas, defining a tailored surgical treatment in the future.
Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
Authors: Skaar David A. , Dietze Eric C. , Alva-Ornelas Jackelyn A. , Ann David , Schones Dustin E. , Hyslop Terry , Sistrunk Christopher , Zalles Carola , Ambrose Adrian , Kennedy Kendall , Idassi Ombeni , Miranda Carboni Gustavo , Gould Michael N. , Jirtle Randy L. , Seewaldt Victoria L.
Published: December 2021

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, KCNK9 gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that KCNK9 is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the KCNK9 gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the KCNK9 DMR predicts for increased TASK3 expression and mitochondrial membrane potential (p < 0.001). This is the first identification of the KCNK9 DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the KCNK9 DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
Is There a Benefit of Oxaliplatin in Combination with Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer? An Updated Meta-Analysis
Authors: Des Guetz Gaëtan , Landre Thierry , Bollet Marc A. , Mathonnet Muriel , Quéro Laurent
Published: December 2021

Background: Neoadjuvant fluoropyrimidine (5FU or capecitabine)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still unclear. Methods: To identify clinical trials combining oxaliplatin in preoperative CRT or perioperative chemotherapy for LARC published until March 2021, we searched PubMed and the Cochrane Library. We also searched for relevant ASCO conference abstracts. The primary endpoint was disease-free survival (DFS). Data were extracted from every study to perform a meta-analysis using Review Manager (version 5.3). Results: A total of seven randomized clinical trials (ACCORD-12, CARO-AIO-04, FOWARC, JIAO, NSABP, PETACC-6, and STAR-01) with 5782 stage II or III rectal cancer patients were analyzed, including 2727 patients with OXP + 5FU regimen and 3055 patients with 5FU alone. Compared with the 5FU alone group, the OXP + 5FU regimen improved DFS (HR = 0.90, 95% CI: 0.81–0.99, p = 0.03) and pathologic complete response (pCR) (OR = 1.21, 95% CI: 1.07–1.37, p = 0.002). Patients treated with the OXP + 5FU regimen had significantly less metastatic progression (OR = 0.79; 95% CI, 0.67 to 0.94; p = 0.007). Considering adverse events (AEs), there was more grade 3–4 diarrhea with OXP + 5FU (OR = 2.41, 95% CI: 1.74–3.32, p < 0.00001). However, there were no significant differences grade 3–4 hematologic AEs (OR = 1.16, 95% CI: 0.87–1.57, p = 0.31). Conclusions: Our meta-analysis with long-term results from the randomized studies showed a benefit of the addition of OXP + 5FU regiment in terms of DFS, metastatic progression, and pCR rate that did not translate to improved OS.
Proteomic Analysis Identifies NDUFS1 and ATP5O as Novel Markers for Survival Outcome in Prostate Cancer
Authors: Wiebringhaus Robert , Pecoraro Matteo , Neubauer Heidi , Trachtová Karolína , Trimmel Bettina , Wieselberg Maritta , Pencik Jan , Egger Gerda , Krall Christoph , Moriggl Richard , Mann Matthias , Hantusch Brigitte , Kenner Lukas
Published: December 2021

We aimed to identify novel markers for aggressive prostate cancer in a STAT3-low proteomics-derived dataset of mitochondrial proteins by immunohistochemical analysis and correlation with transcriptomic data and biochemical recurrence in a STAT3 independent PCa cohort. Formalin-fixed paraffin-embedded tissue (FFPE) sample selection for proteomic analysis and tissue-microarray (TMA) generation was conducted from a cohort of PCa patients. Retrospective data analysis was performed with the same cohort. 153 proteins differentially expressed between STAT3-low and STAT3-high samples were identified. Out of these, 46 proteins were associated with mitochondrial processes including oxidative phosphorylation (OXPHOS), and 45 proteins were upregulated, including NDUFS1/ATP5O. In a STAT3 independent PCa cohort, high expression of NDUFS1/ATP5O was confirmed by immunocytochemistry (IHC) and was significantly associated with earlier biochemical recurrence (BCR). mRNA expression levels for these two genes were significantly higher in intra-epithelial neoplasia and in PCa compared to benign prostate glands. NDUFS1/ATP5O levels are increased both at the mRNA and protein level in aggressive PCa. Our results provide evidence that NDUFS1/ATP5O could be used to identify high-risk PCa patients.
The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age
Authors: Zurnadzhy Liudmyla , Bogdanova Tetiana , Rogounovitch Tatiana I. , Ito Masahiro , Tronko Mykola , Yamashita Shunichi , Mitsutake Norisato , Chernyshov Serhii , Masiuk Sergii , Saenko Vladimir A.
Published: December 2021

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.
Vaccine-Based Immunotherapy for Head and Neck Cancers
Authors: Beyaert Simon , Machiels Jean-Pascal , Schmitz Sandra
Published: December 2021

In 2019, the FDA approved pembrolizumab, a monoclonal antibody targeting PD-1, for the first-line treatment of recurrent or metastatic head and neck cancers, despite only a limited number of patients benefiting from the treatment. Promising effects of therapeutic vaccination led the FDA to approve the use of the first therapeutic vaccine in prostate cancer in 2010. Research in the field of therapeutic vaccination, including possible synergistic effects with anti-PD(L)1 treatments, is evolving each year, and many vaccines are in pre-clinical and clinical studies. The aim of this review article is to discuss vaccines as a new therapeutic strategy, particularly in the field of head and neck cancers. Different vaccination technologies are discussed, as well as the results of the first clinical trials in HPV-positive, HPV-negative, and EBV-induced head and neck cancers.
CHFR and Paclitaxel Sensitivity of Ovarian Cancer
Authors: Wahner Hendrickson Andrea E. , Visscher Daniel W. , Hou Xiaonan , Goergen Krista M. , Atkinson Hunter J. , Beito Thomas G. , Negron Vivian , Lingle Wilma L. , Bruzek Amy K. , Hurley Rachel M. , Wagner Jill M. , Flatten Karen S. , Peterson Kevin L. , Schneider Paula A. , Larson Melissa C. , Maurer Matthew J. , Kalli Kimberly R. , Oberg Ann L. , Weroha S. John , Kaufmann Scott H.
Published: December 2021

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.
Modeling Tumor: Lymphatic Interactions in Lymphatic Metastasis of Triple Negative Breast Cancer
Authors: Ji Kyungmin , Zhao Zhiguo , Sameni Mansoureh , Moin Kamiar , Xu Yong , Gillies Robert J. , Sloane Bonnie F. , Mattingly Raymond R.
Published: December 2021

Breast cancer frequently metastasizes to lymphatics and the presence of breast cancer cells in regional lymph nodes is an important prognostic factor. Delineating the mechanisms by which breast cancer cells disseminate and spatiotemporal aspects of interactions between breast cancer cells and lymphatics is needed to design new therapies to prevent lymphatic metastases. As triple-negative breast cancer (TNBC) has a high incidence of lymphatic metastasis, we used a three-dimensional (3D) coculture model of human TNBC cells and human microvascular lymphatic endothelial cells (LECs) to analyze TNBC:LEC interactions. Non-invasive analyses such as live-cell imaging in real-time and collection of conditioned media for secretomic analysis were facilitated by our novel microfluidic chambers. The volumes of 3D structures formed in TNBC:LEC cocultures are greater than that of 3D structures formed by either LEC or TNBC monocultures. Over 4 days of culture there is an increase in multicellular invasive outgrowths from TNBC spheroids and an association of TNBC spheroids with LEC networks. The increase in invasive phenotype also occurred when TNBC spheroids were cultured in LEC-conditioned media and in wells linked to ones containing LEC networks. Our results suggest that modeling spatiotemporal interactions between TNBC and LECs may reveal paracrine signaling that could be targeted to reduce lymphatic metastasis.
Oxidative Distress Induces Wnt/β-Catenin Pathway Modulation in Colorectal Cancer Cells: Perspectives on APC Retained Functions
Authors: Catalano Teresa , D’Amico Emira , Moscatello Carmelo , Di Marcantonio Maria Carmela , Ferrone Alessio , Bologna Giuseppina , Selvaggi Federico , Lanuti Paola , Cotellese Roberto , Curia Maria Cristina , Lattanzio Rossano , Aceto Gitana Maria
Published: December 2021

Colorectal cancer (CRC) is a multistep process that arises in the colic tissue microenvironment. Oxidative stress plays a role in mediating CRC cell survival and progression, as well as promoting resistance to therapies. CRC progression is associated with Wnt/β-Catenin signaling dysregulation and loss of proper APC functions. Cancer recurrence/relapse has been attributed to altered ROS levels, produced in a cancerous microenvironment. The effect of oxidative distress on Wnt/β-Catenin signaling in the light of APC functions is unclear. This study evaluated the effect of H2O2-induced short-term oxidative stress in HCT116, SW480 and SW620 cells with different phenotypes of APC and β-Catenin. The modulation and relationship of APC with characteristic molecules of Wnt/β-Catenin were assessed in gene and protein expression. Results indicated that CRC cells, even when deprived of growth factors, under acute oxidative distress conditions by H2O2 promote β-Catenin expression and modulate cytoplasmic APC protein. Furthermore, H2O2 induces differential gene expression depending on the cellular phenotype and leading to favor both Wnt/Catenin-dependent and -independent signaling. The exact mechanism by which oxidative distress can affect Wnt signaling functions will require further investigation to reveal new scenarios for the development of therapeutic approaches for CRC, in the light of the conserved functions of APC.
Use of Smartphones for the Detection of Uterine Cervical Cancer: A Systematic Review
Authors: Champin Denisse , Ramírez-Soto Max Carlos , Vargas-Herrera Javier
Published: December 2021

Little is known regarding the usefulness of the smartphone in the detection of uterine cervical lesions or uterine cervical cancer. Therefore, we evaluated the usefulness of the smartphone in the detection of uterine cervical lesions and measured its diagnostic accuracy by comparing its findings with histological findings. We conducted a systematic review to identify studies on the usefulness of the smartphone in detecting uterine cervical lesions indexed in SCOPUS, MEDLINE/PubMed, Cochrane, OVID, Web of Science, and SciELO until November 2020. The risk of bias and applicability was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 16 studies that evaluated the usefulness of the smartphone in the detection of uterine cervical lesions based on the images clicked after visual inspection with acetic acid (VIA), Lugol’s iodine (VILI), or VIA/VILI combination were included in the study. Five studies estimated diagnostic sensitivity and specificity, nine described diagnostic concordance, and five described the usefulness of mobile technology. Among the five first studies, the sensitivity ranged between 66.7% (95% confidence interval (CI); 30.0–90.3%) and 94.1% (95% CI; 81.6–98.3%), and the specificity ranged between 24.0% (95% CI; 9.0–45.0%) and 85.7% (95% CI; 76.7–91.6%). The risk of bias was low (20%), and the applicability was high. In conclusion, the smartphone images clicked after a VIA were found to be more sensitive than those following the VILI method or the VIA/VILI combination and naked-eye techniques in detecting uterine cervical lesions. Thus, a smartphone may be useful in the detection of uterine cervical lesions; however, its sensitivity and specificity are still limited.
Deep Learning Predicts the Malignant-Transformation-Free Survival of Oral Potentially Malignant Disorders
Authors: Adeoye John , Koohi-Moghadam Mohamad , Lo Anthony Wing Ip , Tsang Raymond King-Yin , Chow Velda Ling Yu , Zheng Li-Wu , Choi Siu-Wai , Thomson Peter , Su Yu-Xiong
Published: December 2021

Machine-intelligence platforms for the prediction of the probability of malignant transformation of oral potentially malignant disorders are required as adjunctive decision-making platforms in contemporary clinical practice. This study utilized time-to-event learning models to predict malignant transformation in oral leukoplakia and oral lichenoid lesions. A total of 1098 patients with oral white lesions from two institutions were included in this study. In all, 26 features available from electronic health records were used to train four learning algorithms—Cox-Time, DeepHit, DeepSurv, random survival forest (RSF)—and one standard statistical method—Cox proportional hazards model. Discriminatory performance, calibration of survival estimates, and model stability were assessed using a concordance index (c-index), integrated Brier score (IBS), and standard deviation of the averaged c-index and IBS following training cross-validation. This study found that DeepSurv (c-index: 0.95, IBS: 0.04) and RSF (c-index: 0.91, IBS: 0.03) were the two outperforming models based on discrimination and calibration following internal validation. However, DeepSurv was more stable than RSF upon cross-validation. External validation confirmed the utility of DeepSurv for discrimination (c-index—0.82 vs. 0.73) and RSF for individual survival estimates (0.18 vs. 0.03). We deployed the DeepSurv model to encourage incipient application in clinical practice. Overall, time-to-event models are successful in predicting the malignant transformation of oral leukoplakia and oral lichenoid lesions.
The Function of Immunoproteasomes—An Immunologists’ Perspective
Authors: van den Eshof Bart L. , Medfai Lobna , Nolfi Emanuele , Wawrzyniuk Magdalena , Sijts Alice J. A. M.
Published: December 2021

Proteasomes are responsible for intracellular proteolysis and play an important role in cellular protein homeostasis. Cells of the immune system assemble a specialized form of proteasomes, known as immunoproteasomes, in which the constitutive catalytic sites are replaced for cytokine-inducible homologues. While immunoproteasomes may fulfill all standard proteasome’ functions, they seem specially adapted for a role in MHC class I antigen processing and CD8+ T-cell activation. In this way, they may contribute to CD8+ T-cell-mediated control of intracellular infections, but also to the immunopathogenesis of autoimmune diseases. Starting at the discovery of its catalytic subunits in the genome, here, we review the observations shaping our current understanding of immunoproteasome function, and the consequential novel opportunities for immune intervention.
Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis
Authors: Guerra Gabriela Maria , May Doreen , Kroll Torsten , Koch Philipp , Groth Marco , Wang Zhao-Qi , Li Tang-Liang , Grigaravičius Paulius
Published: December 2021

SMG6 is an endonuclease, which cleaves mRNAs during nonsense-mediated mRNA decay (NMD), thereby regulating gene expression and controling mRNA quality. SMG6 has been shown as a differentiation license factor of totipotent embryonic stem cells. To investigate whether it controls the differentiation of lineage-specific pluripotent progenitor cells, we inactivated Smg6 in murine embryonic neural stem cells. Nestin-Cre-mediated deletion of Smg6 in mouse neuroprogenitor cells (NPCs) caused perinatal lethality. Mutant mice brains showed normal structure at E14.5 but great reduction of the cortical NPCs and late-born cortical neurons during later stages of neurogenesis (i.e., E18.5). Smg6 inactivation led to dramatic cell death in ganglionic eminence (GE) and a reduction of interneurons at E14.5. Interestingly, neurosphere assays showed self-renewal defects specifically in interneuron progenitors but not in cortical NPCs. RT-qPCR analysis revealed that the interneuron differentiation regulators Dlx1 and Dlx2 were reduced after Smg6 deletion. Intriguingly, when Smg6 was deleted specifically in cortical and hippocampal progenitors, the mutant mice were viable and showed normal size and architecture of the cortex at E18.5. Thus, SMG6 regulates cell fate in a cell type-specific manner and is more important for neuroprogenitors originating from the GE than for progenitors from the cortex.
Ion Channel Expression and Electrophysiology of Singular Human (Primary and Induced Pluripotent Stem Cell-Derived) Cardiomyocytes
Authors: Schmid Christina , Abi-Gerges Najah , Leitner Michael , Zellner Dietmar , Rast Georg
Published: December 2021

Subtype-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising tools, e.g., to assess the potential of drugs to cause chronotropic effects (nodal hiPSC-CMs), atrial fibrillation (atrial hiPSC-CMs), or ventricular arrhythmias (ventricular hiPSC-CMs). We used single-cell patch-clamp reverse transcriptase-quantitative polymerase chain reaction to clarify the composition of the iCell cardiomyocyte population (Fujifilm Cellular Dynamics, Madison, WI, USA) and to compare it with atrial and ventricular Pluricytes (Ncardia, Charleroi, Belgium) and primary human atrial and ventricular cardiomyocytes. The comparison of beating and non-beating iCell cardiomyocytes did not support the presence of true nodal, atrial, and ventricular cells in this hiPSC-CM population. The comparison of atrial and ventricular Pluricytes with primary human cardiomyocytes showed trends, indicating the potential to derive more subtype-specific hiPSC-CM models using appropriate differentiation protocols. Nevertheless, the single-cell phenotypes of the majority of the hiPSC-CMs showed a combination of attributes which may be interpreted as a mixture of traits of adult cardiomyocyte subtypes: (i) nodal: spontaneous action potentials and high HCN4 expression and (ii) non-nodal: prominent INa-driven fast inward current and high expression of SCN5A. This may hamper the interpretation of the drug effects on parameters depending on a combination of ionic currents, such as beat rate. However, the proven expression of specific ion channels supports the evaluation of the drug effects on ionic currents in a more realistic cardiomyocyte environment than in recombinant non-cardiomyocyte systems.
Growth Hormone and IGF1 Actions in Kidney Development and Function
Authors: Gurevich Evgenia , Segev Yael , Landau Daniel
Published: December 2021

Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD.
Proliferating CD8+ T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
Authors: Mauldin Ileana S. , Jo Jasmin , Wages Nolan A. , Yogendran Lalanthica V. , Mahmutovic Adela , Young Samuel J. , Lopes Maria Beatriz , Slingluff Craig L. , Erickson Loren D. , Fadul Camilo E.
Published: December 2021

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.
Prognostic Risk Factors for Severe Outcome in the Acute Phase of Neonatal Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study
Authors: Suppiej Agnese , Vitaliti Giovanna , Talenti Giacomo , Cuteri Vittoria , Trevisanuto Daniele , Fanaro Silvia , Cainelli Elisa
Published: December 2021

In the first days after birth, a major focus of research is to identify infants with hypoxic-ischemic encephalopathy at higher risk of death or severe neurological impairment, despite therapeutic hypothermia (TH). This is especially crucial to consider redirection of care, according to neonatal outcome severity. We aimed to seek associations between some neonatal routine parameters, usually recorded in Neonatal Intensive Care Units, and the development of severe outcomes. All consecutive patients prospectively recruited for TH for perinatal asphyxia, born between February 2009 and July 2016, were eligible for this study. Severe outcome was defined as death or major neurological sequelae at one year of age. Among all eligible neonates, the final analysis included 83 patients. Severe outcome was significantly associated with pH and base excess measured in the first hour of life, mode of delivery, Apgar score, Sarnat and Sarnat score, electroencephalogram-confirmed neonatal epileptic seizures, and antiepileptic therapy. Studying univariate analysis by raw relative risk (RR) and 95% confidence intervals (CI), severe outcome was significantly associated with pH (p = 0.011), Apgar score (p = 0.003), Sarnat score (p < 0.001), and Caesarian section (p = 0.015). Conclusions. In addition to clinical examination, we suggest a clinical-electroencephalographic protocol useful to identify neonates at high neurological risk, available before rewarming from TH.
Linking Pedigree Information to the Gene Expression Phenotype to Understand Differential Family Survival Mechanisms in Highly Fecund Fish: A Case Study in the Larviculture of Pacific Bluefin Tuna
Authors: Yasuike Motoshige , Kumon Kazunori , Tanaka Yosuke , Saitoh Kenji , Sugaya Takuma
Published: December 2021

Mass spawning in fish culture often brings about a marked variance in family size, which can cause a reduction in effective population sizes in seed production for stock enhancement. This study reports an example of combined pedigree information and gene expression phenotypes to understand differential family survival mechanisms in early stages of Pacific bluefin tuna, Thunnus orientalis, in a mass culture tank. Initially, parentage was determined using the partial mitochondrial DNA control region sequence and 11 microsatellite loci at 1, 10, 15, and 40 days post-hatch (DPH). A dramatic proportional change in the families was observed at around 15 DPH; therefore, transcriptome analysis was conducted for the 15 DPH larvae using a previously developed oligonucleotide microarray. This analysis successfully addressed the family-specific gene expression phenotypes with 5739 differentially expressed genes and highlighted the importance of expression levels of gastric-function-related genes at the developmental stage for subsequent survival. This strategy demonstrated herein can be broadly applicable to species of interest in aquaculture to comprehend the molecular mechanism of parental effects on offspring survival, which will contribute to the optimization of breeding technologies.