bluuebunny/crossref_metadata_2025 huggingface dataset:
Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
Authors: Tousif Sultan , Wang Yong , Jackson Joshua , Hough Kenneth P. , Strenkowski John G. , Athar Mohammad , Thannickal Victor J. , McCusker Robert H. , Ponnazhagan Selvarangan , Deshane Jessy S.
Published: November 2021

Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiationin-vitroin an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulatingin-vivoandex-vivodifferentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.
Emerging Impact of Non-coding RNAs in the Pathology of Stroke
Authors: Ghafouri-Fard Soudeh , Shirvani-Farsani Zeinab , Hussen Bashdar Mahmud , Taheri Mohammad , Arefian Noormohammad
Published: November 2021

Ischemic stroke (IS) is an acute cerebral vascular event with high mortality and morbidity. Though the precise pathophysiologic routes leading to this condition are not entirely clarified, growing evidence from animal and human experiments has exhibited the impact of non-coding RNAs in the pathogenesis of IS. Various lncRNAs namely MALAT1, linc-SLC22A2, linc-OBP2B-1, linc_luo_1172, linc-DHFRL1-4, SNHG15, linc-FAM98A-3, H19, MEG3, ANRIL, MIAT, and GAS5 are possibly involved in the pathogenesis of IS. Meanwhile, lots of miRNAs contribute in this process. Differential expression of lncRNAs and miRNAs in the sera of IS patients versus unaffected individuals has endowed these transcripts the aptitude to distinguish at risk patients. Despite conduction of comprehensive assays for evaluation of the influence of lncRNAs/miRNAs in the pathogenesis of IS, therapeutic impacts of these transcripts in IS have not been clarified. In the present paper, we review the impact of lncRNAs/miRNAs in the pathobiology of IS through assessment of evidence provided by human and animal studies.
Projections of the Mouse Primary Visual Cortex
Authors: Resulaj Arbora
Published: November 2021

Lesion or damage to the primary visual cortex (V1) results in a profound loss of visual perception in humans. Similarly, in mice, optogenetic silencing of V1 profoundly impairs discrimination of orientated gratings. V1 is thought to have such a critical role in perception in part due to its position in the visual processing hierarchy. It is the first brain area in the neocortex to receive visual input, and it distributes this information to more than 18 brain areas. Here I review recent advances in our understanding of the organization and function of the V1 projections in the mouse. This progress is in part due to new anatomical and viral techniques that allow for efficient labeling of projection neurons. In the final part of the review, I conclude by highlighting challenges and opportunities for future research.
Single Cell Scale Neuronal and Glial Gene Expression and Putative Cell Phenotypes and Networks in the Nucleus Tractus Solitarius in an Alcohol Withdrawal Time Series
Authors: O’Sullivan Sean J. , McIntosh-Clarke Damani , Park James , Vadigepalli Rajanikanth , Schwaber James S.
Published: November 2021

Alcohol withdrawal syndrome (AWS) is characterized by neuronal hyperexcitability, autonomic dysregulation, and severe negative emotion. The nucleus tractus solitarius (NTS) likely plays a prominent role in the neurological processes underlying these symptoms as it is the main viscerosensory nucleus in the brain. The NTS receives visceral interoceptive inputs, influences autonomic outputs, and has strong connections to the limbic system and hypothalamic-pituitary-adrenal axis to maintain homeostasis. Our prior analysis of single neuronal gene expression data from the NTS shows that neurons exist in heterogeneous transcriptional states that form distinct functional subphenotypes. Our working model conjectures that the allostasis secondary to alcohol dependence causes peripheral and central biological network decompensation in acute abstinence resulting in neurovisceral feedback to the NTS that substantially contributes to the observed AWS. We collected single noradrenergic and glucagon-like peptide-1 (GLP-1) neurons and microglia from rat NTS and measured a subset of their transcriptome as pooled samples in an alcohol withdrawal time series. Inflammatory subphenotypes predominate at certain time points, and GLP-1 subphenotypes demonstrated hyperexcitability post-withdrawal. We hypothesize such inflammatory and anxiogenic signaling contributes to alcohol dependence via negative reinforcement. Targets to mitigate such dysregulation and treat dependence can be identified from this dataset.
Evaluating the Risk of Breast Cancer Recurrence and Metastasis After Adjuvant Tamoxifen Therapy by Integrating Polymorphisms in Cytochrome P450 Genes and Clinicopathological Characteristics
Authors: Pang Hui , Zhang Guoqiang , Yan Na , Lang Jidong , Liang Yuebin , Xu Xinyuan , Cui Yaowen , Wu Xueya , Li Xianjun , Shan Ming , Wang Xiaoqin , Meng Xiangzhi , Liu Jiaxiang , Tian Geng , Cai Li , Yuan Dawei , Wang Xin
Published: November 2021

Tamoxifen (TAM) is the most commonly used adjuvant endocrine drug for hormone receptor-positive (HR+) breast cancer patients. However, how to accurately evaluate the risk of breast cancer recurrence and metastasis after adjuvant TAM therapy is still a major concern. In recent years, many studies have shown that the clinical outcomes of TAM-treated breast cancer patients are influenced by the activity of some cytochrome P450 (CYP) enzymes that catalyze the formation of active TAM metabolites like endoxifen and 4-hydroxytamoxifen. In this study, we aimed to first develop and validate an algorithm combining polymorphisms in CYP genes and clinicopathological signatures to identify a subpopulation of breast cancer patients who might benefit most from TAM adjuvant therapy and meanwhile evaluate major risk factors related to TAM resistance. Specifically, a total of 256 patients with invasive breast cancer who received adjuvant endocrine therapy were selected. The genotypes at 10 loci from three TAM metabolism-related CYP genes were detected by time-of-flight mass spectrometry and multiplex long PCR. Combining the 10 loci with nine clinicopathological characteristics, we obtained 19 important features whose association with cancer recurrence was assessed by importance score via random forests. After that, a logistic regression model was trained to calculate TAM risk-of-recurrence score (TAM RORs), which is adopted to assess a patient’s risk of recurrence after TAM treatment. The sensitivity and specificity of the model in an independent test cohort were 86.67% and 64.56%, respectively. This study showed that breast cancer patients with high TAM RORs were less sensitive to TAM treatment and manifested more invasive characteristics, whereas those with low TAM RORs were highly sensitive to TAM treatment, and their conditions were stable during the follow-up period. There were some risk factors that had a significant effect on the efficacy of TAM. They were tissue classification (tumor Grade < 2 vs. Grade ≥ 2, p = 2.2e−16), the number of lymph node metastases (Node-Negative vs. Node < 4, p = 5.3e−07; Node < 4 vs. Node ≥ 4, p = 0.003; Node-Negative vs. Node ≥ 4, p = 7.2e−15), and the expression levels of estrogen receptor (ER) and progesterone receptor (PR) (ER < 50% vs. ER ≥ 50%, p = 1.3e−12; PR < 50% vs. PR ≥ 50%, p = 2.6e−08). The really remarkable thing is that different genotypes of CYP2D6*10(C188T) show significant differences in prediction function (CYP2D6*10 CC vs. TT, p < 0.019; CYP2D6*10 CT vs. TT, p < 0.037). There are more than 50% Chinese who have CYP2D6*10 mutation. So the genotype of CYP2D6*10(C188T) should be tested before TAM therapy.
Cancer-Associated Fibroblasts Promote the Upregulation of PD-L1 Expression Through Akt Phosphorylation in Colorectal Cancer
Authors: Gao Yang , Sun Zhao , Gu Junjie , Li Zhe , Xu Xiuxiu , Xue Chunling , Li Xuechun , Zhao Lin , Zhou Jianfeng , Bai Chunmei , Han Qin , Zhao Robert Chunhua
Published: November 2021

Upregulation of immune checkpoint proteins is one of the main mechanisms for tumor immune escape. The expression of programmed death ligand-1 (PD-L1) in colorectal cancer (CRC) is higher than in normal colorectal epithelial tissue, and patients with higher PD-L1 expression have a poorer prognosis. Additionally, PD-L1 expression in CRC is affected by the tumor microenvironment (TME). As a major component of the TME, cancer-associated fibroblasts (CAFs) can act as immune regulators and generate an immunosuppressive tumor microenvironment. Therefore, we speculated that CAFs may be related to the upregulation of PD-L1 in CRC, which leads to tumor immune escape. We found that CAFs upregulate PD-L1 expression in CRC cells through AKT phosphorylation, thereby reducing the killing of CRC cells by peripheral blood mononuclear cells. The ratio of CAFs to CRC cells was positively correlated with AKT phosphorylation and the expression of PD-L1 in CRC in vitro. Consistent with the in vitro results, high CAF content and high expression of PD-L1 were negatively correlated with disease-free survival (DFS) of CRC patients. These results indicate that the upregulation of PD-L1 expression in CRC by CAFs through the activation of Akt is one of the molecular mechanisms of tumor immune escape. Thus, targeted anti-CAF therapy may help improve the efficacy of immunotherapy.
ACSL4 Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer
Authors: Luo Wenjie , Wang Jin , Dai Xiaoyan , Zhang Hailiang , Qu Yuanyuan , Xiao Wenjun , Ye Dingwei , Zhu Yiping
Published: November 2021

Objective

This study aimed to explore the role of ACSL4 in CD8+ T cell tumor infiltration and outcomes of bladder cancer (BLCA) patients after immunotherapy.

Methods

The correlation between ACSL4 expression and tumor infiltration of immune cells was analyzed using the Tumor Immune Estimation Resource database. The prognostic significance of ACSL4 in BLCA was analyzed using Kaplan–Meier curves. Immunohistochemistry was used to detect CD8+ T cell infiltration in tumors with high and low ACSL4 expression obtained from patients at the Fudan University Shanghai Cancer Center. The relationships between immune checkpoint genes and immune response were analyzed using The Cancer Genome Atlas and IMvigor 210 cohorts. The molecular functions, cellular components, and biological processes involving ACSL4 were explored using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment pathway analyses.

Results

The expression level of ACSL4 was significantly correlated with the infiltration of CD8+ T cells in BLCA tumors (r = 0.192, P = 2.22e-04). Elevated ACSL4 was associated with suppressed tumor progression and better outcomes for BLCA patients. The higher expression level of ACSL4 predicted better immunotherapeutic responses and was associated with higher expression levels of core immune checkpoint genes, including CD274, CTLA4, PDCD1, and LAG3, compared with the low ACSL4 expression group.

Conclusion

This study demonstrated for the first time that elevated ACSL4 correlated significantly with CD8+ T cell infiltration and contributed to better immunotherapeutic responses in BLCA patients. Furthermore, ACSL4 serves as a novel biomarker for predicting patient outcomes after immunotherapeutic treatments, which may improve the development of individualized immunotherapy for BLCA.
Durable Complete Response to Pembrolizumab in Esophageal Squamous Cell Carcinoma With Divergent Microsatellite Status: A Case Report
Authors: Zeng Tian , Zhang Lei , Chen Can , Zhao Xiang , Liu Xiaoqing , Ran Fengwei , Yong Tingting , Yang Ying , Zhang Henghui , Zhang Yanling
Published: November 2021

Microsatellite instability-high (MSI-H) is widely believed to be a biomarker for immune checkpoint inhibitors (ICIs) such as pembrolizumab in solid tumors. However, due to the low prevalence of MSI-H in most cancers, it tends to be insufficient to identify whether patients should receive ICIs according to this biomarker alone. Here, we report a Chinese esophageal squamous cell carcinoma (ESCC) patient with unusual divergent MSI status between the primary lesion (MSS) and metastatic lesion (MSI-H) which developed after platinum-based therapy and radiotherapy. Both his primary and metastatic tumors responded well to pembrolizumab-containing therapies or pembrolizumab monotherapy and maintained a complete response for over 24 months. Whole-exome sequencing and multiplex immunohistochemistry were used to examine his tissue specimens. Notably, there were multiple high-frequency mutations of DDR (DNA damage repair) genes shared in the primary lesion and metastatic lesion, especially in the latter. Besides, we observed considerable degrees of infiltrating CD3+/CD8+ lymphocytes in both of his primary tumor and metastatic tumor without obvious difference, suggesting that the conversion of microsatellite status had little effect on the infiltration of lymphocytes. Collectively, given the predictive role of DDR alterations for ICIs in other malignancies, the alterations of DDR genes might also be promising biomarkers in ESCC individuals receiving ICIs.
Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation
Authors: Zhou Zijing , Li Jinyuan Vero , Martinac Boris , Cox Charles D.
Published: November 2021

Missense mutations in the gene that encodes for the mechanically-gated ion channel Piezo1 have been linked to a number of diseases. Gain-of-function variants are linked to a hereditary anaemia and loss-of-function variants have been linked to generalized lymphatic dysplasia and bicuspid aortic valve. Two previously characterized mutations, S217L and G2029R, both exhibit reduced plasma membrane trafficking. Here we show that both mutations also display reduced stability and higher turnover rates than wild-type Piezo1 channels. This occurs through increased ubiquitination and subsequent proteasomal degradation. Congruent with this, proteasome inhibition using N-acetyl-l-leucyl-l-leucyl-l-norleucinal (ALLN) reduced the degradation of both mutant proteins. While ALLN treatment could not rescue the function of S217L we show via multiple complementary methodologies that proteasome inhibition via ALLN treatment can not only prevent G2029R turnover but increase the membrane localized pool of this variant and the functional Piezo1 mechanosensitive currents. This data in combination with a precision medicine approach provides a new potential therapeutic avenue for the treatment of Piezo1 mediated channelopathies.
Large Screening Identifies ACE2 Positively Correlates With NF-κB Signaling Activity and Targeting NF-κB Signaling Drugs Suppress ACE2 Levels
Authors: Yan Meichen , Dong Yuan , Bo Xuena , Cheng Yong , Cheng Jinbo
Published: November 2021

Coronaviruses SARS-CoV-2 infected more than 156 million people and caused over 3 million death in the whole world, therefore a better understanding of the underlying pathogenic mechanism and the searching for more effective treatments were urgently needed. Angiotensin-converting enzyme 2 (ACE2) was the receptor for SARS-CoV-2 infection. In this study, we found that ACE2 was an interferon-stimulated gene (ISG) in human cell lines. By performing an ISG library screening, we found that ACE2 levels were positively regulated by multiple ISGs. Interestingly, ACE2 levels were highly correlated with ISGs-induced NF-κB activities, but not IFNβ levels. Furthermore, using an approved clinical durgs library, we found two clinical drugs, Cepharanthine and Glucosamine, significantly inhibited ACE2 level, IFNβ level, and NF-κB signaling downstream TNFα and IL6 levels. Our finding suggested the possible inhibitory effects of Cepharanthine and Glucosamine during SARS-CoV-2 infection and the subsequent inflammatory cytokine storm.
Deep Learning-Augmented Head and Neck Organs at Risk Segmentation From CT Volumes
Authors: Wang Wei , Wang Qingxin , Jia Mengyu , Wang Zhongqiu , Yang Chengwen , Zhang Daguang , Wen Shujing , Hou Delong , Liu Ningbo , Wang Ping , Wang Jun
Published: November 2021

Purpose: A novel deep learning model, Siamese Ensemble Boundary Network (SEB-Net) was developed to improve the accuracy of automatic organs-at-risk (OARs) segmentation in CT images for head and neck (HaN) as well as small organs, which was verified for use in radiation oncology practice and is therefore proposed.

Methods: SEB-Net was designed to transfer CT slices into probability maps for the HaN OARs segmentation purpose. Dual key contributions were made to the network design to improve the accuracy and reliability of automatic segmentation toward the specific organs (e.g., relatively tiny or irregularly shaped) without sacrificing the field of view. The first implements an ensemble of learning strategies with shared weights that aggregates the pixel-probability transfer at three orthogonal CT planes to ameliorate 3D information integrity; the second exploits the boundary loss that takes the form of a distance metric on the space of contours to mitigate the challenges of conventional region-based regularization, when applied to highly unbalanced segmentation scenarios. By combining the two techniques, enhanced segmentation could be expected by comprehensively maximizing inter- and intra-CT slice information. In total, 188 patients with HaN cancer were included in the study, of which 133 patients were randomly selected for training and 55 for validation. An additional 50 untreated cases were used for clinical evaluation.

Results: With the proposed method, the average volumetric Dice similarity coefficient (DSC) of HaN OARs (and small organs) was 0.871 (0.900), which was significantly higher than the results from Ua-Net, Anatomy-Net, and SRM by 4.94% (26.05%), 7.80% (24.65%), and 12.97% (40.19%), respectively. By contrast, the average 95% Hausdorff distance (95% HD) of HaN OARs (and small organs) was 2.87 mm (0.81 mm), which improves the other three methods by 50.94% (75.45%), 88.41% (79.07%), and 5.59% (67.98%), respectively. After delineation by SEB-Net, 81.92% of all organs in 50 HaN cancer untreated cases did not require modification for clinical evaluation.

Conclusions: In comparison to several cutting-edge methods, including Ua-Net, Anatomy-Net, and SRM, the proposed method is capable of substantially improving segmentation accuracy for HaN and small organs from CT imaging in terms of efficiency, feasibility, and applicability.
Comparing Genomic Prediction Models by Means of Cross Validation
Authors: Schrauf Matías F. , de los Campos Gustavo , Munilla Sebastián
Published: November 2021

In the two decades of continuous development of genomic selection, a great variety of models have been proposed to make predictions from the information available in dense marker panels. Besides deciding which particular model to use, practitioners also need to make many minor choices for those parameters in the model which are not typically estimated by the data (so called “hyper-parameters”). When the focus is placed on predictions, most of these decisions are made in a direction sought to optimize predictive accuracy. Here we discuss and illustrate using publicly available crop datasets the use of cross validation to make many such decisions. In particular, we emphasize the importance of paired comparisons to achieve high power in the comparison between candidate models, as well as the need to define notions of relevance in the difference between their performances. Regarding the latter, we borrow the idea of equivalence margins from clinical research and introduce new statistical tests. We conclude that most hyper-parameters can be learnt from the data by either minimizing REML or by using weakly-informative priors, with good predictive results. In particular, the default options in a popular software are generally competitive with the optimal values. With regard to the performance assessments themselves, we conclude that the paired k-fold cross validation is a generally applicable and statistically powerful methodology to assess differences in model accuracies. Coupled with the definition of equivalence margins based on expected genetic gain, it becomes a useful tool for breeders.
The Multi-Modal Risk Analysis and Medical Prevention of Lumbar Degeneration, Fatigue, and Injury Based on FEM/BMD for Elderly Chinese Women Who Act as Stay-Home Grandchildren Sitters
Authors: Li Na , Cavagnaro María José , Xiong Kun , Du Xianping , Shi Jian
Published: November 2021

Background: An increasing number of Chinese elderly women stay at home and act as grandchildren sitters. In consequence of the frequent load-bearing, chronic lumbar fatigue probably caused a higher risk of lumbar degeneration, fatigue, and injury which has become one of the most important aging and health problems in China. In this study, a multi-mode lumbar finite element model (FEM) with specific bone mineral density (BMD) were developed and validated for further spine injury prevention and control.

Methods: The material properties of lumbar vertebra were modified according to degenerated bone mineral density, and geometry was adjusted based on intervertebral disc height. The motion of lifting children was simulated by a 76 year-old Chinese women's FEM, and the stress distribution was calculated and predicted.

Results: The pressure of L5-S intervertebral disc in the bending 3-year-old dummy lifting posture was significantly higher than the same posture without lifting, the maximum effective stress of endplate cartilage in the upright child lifting posture was 1.6 times that of the bending without lifting posture. And the fatigue risk limitation frequency of the upright with dummy posture was predicted with the functional equation of fatigue and stress which was deduced by genetic algorithm, which combined with the effective stress of lumbar vertebrae spongy bone calculated from FEM.

Conclusions: The child-lifting motion could increase the risk of lumbar degeneration, fatigue, and injury in elderly women, and they should keep below the frequency limit of the motion of lifting children in their daily life. This study could put forward scientific injury prevention guidance to Chinese elderly women who lift children in daily life frequently.
Implementation of the Arizona Pain and Addiction Curriculum: Findings and Implications From a Statewide Evaluation
Authors: Villarroel Lisa , Mardian Aram S. , Timme Evan , Rehman Shakaib , Christ Cara M.
Published: November 2021

Purpose: The U.S. is struggling with dual crises of chronic pain and opioid overdoses. To improve statewide pain and addiction care, the Arizona Department of Health Services and 18 health education programs collaboratively created the evidence-based, comprehensive Arizona Pain and Addiction Curriculum which includes a Toolbox for Operationalization with adult learning theory applications and an annual program survey to assess curriculum implementation. The purpose of this study is to analyze the first year's survey data to better understand the implementation of a novel curriculum across all programs in the state.

Materials and Methods: Program surveys were sent 6 months after curriculum publication to all 18 health education programs in Arizona to assess the 6 Ds of curriculum implementation: Degree of implementation, Difficulty of implementation, Delivery methods, Faculty Development, Didactic dissonance and Discussion Opportunities.

Results: Responses from all program types (14/18 programs) indicated that there was widespread implementation of the curriculum, with 71% reporting that all ten Core Components had been included in the past academic year. The majority of programs did not find the Components difficult to implement and had implemented them through lectures. Seventy-seven percent of programs did not have a process to ensure clinical rotation supervisors are teaching content consistent with the curriculum, 77% reported not addressing student's didactic dissonance, and 77% of programs did not report asking students about their interactions with industry representatives.

Conclusion: In < 1 year after creation of the Arizona Pain and Addiction Curriculum, all program types reported wide implementation with little difficulty. This may represent a first step toward the transformation of pain and addiction education, and occurred statewide, across program types. Further focus on didactic dissonance, problem solving and faculty development is indicated, along with systematic education on pharmaceutical and industry influence on learners. Other programs may benefit from adopting this curriculum and may not experience significant challenges in doing so.
Prescribing Patterns for Upper Respiratory Tract Infections: A Prescription-Review of Primary Care Practice in Quetta, Pakistan and the Implications
Authors: Hashmi Hania , Sasoli Nazeer Ahmad , Sadiq Abdul , Raziq Abdul , Batool Fakhra , Raza Shanaz , Iqbal Qaiser , Haider Sajjad , Umer Jan Syed , Mengal Muhammad Alam , Tareen Abdul Malik , Khalid Adnan , Saleem Fahad
Published: November 2021

Background:To identify and address the potential overuse of antibiotics, it is important to ascertain the prescribing practices of physicians. We, therefore, conducted this prescription analysis to document URTI-specific antibiotic prescription frequency in a public primary healthcare setting of Quetta city, Pakistan.

Methods:A retrospective record review was conducted of all prescriptions for URTIs in Combined Military Hospital, Quetta from 1 March to 31st May 2021. The Mann-Whitney U and Jonckheere–Terpstra test was used to evaluate the association between the tendencies of a different group of prescribers.p-value of <0.05 was of statistical significance.

Results:Over the 3 months, 50,705 prescriptions were screened and analyzed according to the established inclusion and exclusion criteria. A total of 4,126 (8.13%) URTI prescriptions met the inclusion criteria, of which 2,880 (69.80%) prescriptions contained antibiotics. Among all antibiotics, penicillins (Amoxicillin + Clavulanate) were the most prescribed antibiotic, constituting 1,323 (45.9%) of total antibiotics prescribed for all cases, followed by the Macrolide group 527 (18.2%). The Jonckheere–Terpstra test revealed a statistically significant association between the status of the prescriber and the diagnosis (p= 0.002). Furthermore, a moderate positive trend was reported with specialists being more competent in antibiotic prescribing based on their diagnosis, followed by postgraduates and house officers (τ = 0.322).

Conclusion:The prescribing patterns for the management of URTIs in the hospital were inconsistent with current guidelines. Strict adherence to guidelines must be ensured and antibiotic prescribing for URTIs should be discouraged.
Recent Advances in Studying Age-Associated Lipids Alterations and Dietary Interventions in Mammals
Authors: Gille Benedikt , Galuska Christina E. , Fuchs Beate , Peleg Shahaf
Published: November 2021

Lipids are involved in a broad spectrum of canonical biological functions, from energy supply and storage by triacylglycerols to membrane formation by sphingolipids, phospholipids and glycolipids. Because of this wide range of functions, there is an overlap between age-associated processes and lipid pathways. Lipidome analysis revealed age-related changes in the lipid composition of various tissues in mice and humans, which were also influenced by diet and gender. Some changes in the lipid profile can be linked to the onset of age-related neurodegenerative diseases like Alzheimer’s disease. Furthermore, the excessive accumulation of lipid storage organelles, lipid droplets, has significant implications for the development of inflammaging and non-communicable age-related diseases. Dietary interventions such as caloric restriction, time-restrictive eating, and lipid supplementation have been shown to improve pertinent health metrics or even extend life span and thus modulate aging processes.
Trust, Sociability, and Quality of Life of Sub-Saharan African Migrants in Germany
Authors: Adedeji Adekunle , Akintunde Tosin Yinka , Idemudia Erhabor S. , Ibrahim Elhakim , Metzner Franka
Published: November 2021

Poor social integration is associated with poor quality of life among minority groups. The current study hypothesized that trust and sociability may significantly explain the quality of life performance among Sub-Saharan African migrants in Germany. Data from 518 migrants were analyzed. Hierarchical multiple linear regression models were calculated to assess the predictive effect of trust and sociability on aggregate quality of life. Results show that general trust and sociability explained about 21% of the variance in quality of life score (adjusted R2 = .206; p < .001) for the total sample. Socioeconomic and demographic features suggested an added predictive effect of about 8% for total sample (adjusted R2 = .279; p < .001), 10% for male (adjusted R2 = .322; p < .001) and 4% for female (adjusted R2 = .211; p < .001). The results support trust and sociability as essential in connecting to a new environment and enhancing the quality of life.
Reliability of Wastewater Analysis for Monitoring COVID-19 Incidence Revealed by a Long-Term Follow-Up Study
Authors: Sanjuán Rafael , Domingo-Calap Pilar
Published: November 2021

Wastewater-based epidemiology has been used for monitoring human activities and waterborne pathogens. Although wastewaters can also be used for tracking SARS-CoV-2 at the population level, the reliability of this approach remains to be established, especially for early warning of outbreaks. We collected 377 samples from different treatment plants processing wastewaters of >1 million inhabitants in Valencia, Spain, between April 2020 and March 2021. Samples were cleaned, concentrated, and subjected to RT-qPCR to determine SARS-CoV-2 concentrations. These data were compared with cumulative disease notification rates over 7 and 14 day periods. We amplified SARS-CoV-2 RNA in 75% of the RT-qPCRs, with an estimated detection limit of 100 viral genome copies per liter (gc/L). SARS-CoV-2 RNA concentration correlated strongly with disease notification rates over 14-day periods (Pearson r = 0.962, P < 0.001). A concentration >1000 gc/L showed >95% sensitivity and specificity as an indicator of more than 25 new cases per 100,000 inhabitants. Albeit with slightly higher uncertainty, these figures were reproduced using a 7-day period. Time series were similar for wastewaters data and declared cases, but wastewater RNA concentrations exhibited transient peaks that were not observed in declared cases and preceded major outbreaks by several weeks. In conclusion, wastewater analysis provides a reliable tool for monitoring COVID-19, particularly at low incidence values, and is not biased by asymptomatic cases. Moreover, this approach might reveal previously unrecognized features of COVID-19 transmission.
The Potential of Induced Pluripotent Stem Cells to Advance the Treatment of Pancreatic Ductal Adenocarcinoma
Authors: Krog Ricki T. , de Miranda Noel F. C. C. , Vahrmeijer Alexander L. , Kooreman Nigel G.
Published: November 2021

Advances in the treatment of pancreatic ductal adenocarcinoma (PDAC) using neoadjuvant chemoradiotherapy, chemotherapy, and immunotherapy have had minimal impact on the overall survival of patients. A general lack of immunogenic features and a complex tumor microenvironment (TME) are likely culprits for therapy refractoriness in PDAC. Induced pluripotent stem cells (iPSCs) should be explored as a means to advance the treatment options for PDAC, by providing representative in vitro models of pancreatic cancer development. In addition, iPSCs could be used for tailor-made cellular immunotherapies or as a source of tumor-associated antigens in the context of vaccination.
High Grade of Amplification of Six Regions on Chromosome 2p in a Neuroblastoma Patient with Very Poor Outcome: The Putative New Oncogene TSSC1
Authors: Ognibene Marzia , Amoroso Loredana , Melchionda Fraia , Cangelosi Davide , Zara Federico , Parodi Stefano , Pezzolo Annalisa
Published: November 2021

We observed a case of high-risk neuroblastoma (NB) carried by a 28-month-old girl, displaying metastatic disease and a rapid decline of clinical conditions. By array-CGH analysis of the tumor tissue and of the metastatic bone marrow aspirate cells, we found a high-grade amplification of six regions besides MYCN on bands 2p25.3–p24.3. The genes involved in these amplifications were MYT1L, TSSC1, CMPK2, RSAD2, RNF144A, GREB1, NTSR2, LPIN1, NBAS, and the two intergenic non-protein coding RNAs LOC730811 and LOC339788. We investigated if these DNA co-amplifications may have an effect on enhancing tumor aggressiveness. We evaluated the association between the high expression of the amplified genes and NB patient’s outcome using the integration of gene expression data of 786 NB samples profiled with different public platforms from patients with at least five-year follow-up. NB patients with high expression of the TSSC1 gene were associated with a reduced survival rate. Immunofluorescence staining on primary tumor tissues confirmed that the TSSC1 protein expression was high in the relapsed or dead stage 4 cases, but it was generally low in NB patients in complete remission. TSSC1 appears as a putative new oncogene in NB.
PSMA-PET/MRI-Based Focal Dose Escalation in Patients with Primary Prostate Cancer Treated with Stereotactic Body Radiation Therapy (HypoFocal-SBRT): Study Protocol of a Randomized, Multicentric Phase III Trial
Authors: Zamboglou Constantinos , Spohn Simon K. B. , Adebahr Sonja , Huber Maria , Kirste Simon , Sprave Tanja , Gratzke Christian , Chen Ronald C. , Carl Ernst Günther , Weber Wolfgang A. , Mix Michael , Benndorf Matthias , Wiegel Thomas , Baltas Dimos , Jenkner Carolin , Grosu Anca L.
Published: November 2021

Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time, and by (ii) enabling safe delivery of high RT doses. Several studies proposed a dose–response relationship for patients with primary PCa and especially in patients with high-risk features, as dose escalation leads to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography targeting prostate-specific-membrane antigen (PSMA-PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT/stereotactic body RT, with focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel strategy will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS), and we will assess quality of life in order to detect potential changes.
A Controlled Study of Major Depressive Episodes in Long-Term Childhood, Adolescence, and Young Adult Cancer Survivors (The NOR-CAYACS Study)
Authors: Dahl Alv A. , Kiserud Cecilie Essholt , Fosså Sophie D. , Loge Jon Håvard , Reinertsen Kristin Valborg , Ruud Ellen , Lie Hanne C.
Published: November 2021

Background: A major depressive episode (MDE) is typically self-rated by screening forms identifying probable MDE (pMDE). This population-based cross-sectional questionnaire study examined the prevalence rates of pMDE identified by the PHQ-9 screener in long-term survivors of childhood and adolescence (CACSs) and young adult cancer (YACSs) and a normative sample (NORMs). Methods: Data from 488 CACSs, 1202 YACSs, and 1453 NORMs were analyzed, and pMDE was defined both by cut-off ≥10 on the total PHQ-9 score and by an algorithm. Results: The prevalence rates of pMDE among CACSs were 21.5%, 16.6% in YACSs, and 9.2% among NORMs using the cut-off definition. With the algorithm, the prevalence rates of pMDE were 8.0% among CACSs, 8.1% among YACSs, and 3.9% among NORMs. Independent of definition, CACSs and YACSs had significantly increased prevalence rates of pMDE compared to NORMs. Psychosocial factors and self-rated health were significantly associated with both definitions of pMDE in multivariable analyses, while survivor groups, cancer types, and adverse events were not. Conclusion: Since pMDE has negative health consequences and is amenable to treatment, healthcare providers should be attentive and screen for pMDE in young cancer survivors. For PHQ-9, the preferred type of definition of pMDE should be determined.
Dual-Wavelength Fluorescence Monitoring of Photodynamic Therapy: From Analytical Models to Clinical Studies
Authors: Kirillin Mikhail , Khilov Aleksandr , Kurakina Daria , Orlova Anna , Perekatova Valeriya , Shishkova Veronika , Malygina Alfia , Mironycheva Anna , Shlivko Irena , Gamayunov Sergey , Turchin Ilya , Sergeeva Ekaterina
Published: November 2021

Fluorescence imaging modalities are currently a routine tool for the assessment of marker distribution within biological tissues, including monitoring of fluorescent photosensitizers (PSs) in photodynamic therapy (PDT). Conventional fluorescence imaging techniques provide en-face two-dimensional images, while depth-resolved techniques require complicated tomographic modalities. In this paper, we report on a cost-effective approach for the estimation of fluorophore localization depth based on dual-wavelength probing. Owing to significant difference in optical properties of superficial biotissues for red and blue ranges of optical spectra, simultaneous detection of fluorescence excited at different wavelengths provides complementary information from different measurement volumes. Here, we report analytical and numerical models of the dual-wavelength fluorescence imaging of PS-containing biotissues considering topical and intravenous PS administration, and demonstrate the feasibility of this approach for evaluation of the PS localization depth based on the fluorescence signal ratio. The results of analytical and numerical simulations, as well as phantom experiments, were translated to the in vivo imaging to interpret experimental observations in animal experiments, human volunteers, and clinical studies. The proposed approach allowed us to estimate typical accumulation depths of PS localization which are consistent with the morphologically expected values for both topical PS administration and intravenous injection.
Uterine Preservation Treatments in Sarcomas: Oncological Problems and Reproductive Results: A Systematic Review
Authors: Dondi Giulia , Porcu Eleonora , De Palma Alessandra , Damiano Giuseppe , De Crescenzo Eugenia , Cipriani Linda , Dirodi Maria , Ravegnini Gloria , De Leo Antonio , Nannini Margherita , Ferioli Martina , Morganti Alessio G. , Pantaleo Maria Abbondanza , De Iaco Pierandrea , Perrone Anna Myriam
Published: November 2021

Uterine sarcomas are rare cancers, sometimes diagnosed in women of childbearing age. Hysterectomy is the standard treatment in early stages. The option of lesion removal to save fertility is described in the literature, but it is still considered experimental. The objective of this systematic review is to report on the available evidence on the reproductive and oncological outcomes of fertility-sparing treatment in women with uterine sarcomas. PubMed, Scopus and Cochrane Central Register of Controlled Trials were searched between 1 January 2011 and 21 June 2021 for publications in English about women with uterine sarcoma treated with a fertility-sparing intervention. Thirty-seven studies were included for a total of 210 patients: 63 low-grade endometrial stromal sarcomas, 35 embryonal rhabdomyosarcomas of the cervix, 19 adenosarcomas, 7 leiomyosarcomas and 2 uterine tumors resembling an ovarian sex cord. Conservative treatment ensured pregnancy in 32% of cases. In terms of oncological outcomes, relapse was related to histology and the worst prognosis was reported for leiomyosarcoma, followed by low-grade endometrial stromal sarcoma, which relapsed in 71% and 54% of cases, respectively. The highest death rate was associated with leiomyosarcoma (57.1%). This study demonstrated that fertility-sparing treatments may be employed in selected cases of early stage uterine sarcoma.
Low-Cost Eddy-Resolving Simulation in the Near-Field of an Annular Swirling Jet for Spray Drying Applications
Authors: Gutiérrez Suárez Jairo Andrés , Gómez Mejía Alexánder , Galeano Urueña Carlos Humberto
Published: November 2021

Spray drying is one of many industrial applications that use annular swirling jets. For this particular application, the flow characteristics in the near-field of the jet are fundamental to obtaining high-quality dried products. In this article, an annular swirling jet configuration is numerically studied using three low-cost eddy-resolving turbulence methods: detached-eddy simulation (DES), delayed-DES (DDES) and scale-adaptive simulation (SAS). To focus in industrial applicability, very coarse grids are used. The individual performance of these models is assessed through a comparison with laser-Doppler anemometry (LDA) measurements and large-eddy simulation (LES) data from available studies. Results show that all the three turbulence models are suitable for performing industrial cost-effective simulations, capable of reproducing LES results of mean velocities and first-order turbulence statistics at a fraction of the computational cost. Differences in the results of the evaluated models were minor; however, the simulation with DDES still provided a better reproduction of experimental results, especially in the very-near field of the jet, as it enforced RANS behavior near the inlet walls and a better transition from modeled to resolved scales.
Examining Treatment Patterns and Real-World Outcomes in Chronic Lymphocytic Leukemia Using Administrative Data in Ontario
Authors: Seung Soo Jin , Hurry Manjusha , Hassan Shazia , Elnoursi Ashlie , Scheider Krystin A. B. , Wagner Dennis , Edwin Jonathan J. , Aw Andrew T. W.
Published: November 2021

Information on the real-world experience of Canadians diagnosed with chronic lymphocytic leukemia (CLL) is limited. This study was conducted to report treatment patterns and outcomes of CLL using Ontario administrative data. A retrospective cohort study was conducted in patients diagnosed with CLL between 1 January 2010 and 31 December 2017 identified in the Ontario Cancer Registry (OCR). Data were accessed using the Institute of Clinical Evaluative Sciences (ICES), which collects various population-level health information. In the Ontario Cancer Registry, 2887 CLL patients receiving treatment and diagnosed between 2010–2017 were identified. Fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapy was most frequently used as a first line, but use declined since ibrutinib and obinutuzumab combinations were funded in 2015. In patients treated with frontline FCR, survival at year one was 89% pre-2015 and 96% post-2015; at year four, survival was 73% and 87%, respectively. Survival in patients treated with frontline chlorambucil was 76% pre-2015 and 75% post-2015 in year 1, and 45% and 56% in year 3. Our analysis shows that, as the treatment landscape for CLL has shifted, use of newer and novel agents as a first line or earlier in the relapsed/refractory setting has resulted in improved survival outcomes.
Biodiversity Management in a Mediterranean National Park: The Long, Winding Path from a Species-Centred to an Ecosystem-Centred Approach
Authors: Boudouresque Charles-François , Barcelo Alain , Blanfuné Aurélie , Changeux Thomas , Martin Gilles , Médail Frédéric , Perret-Boudouresque Michèle , Ponel Philippe , Ruitton Sandrine , Taupier-Letage Isabelle , Thibaut Thierry
Published: November 2021

The Port-Cros National Park (PCNP), established in 1963, was one of the earliest terrestrial and marine parks in the Mediterranean Sea. From 2012, it engaged in a major redefinition and extension of its territory (N-PCNP—New Port-Cros National Park). This case is particularly interesting insofar as the protected area has been competently and efficiently managed since its creation, and protection and management measures have been strictly implemented: in the Mediterranean, the PCNP has often been considered as a benchmark. Here, we critically analyse almost 60 years of the management of the biodiversity and the human uses, with their share of successes and failures, certain operations which are today regarded as errors, and a doctrine today of a priori non-interventionism, in contrast to the doctrine in vogue in the early years. Of particular interest is the change in outlook with regard to actions favouring flagship species, such as building a tower for bats, setting up artificial nests for seabirds, and constructing an artificial reef at sea. The question of the natural arrival of the wild boar, a native species, and the hostility of the public and some species-centred scientists, is particularly instructive. We analyse these changes in the light of the ongoing trends in concepts in ecology and nature conservation, and the shift from a species-centred to an ecosystem-centred approach. It is worth emphasizing that a critical review of almost 60 years of management is a very rare exercise in a national park anywhere in the world.
Systematic Design Applied in Outdoor Spatiotemporal Lighting
Authors: Papacharalampopoulos Alexios , Balafoutis Thanos
Published: November 2021

Outdoor lighting design consists of many different objectives, depending on the area that is illuminated. In addition, besides functional lighting, extra messages may be superimposed to a lighting configuration. This adds to the complexity of the lighting design. Furthermore, temporal variations in lighting may be used as an additional tool of expressivity. All the above require some basic training and also some familiarity with expression tools. In this work, a framework is given for seamless communication through lighting, including both spatial and temporal lighting patterns. To this end, two different kinds of time scales are considered, leading to case studies for both seasonal lighting and communication through rapid spatiotemporal differentiations in it. The framework is two-fold, allowing for both diagrammatic and quasi-algebraic elaboration, leading to interesting visual results and providing the first step towards optimization. Different cases of outdoor lighting are considered as case studies, namely façade lighting and glass cases. These are used to illustrate the applicability and the added value of the current framework, that is, the systematization of the lighting procedure taking into account artistic interventions, which can be considered an extension of utilizing semantics.