bluuebunny/crossref_metadata_2025 huggingface dataset:
The Trend of TIM3 Expression on T Cells in Patients With Nontuberculous Mycobacterial Lung Disease: From Immune Cell Dysfunction to Clinical Severity
Authors: Wang Ping-Huai , Wu Ming-Fang , Hsu Chi-Yu , Pan Sheng-Wei , Shu Chin-Chung , Cheng Shih-Lung
Published: November 2021

Background

The incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied.

Methods

Patients with NTM-LD and healthy controls were prospectively recruited from July 2014 to August 2019 at three tertiary referral centers in Taiwan. We examined TIM3 expression on the T cells from the participants using flow cytometry. TIM3 expression was analyzed for different disease statuses and after treatment. The apoptosis and cytokine profiles were analyzed according to the TIM3 expression.

Results

Among enrolled subjects (47 patients and 46 controls), TIM3 on CD4+ cells (6.44% vs. 4.12%, p = 0.028) and CD8+ cells (18.47% vs. 9.13%, p = 0.003) were higher in NTM-LD patients than in the controls. The TIM3 level on CD4+ and CD8+ T cells was positively associated with T-cell apoptosis in the NTM-LD patients. In stimulating peripheral blood mononuclear cells using PMA plus ionomycin, a high TIM3 level on T cells correlated with low interleukin-2 and tumor necrosis factor-alpha (TNF-α) on CD4+ cells and interferon-gamma and TNF-α on CD8+ T cells. For clinical manifestation, low body mass index (BMI), positive sputum acid-fast smear, and high radiographic score correlated with high TIM3 expression on T cells. After NTM treatment, TIM3+ decreased significantly on CD4+ and CD8+ T cells.

Conclusions

In patients with NTM-LD, TIM3+ expression increased over CD4+ and CD8+ T cells and correlated with cell apoptosis and specific cytokine attenuation. Clinically, TIM3+ T cells increased in patients with low BMI, high disease extent, and high bacilli burden but decreased after treatment.
Culture Enrichment Combined With Long-Read Sequencing Facilitates Genomic Understanding of Hadal Sediment Microbes
Authors: Wang Huan , Wang Meng , Fan Shen , Lu Jie , Lan Yi , Li Menggong , Li Jiangyan , Liu Rulong , Sun Jin , Fang Jiasong , Qian Pei-Yuan , Zhang Yu-Zhong , Zhang Weipeng
Published: November 2021

Culture enrichment was developed to discover the uncharted microbial species in the environmental microbiota. Yet this strategy has not been widely used to study microbes of deep-sea environments. Here, we report the cultivation and metagenomic analysis of oceanic sediment microbiota collected from 6,477 m deep in the Mariana Trench. The sediment samples were cultured anaerobically in the laboratory for 4 months, before being subjected to full-length 16S rRNA gene sequencing using the PacBio technique and metagenome sequencing using both the Illumina and Oxford Nanopore techniques. The 16S rRNA gene analyses revealed 437 operational taxonomic units specific to the cultured microbes, despite the lower diversity of the cultured microbiota in comparison with the original. Metagenome analyses revealed the prevalence of functions related to respiration, energy production, and stress response in the cultured microbes, suggesting these functions may contribute to microbial proliferation under laboratory conditions. Binning of the assembled metagenome contigs of the cultured microbiota generated four nearly complete genomes affiliated to yet unclassified species under the genera Alcanivorax, Idiomarina, Sulfitobacter, and Erythrobacter. Excepting Alcanivorax, the other three genera were almost undetectable in the original samples and largely enriched in the cultured samples. The four genomes possessed a variety of genes for carbohydrate utilization and nitrite reduction, pointing to an ability to respire diverse carbon sources using nitrite as the final electron acceptor. Taken together, the findings suggest that a combination of culture enrichment and long-read sequencing is an ideal way to mine novel microbial species in the hadal environment, particularly species that are rare in their native environmental niches, and thus expand our understanding of the hadal microbial diversity and function.
Reducing Calibration Time in PET Systems Based on Monolithic Crystals
Authors: Freire Marta , Cañizares Gabriel , Echegoyen Sara , Gonzalez-Montoro Andrea , Gonzalez Antonio J.
Published: November 2021

In the past years, the gamma-ray detector designs based on the monolithic crystals have demonstrated to be excellent candidates for the design of high-performance PET systems. The monolithic crystals allow to achieve the intrinsic detector resolutions well below state-of-the-art; to increase packing fraction thus, increasing the system sensitivity; and to improve lesion detectability at the edges of the scanner field of view (FOV) because of their intrinsic depth of interaction (DOI) capabilities. The bottleneck to translate to the clinical PET systems based on a large number of monolithic detectors is eventually the requirement of mechanically complex and time-consuming calibration processes. To mitigate this drawback, several methods have been already proposed, such as using non-physically collimated radioactive sources or implementing the neuronal networks (NN) algorithms trained with simulated data. In this work, we aimed to simplify and fasten a calibration process of the monolithic based systems. The Normal procedure consists of individually acquiring a 11 × 11 22Na source array for all the detectors composing the PET system and obtaining the calibration map for each module using a method based on the Voronoi diagrams. Two reducing time methodologies are presented: (i) TEST1, where the calibration map of one detector is estimated and shared among all others, and (ii) TEST2, where the calibration map is slightly modified for each module as a function of their detector uniformity map. The experimental data from a dedicated prostate PET system was used to compare the standard calibration procedure with both the proposed methods. A greater similarity was exhibited between the TEST2 methodology and the Normal procedure; obtaining spatial resolution variances within 0.1 mm error bars and count rate deviations as small as 0.2%. Moreover, the negligible reconstructed image differences (13% deviation at most in the contrast-to-noise ratio) and almost identical contrast values were reported. Therefore, this proposed method allows us to calibrate the PET systems based on the monolithic crystals reducing the calibration time by approximately 80% compared with the Normal procedure.
Case Report: Relevance of an Accurate Diagnosis and Monitoring of Infective Dermatitis Associated With Human T-Lymphotropic Virus Type 1 in Childhood
Authors: Benencio Paula , Ducasa Nicolás , Arruvito Lourdes , Irurzun Inés , Praino Laura , Lamberti Magdalena , Beraza María , Berini Carolina , Biglione Mirna
Published: November 2021

Human T-lymphotropic virus type 1 (HTLV-1) is a neglected retrovirus distributed worldwide and the ethiological agent of several pathologies, such as adult T-cell leukemia/lymphoma (ATLL), a chronic myelopathy known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). HTLV-1 presents tropism for CD4+ T cells and induces deregulation of the cytokine profile. IDH is a severe, chronic superinfected eczema generally associated with Staphylococcus aureus and/or Streptococcus beta haemolyticus infection that responds partially to antibiotic therapy but prompt recurrence develops upon treatment withdrawal. IDH could be a risk factor for progression toward both HAM/TSP and ATLL and, similarly to other diseases associated with HTLV-1, it is sub-diagnosed particularly in non-endemic areas. Here, we present a case of IDH in a young boy living in Buenos Aires with symptoms since 2010, at the age of 5. HTLV-1 infection was suspected and confirmed in 2016. The patient exhibited chronic dermatosis with exudative eruption involving mainly the scalp, retroauricular regions, neck and abdomen. Clinical evaluations, routine laboratory tests, full blood count, and HTLV-1 diagnosis for this case are included.
Proton Pump Inhibitor Therapy Does Not Affect Prognosis of Cirrhosis Patients With Acute Decompensation and Acute-on-Chronic Liver Failure: A Single-Center Prospective Study
Authors: Sun Shanshan , Ye Wenyi , Zhao Ruihong , Hu Jianhua , Zhang Xuan , Yang Meifang , Zhao Hong , Sheng Jifang
Published: November 2021

Background: The aim of this study was to investigate the impact of proton pump inhibitor (PPI) therapy on complications and prognosis in cirrhosis patients with and without acute-on-chronic liver failure (ACLF).

Materials and Methods: Cirrhosis patients with acute decompensation (AD) (n = 489) admitted in our center were enrolled in this prospective observational cohort study. According to treatment received, patients were identified as users or nonusers of PPI. Clinical and laboratory data, complications during hospitalization, and overall survival were recorded in all the patients.

Results: Of the 489 patients, 299 (61.1%) patients received PPI therapy. The logistic regression analysis showed that age, albumin, history of previous hepatic encephalopathy (HE), and the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score were independent risk factors for HE in patients with decompensated cirrhosis [odds ratio (OR) = 1.07, 95% CI: 1.03–1.12, p = 0.001; OR = 1.13, 95% CI: 1.04–1.24, p = 0.006; OR = 242.52, 95% CI: 40.17–1464.11, p < 0.001; and OR = 2.89, 95% CI: 2.11–3.96, p < 0.001, respectively]. Previous severe liver injury and previous bacterial infections were independent risk factors for spontaneous bacterial peritonitis (SBP) in patients with decompensated cirrhosis (OR = 3.43, 95% CI: 1.16–10.17, p = 0.026 and OR = 6.47, 95% CI: 2.29–18.29, p < 0.001, respectively). The multivariate Cox proportional hazards regression model showed that the type and dose of the PPI used were not related to 28-day and 90-day mortality in cirrhosis patients with AD or ACLF.

Conclusion: PPI use does not appear to increase mortality or the risk of HE and SBP in the hospitalized cirrhosis patients with and without ACLF.
Optimal Detection of Fusion Pore Dynamics Using Polarized Total Internal Reflection Fluorescence Microscopy
Authors: Nikolaus Joerg , Hancock Kasey , Tsemperouli Maria , Baddeley David , Karatekin Erdem
Published: November 2021

The fusion pore is the initial narrow connection that forms between fusing membranes. During vesicular release of hormones or neurotransmitters, the nanometer-sized fusion pore may open-close repeatedly (flicker) before resealing or dilating irreversibly, leading to kiss-and-run or full-fusion events, respectively. Pore dynamics govern vesicle cargo release and the mode of vesicle recycling, but the mechanisms are poorly understood. This is partly due to a lack of reconstituted assays that combine single-pore sensitivity and high time resolution. Total internal reflection fluorescence (TIRF) microscopy offers unique advantages for characterizing single membrane fusion events, but signals depend on effects that are difficult to disentangle, including the polarization of the excitation electric field, vesicle size, photobleaching, orientation of the excitation dipoles of the fluorophores with respect to the membrane, and the evanescent field depth. Commercial TIRF microscopes do not allow control of excitation polarization, further complicating analysis. To overcome these challenges, we built a polarization-controlled total internal reflection fluorescence (pTIRF) microscope and monitored fusion of proteoliposomes with planar lipid bilayers with single molecule sensitivity and ∼15 ms temporal resolution. Using pTIRF microscopy, we detected docking and fusion of fluorescently labeled small unilamellar vesicles, reconstituted with exocytotic/neuronal v-SNARE proteins (vSUVs), with a supported bilayer containing the cognate t-SNAREs (tSBL). By varying the excitation polarization angle, we were able to identify a dye-dependent optimal polarization at which the fluorescence increase upon fusion was maximal, facilitating event detection and analysis of lipid transfer kinetics. An improved algorithm allowed us to estimate the size of the fusing vSUV and the fusion pore openness (the fraction of time the pore is open) for every event. For most events, lipid transfer was much slower than expected for diffusion through an open pore, suggesting that fusion pore flickering limits lipid release. We find a weak correlation between fusion pore openness and vesicle area. The approach can be used to study mechanisms governing fusion pore dynamics in a wide range of membrane fusion processes.
An Integrative Pan-Cancer Analysis of PBK in Human Tumors
Authors: Wen Huantao , Chen Zitao , Li Min , Huang Qiongzhen , Deng Yuhao , Zheng Jiawei , Xiong Moliang , Wang Pengfei , Zhang Wangming
Published: November 2021

Background: PDZ binding kinase (PBK) is a serine/threonine kinase, which belongs to the mitogen-activated protein kinase kinase (MAPKK) family. It has been shown to be a critical gene in the regulation of mitosis and tumorigenesis, but the role of PBK in various cancers remains unclear. In this study, we systematically explored the prognostic and predictive value of PBK expression in 33 cancer types.

Methods: Public databases including the cBioPortal database, GDSC database, GTEx database, CCLE database, and TCGA database were used to detect the PBK expression and its association with the prognosis, clinicopathologic stage, TMB, MSI, immune microenvironment, immune checkpoints, immune cell infiltration, enrichment pathways, and IC50 across pan-cancer. The statistical analyses and visualization were conducted using R software.

Results: PBK expression is relatively high in most cancers compared to their normal counterparts, and this gene is barely expressed in normal tissues. High expression of PBK is significantly associated with poor prognosis and clinicopathologic stages I, II, and III in different cancers. Furthermore, PBK expression is strongly associated with TMB in 23 cancer types and associated with MSI in nine cancer types. Moreover, the correlation analysis of the microenvironment and immune cells indicated that PBK is negatively correlated with the immune infiltration levels but positively correlated with the infiltration levels of M0 and M1 macrophages, T cells CD4 memory activated, and T cells follicular helper. GSEA analysis revealed that the biological function or pathways relevant to the cell cycle and mitosis were frequently enriched at the level of high expression of PBK.

Conclusion: These results revealed the oncogenic role of PBK, which is significantly upregulated in various cancers and indicated poor prognosis and immune infiltration in multiple cancers. It also suggested that PBK may serve as a biomarker in multiple tumor progress and patient survival.
Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio in Patients With Newly Diagnosed Moyamoya Disease: A Cross-Sectional Study
Authors: Ma Wenyuan , Cui Changmeng , Feng Song , Li Genhua , Han Guangkui , Liu Jilan , Qin Xianyun , Hu Yawei , Wang Mengjie , Zhang Lu , Jin Feng
Published: November 2021

Inflammation has been proven to be one of the key factors in the pathogenesis of moyamoya disease (MMD). Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are cheap and reliable biomarkers of inflammation. Nevertheless, evidence regarding the relationship among PLR and NLR in patients with MMD is limited. The focus of this subject was to explore the relationship between PLR and NLR in patients with newly diagnosed MMD.

Patients and methods: A cross-sectional study was performed including 261 patients with diagnosed MMD for the first time who were enrolled from our hospital, from 24 March 2013 to 24 December 2018. The clinical characteristics were collected for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were showed.

Results: The mean levels or median values (interquartile range) of PLR and NLR were 146.979 ± 51.203 and 2.241 (1.589–2.984), respectively. A significant positive correlation between PLR and NLR levels (P < 0.001) was showed by the univariate analysis. Furthermore, a non-linear relationship was detected between PLR and NLR by smooth curve fitting after adjusting for potential confounders. A multivariate piecewise linear regression model revealed a significant positive correlation between PLR and NLR when the PLR level was lower than 219.82 (β 0.012, 95% CI 0.005, 0.019; P = 0.001). PLR was also significantly positively associated with NLR when PLR concentrations were >219.82 (β 0.098, 95% CI 0.069, 0.128; P < 0.001).

Conclusion: There seemed to be a positive association between PLR and NLR in patients with MMD. This may help to further explain the role of inflammation in the occurrence and progress of MMD.
Transplanted Human Oligodendrocyte Progenitor Cells Restore Neurobehavioral Deficits in a Rat Model of Preterm White Matter Injury
Authors: Wang Xiaohua , Zang Jing , Yang Yinxiang , Lu Siliang , Guan Qian , Ye Dou , Wang Zhaoyan , Zhou Haipeng , Li Ke , Wang Qian , Wu Youjia , Luan Zuo
Published: November 2021

Background: Preterm white matter injury (PWMI) is a common brain injury and a leading cause of life-long neurological deficits in premature infants; however, no effective treatment is available yet. This study aimed to investigate the fate and effectiveness of transplanted human oligodendrocyte progenitor cells (hOPCs) in a rat model of PWMI.

Methods: Hypoxia-ischemia was induced in rats at postnatal day 3, and hOPCs (6 × 105 cells/5 μL) were intracerebroventricularly transplanted at postnatal day 7. Neurobehavior was assessed 12 weeks post-transplant using the CatWalk test and Morris water maze test. Histological analyses, as well as immunohistochemical and transmission electron microscopy, were performed after transcardial perfusion.

Results: Transplanted hOPCs survived for 13 weeks in PWMI brains. They were widely distributed in the injured white matter, and migrated along the corpus callosum to the contralateral hemisphere. Notably, 82.77 ± 3.27% of transplanted cells differentiated into mature oligodendrocytes, which produced myelin around the axons. Transplantation of hOPCs increased the fluorescence intensity of myelin basic protein and the thickness of myelin sheaths as observed in immunostaining and transmission electron microscopy, while it reduced white matter atrophy at the level of gross morphology. With regard to neurobehavior, the CatWalk test revealed improved locomotor function and inter-paw coordination after transplantation, and the cognitive functions of hOPC-transplanted rats were restored as revealed by the Morris water maze test.

Conclusions: Myelin restoration through the transplantation of hOPCs led to neurobehavioral improvements in PWMI rats, suggesting that transplanting hOPCs may provide an effective and promising therapeutic strategy in children with PWMI.
The Brainstem-Informed Autism Framework: Early Life Neurobehavioral Markers
Authors: Burstein Or , Geva Ronny
Published: November 2021

Autism spectrum disorders (ASD) have long-term implications on functioning at multiple levels. In this perspective, we offer a brainstem-informed autism framework (BIAF) that traces the protracted neurobehavioral manifestations of ASD to early life brainstem dysfunctions. Early life brainstem-mediated markers involving functions of autonomic/arousal regulation, sleep-wake homeostasis, and sensorimotor integration are delineated. Their possible contributions to the early identification of susceptible infants are discussed. We suggest that the BIAF expands our multidimensional understanding of ASD by focusing on the early involvement of brainstem systems. Importantly, we propose an integrated BIAF screener that brings about the prospect of a sensitive and reliable early life diagnostic scheme for weighing the risk for ASD. The BIAF screener could provide clinicians substantial gains in the future and may carve customized interventions long before the current DSM ASD phenotype is manifested using dyadic co-regulation of brainstem-informed autism markers.
First Line and Second Line Chemotherapy in Advanced Cholangiocarcinoma and Impact of Dose Reduction of Chemotherapy: A Retrospective Analysis
Authors: Möhring Christian , Feder Jan , Mohr Raphael U. , Sadeghlar Farsaneh , Bartels Alexandra , Mahn Robert , Zhou Taotao , Marinova Milka , Feldmann Georg , Brossart Peter , von Websky Martin , Matthaei Hanno , Manekeller Steffen , Glowka Tim , Kalff Jörg C. , Weismüller Tobias J. , Strassburg Christian P. , Gonzalez-Carmona Maria A.
Published: November 2021

Objective

Prognosis of patients with irresectable cholangiocarcinoma is still poor. The ABC-02 trial established the current first line (1L) standard systemic chemotherapy (CT) with gemcitabine/platinum derivate for advanced cholangiocarcinoma. However, the majority of patients needed therapy adaptions. Thus, the aim of this study was to evaluate 1L and second line (2L) therapy regimens and the impact of therapy adaptions in an unselected real-life cohort of patients with advanced cholangiocarcinoma.

Materials and Methods

This is a single institution retrospective analysis of patients with irresectable cholangiocarcinoma who were treated with gemcitabine/platinum derivate from 2010 to 2018. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially with regard to CT de-escalation.

Results

Fifty-eight patients receiving gemcitabine/platinum derivate were included in the analysis. Median OS and PFS were 12.2 and 6.9 months. Interestingly, 41 patients (71%) needed therapy de-escalation. However, despite reduced CT exposition, there was no-significant difference in OS (10.8 months vs. 15.6 months, p = 0.127), and patients suffered from less adverse events during CT. 21 (36%) patients reached 2L CT, most often with FOLFIRI (57%). Survival beyond the end of 1L CT was 7.1 months with 2L CT vs. 2.9 months with BSC.

Conclusion

In our study, the combination of gemcitabine/platinum derivate showed similar OS and PFS as randomized prospective phase II/III trials. Therapy regimen adaptions were needed in the majority of patients. However, individualized modifications of the therapy regimen allowed better tolerance as well as continuation of therapy and did not significantly influence median OS. Furthermore, our study revealed a potential survival benefit with 2L CT for selected patients.
Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma
Authors: Yang Yang , Li Guangbing , Lu Ziwen , Liu Yong , Kong Junjie , Liu Jun
Published: November 2021

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Due to the lack of efficient tools for early detection, asymptomatic HCC patients are diagnosed at an advanced stage, leading to a poor prognosis. To improve survival, serum biomarker prothrombin induced by vitamin K absence-II (PIVKA-II) was under investigation. PIVKA-II is an abnormal protein produced in HCC. The coagulation function was insufficient due to the lack of Gla residues. Elevated PIVKA-II was associated with bad tumor behavior in terms of proliferation, metastasis, and invasion. Three major signaling pathways were proposed to clarify the mechanism. With the advantages including affordability, minimal invasiveness, convenience, and efficiency, PIVKA-II could improve HCC management consisting of four aspects. First, PIVKA-II was an effective and dynamic tool for improving HCC surveillance in high-risk population. Changes in the serum levels of PIVKA-II provided valuable molecular alteration information before imaging discovery. Second, PIVKA-II offered a complementary approach for HCC early detection. Compared to traditional diagnostic approaches, the combination of PIVKA-II and other biomarkers had better performance. Third, PIVKA-II was an indicator for the assessment of response to treatment in HCC. Preoperative assessment was for selecting personalized therapy, and postoperative measurement was for assessing treatment efficacy. Fourth, PIVKA-II was considered as a prognostic predictor for HCC. Patients with elevated PIVKA-II were more likely to develop microvascular invasion, metastasis, and recurrence.
Plasma-Derived Extracellular Vesicles Circular RNAs Serve as Biomarkers for Breast Cancer Diagnosis
Authors: Lin Li , Cai Geng-Xi , Zhai Xiang-Ming , Yang Xue-Xi , Li Min , Li Kun , Zhou Chun-Lian , Liu Tian-Cai , Han Bo-Wei , Liu Zi-Jia , Chen Mei-Qi , Ye Guo-Lin , Wu Ying-Song , Guo Zhi-Wei
Published: November 2021

Breast cancer is the second cause of cancer-associated death among women and seriously endangers women’s health. Therefore, early identification of breast cancer would be beneficial to women’s health. At present, circular RNA (circRNA) not only exists in the extracellular vesicles (EVs) in plasma, but also presents distinct patterns under different physiological and pathological conditions. Therefore, we assume that circRNA could be used for early diagnosis of breast cancer. Here, we developed classifiers for breast cancer diagnosis that relied on 259 samples, including 144 breast cancer patients and 115 controls. In the discovery stage, we compared the genome-wide long RNA profiles of EVs in patients with breast cancer (n=14) and benign breast (n=6). To further verify its potential in early diagnosis of breast cancer, we prospectively collected plasma samples from 259 individuals before treatment, including 144 breast cancer patients and 115 controls. Finally, we developed and verified the predictive classifies based on their circRNA expression profiles of plasma EVs by using multiple machine learning models. By comparing their circRNA profiles, we found 439 circRNAs with significantly different levels between cancer patients and controls. Considering the cost and practicability of the test, we selected 20 candidate circRNAs with elevated levels and detected their levels by quantitative real-time polymerase chain reaction. In the training cohort, we found that BCExoC, a nine-circRNA combined classifier with SVM model, achieved the largest AUC of 0.83 [95% CI 0.77-0.88]. In the validation cohort, the predictive efficacy of the classifier achieved 0.80 [0.71-0.89]. Our work reveals the application prospect of circRNAs in plasma EVs as non-invasive liquid biopsies in the diagnosis and management of breast cancer.
Evaluating Cancer-Related Biomarkers Based on Pathological Images: A Systematic Review
Authors: Xie Xiaoliang , Wang Xulin , Liang Yuebin , Yang Jingya , Wu Yan , Li Li , Sun Xin , Bing Pingping , He Binsheng , Tian Geng , Shi Xiaoli
Published: November 2021

Many diseases are accompanied by changes in certain biochemical indicators called biomarkers in cells or tissues. A variety of biomarkers, including proteins, nucleic acids, antibodies, and peptides, have been identified. Tumor biomarkers have been widely used in cancer risk assessment, early screening, diagnosis, prognosis, treatment, and progression monitoring. For example, the number of circulating tumor cell (CTC) is a prognostic indicator of breast cancer overall survival, and tumor mutation burden (TMB) can be used to predict the efficacy of immune checkpoint inhibitors. Currently, clinical methods such as polymerase chain reaction (PCR) and next generation sequencing (NGS) are mainly adopted to evaluate these biomarkers, which are time-consuming and expansive. Pathological image analysis is an essential tool in medical research, disease diagnosis and treatment, functioning by extracting important physiological and pathological information or knowledge from medical images. Recently, deep learning-based analysis on pathological images and morphology to predict tumor biomarkers has attracted great attention from both medical image and machine learning communities, as this combination not only reduces the burden on pathologists but also saves high costs and time. Therefore, it is necessary to summarize the current process of processing pathological images and key steps and methods used in each process, including: (1) pre-processing of pathological images, (2) image segmentation, (3) feature extraction, and (4) feature model construction. This will help people choose better and more appropriate medical image processing methods when predicting tumor biomarkers.
Integrative Analysis of Epigenome and Transcriptome Data Reveals Aberrantly Methylated Promoters and Enhancers in Hepatocellular Carcinoma
Authors: Huang Peng , Xu Mengxiang , Han Haijun , Zhao Xinyi , Li Ming D. , Yang Zhongli
Published: November 2021

DNA methylation is a key transcription regulator, whose aberration was ubiquitous and important in most cancers including hepatocellular carcinoma (HCC). Whole-genome bisulfite sequencing (WGBS) was conducted for comparison of DNA methylation in tumor and adjacent tissues from 33 HCC patients, accompanying RNA-seq to determine differentially methylated region-associated, differentially expressed genes (DMR-DEGs), which were independently replicated in the TCGA-LIHC cohort and experimentally validated via 5-aza-2-deoxycytidine (5-azadC) demethylation. A total of 9,867,700 CpG sites showed significantly differential methylation in HCC. Integrations of mRNA-seq, histone ChIP-seq, and WGBS data identified 611 high-confidence DMR-DEGs. Enrichment analysis demonstrated activation of multiple molecular pathways related to cell cycle and DNA repair, accompanying repression of several critical metabolism pathways such as tyrosine and monocarboxylic acid metabolism. In TCGA-LIHC, we replicated about 53% of identified DMR-DEGs and highlighted the prognostic significance of combinations of methylation and expression of nine DMR-DEGs, which were more efficient prognostic biomarkers than considering either type of data alone. Finally, we validated 22/23 (95.7%) DMR-DEGs in 5-azadC-treated LO2 and/or HepG2 cells. In conclusion, integration of epigenome and transcriptome data depicted activation of multiple pivotal cell cycle-related pathways and repression of several metabolic pathways triggered by aberrant DNA methylation of promoters and enhancers in HCC.
Premalignant Changes in the Bronchial Epithelium Are Prognostic Factors of Distant Metastasis in Non-Small Cell Lung Cancer Patients
Authors: Pankova Olga V. , Tashireva Liubov A. , Rodionov Evgeny O. , Miller Sergey V. , Tuzikov Sergey A. , Pismenny Dmitry S. , Gerashchenko Tatiana S. , Zavyalova Marina V. , Vtorushin Sergey V. , Denisov Evgeny V. , Perelmuter Vladimir M.
Published: November 2021

Background

The study assessed the possibility of dividing patients into groups based on the assessment of morphological changes in the epithelium of small-caliber bronchi located near the primary tumor in order to predict high and low risks of distant metastasis of non-small cell lung cancer.

Methods

In 171 patients with non-small cell lung cancer (T1-4N0-3M0) in small-caliber bronchi taken at a distance of 3–5 cm from the tumor, various variants of morphological changes in the bronchial epithelium (basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia (D)) were assessed. Long-term results of treatment, namely, distant metastasis, were assessed after 2 and 5 years.

Results

During the follow-up period, distant metastases were found in 35.1% (60/171) of patients. Most often, they were observed in patients of the high-risk group: BCH+SM−D− (51.6%, 40/95) and BCH−SM+D+ (54.4%, 6/11). Less often, distant metastases were observed in low-risk group patients: BCH+SM+D− (6.7%, 3/45) and BCH−SM−D− (10.0%, 2/20). Tumor size, grade, and stage were significant predictors of metastasis only in the high-risk group. The 5-year metastasis-free survival was better in the low-risk group of distant metastases.

Conclusions

Isolated BCH or dysplasia in small bronchi distant from foci of tumor is associated with a high-risk distant metastasis and less 5-year metastasis-free survival.
TERT Promoter Mutations and rs2853669 Polymorphism: Useful Markers for Clinical Outcome Stratification of Patients With Oral Cavity Squamous Cell Carcinoma
Authors: Giunco Silvia , Boscolo-Rizzo Paolo , Rampazzo Enrica , Tirelli Giancarlo , Alessandrini Lara , Di Carlo Roberto , Rossi Marco , Nicolai Piero , Menegaldo Anna , Carraro Valentina , Tofanelli Margherita , Bandolin Luigia , Spinato Giacomo , Emanuelli Enzo , Mantovani Monica , Stellin Marco , Bussani Rossana , Dei Tos Angelo Paolo , Guido Maria , Morello Marzia , Fussey Jonathan , Esposito Giovanni , Polesel Jerry , De Rossi Anita
Published: November 2021

Objective

To date, no useful prognostic biomarker exists for patients with oral squamous cell carcinoma (OCSCC), a tumour with uncertain biological behaviour and subsequent unpredictable clinical course. We aim to investigate the prognostic significance of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of telomerase reverse transcriptase (TERT) gene and the impact of TERT single nucleotide polymorphism (SNP) rs2853669 in patients surgically treated for OCSCC.

Methods

The genetic frequencies of rs2853669, -124 C>T and -146 C>T as well as the telomere length were investigated in 144 tumours and 57 normal adjacent mucosal (AM) specimens from OCSCC patients.

Results

Forty-five tumours harboured TERT promoter mutations (31.3%), with -124 C>T and -146 C>T accounting for 64.4% and 35.6% of the alterations respectively. Patients with -124 C>T TERT promoter mutated tumours had the shortest telomeres in the AM (p=0.016) and showed higher risk of local recurrence (hazard ratio [HR]:2.75, p=0.0143), death (HR:2.71, p=0.0079) and disease progression (HR:2.71, p=0.0024) with the effect being potentiated by the co-occurrence of T/T genotype of rs2853669.

Conclusion

-124 C>T TERT promoter mutation as well as the T/T genotype of the rs2853669 SNP are attractive independent prognostic biomarkers in patients surgically treated for OCSCC, with the coexistence of these genetic variants showing a synergistic impact on the aggressiveness of the disease.
Age and Gender-Specific Reference Intervals for Uric Acid Level in Children Aged 5–14 Years in Southeast Zhejiang Province of China: Hyperuricemia in Children May Need Redefinition
Authors: Dai Chengjun , Wang Chaoban , Xia Fangqin , Liu Zishuo , Mo Yiqi , Shan Xiaoou , Zhou Yonghai
Published: November 2021

Context: Hyperuricemia is defined when the plasma uric acid concentration is above 416 μmol/L (7 mg/dl) in male adults, or 357 μmol/L (6 mg/dl) in female adults. However, there are no explicit criteria yet for children.

Objective: It is necessary to set up reference intervals for the uric acid level in different age groups among children.

Materials and Methods: A total of 5,439 individuals (3,258 males, 2,181 females) were included in the final statistical analysis. Reference values of all age groups were determined by statistical descriptions. Multiple linear regression analysis was applied to determine the relationship between uric acid level, BMI, and age.

Results: The level of uric acid increased with age. Gender differences in uric acid level occurred after the onset of puberty. Additionally, linear regression revealed a positive correlation between the uric acid level and BMI.

Discussion and Conclusion: The reference range of the uric acid level in children is inconsistent with the previous viewpoint. Body mass index plays an important role in uric acid metabolism.
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs
Authors: Al-Hussaini Abdulrahman , AlSaleem Badr , AlHomaidani Hamad , Asery Ali , Alruwaithi Muhanad , Alameer Mohammed , Afashah Waleed , Salman Bashir Muhammed , Almontashiri Naif
Published: November 2021

Background: There are only a few case reports and small case series on neonatal-onset Dubin–Johnson syndrome (DJS), particularly from Far-East Asia, Iranian and Moroccan Jews, and Europe.

Objectives: In this first study from the Arabs and the largest series reported to date, we characterized the clinical, laboratory, and molecular features and outcome of gene-confirmed neonatal-onset DJS.

Methods: We reviewed our database of 533 cases of neonatal cholestasis that presented to our center during the period from 2008 to 2019. We identified neonates with a disease-causing mutation in ABCC2 gene.

Results: Twenty-eight neonates with DJS were diagnosed (5.3%). All of the 28 were full-term, well looking neonates without hepatosplenomegaly, with cholestasis, and normal liver synthetic function since the 1 week of life that resolved within 3–6 months of age, followed by a benign course punctuated by recurrent episodes of jaundice in 43% during a median follow up period of 9.25 (range 2.5–14 years). Alanine aminotransferase levels were within normal range in 26 patients (92%) and mildly elevated in two patients. ALT levels were significantly lower in neonates with DJS than in other cases with neonatal cholestasis from other causes (p < 0.001). The median urinary coproporphyrin I% was 88% (IQ1–IQ3 = 84.2–92.7%). We identified four homozygous variants in the ABCC2 gene (from 22 unrelated families), one splicing variant (c.3258+1G>A; p.?), and three were missense variants; two of which were novel missense variants [c.1594G>A (p.Glu532Lys) and c.2439G>C (p.Lys813Asn)]. The p.Gly758Val mutation has occurred in 23 patients (from 19 unrelated families).

Conclusions: Our study suggests that normal ALT-cholestasis in a well-looking neonate should trigger evaluation for DJS. The p.Gly758Val variant in ABCC2 is the most predominant mutation among Arabs with “founder effects.” Identification of the predominant ABCC2 variant in any population is likely to facilitate rapid molecular analysis by future targeting of that specific mutation.
Distinguishing Between Multisystem Inflammatory Syndrome, Associated With COVID-19 in Children and the Kawasaki Disease: Development of Preliminary Criteria Based on the Data of the Retrospective Multicenter Cohort Study
Authors: Kostik Mikhail M. , Bregel Liudmila V. , Avrusin Ilia S. , Dondurei Elena A. , Matyunova Alla E. , Efremova Olesya S. , Isupova Eugenia A. , Kornishina Tatiana L. , Masalova Vera V. , Snegireva Ludmila S. , Shprakh Vladimir V. , Kozlov Yuri A. , Kalashnikova Olga V. , Chasnyk Vyacheslav G.
Published: November 2021

Objectives: Diagnostic between multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) and Kawasaki disease (KD) can make difficulties due to many similarities. Our study aimed to create a Kawasaki/MIS-C differentiation score (KMDscore) allowing discrimination of MIS-C and KD.

Study design: The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about MIS-C (n = 72) and KD (n = 147). The variables allowed to discriminate both conditions used to construct and validate the diagnostic score called the KMDscore.

Results: Patients with MIS-C were older, had earlier admission to the hospital, had a shorter time before fever resolution, two times frequently had signs of GI and CNS involvement observed, and had more impressive thrombocytopenia, higher level of CRP, ferritin, ALT, AST, LDH, creatinine, triglycerides, troponin, and D-dimer compared to KD patients. Respiratory signs in MIS-C were presented with pleuritis, acute respiratory distress syndrome, oxygen dependency, lung infiltration, and ground-glass opacities in CT. The heart involvement with fast progression of myocarditis provided the severity of MIS-C and ICU admission due to 12 times higher arterial hypotension or shock and required cardiotonic. No differences in the frequency of CA lesions were seen in the majority of cases. Five criteria, CRP >11 mg/dl (18 points), D-dimer >607 ng/ml (27 points), age >5 years (30 points), thrombocytopenia (25 points), and GI involvement (28 points), were included in the KMDscore. The summa >55 points allowed to discriminate MIS-C from KD with a sensitivity of 87.5% and specificity of 89.1%.

Conclusion: The KMDscore can be used to differentiate the diagnostic of MIS-C from KD.
Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone
Authors: Proczka Michał , Przybylski Jacek , Cudnoch-Jędrzejewska Agnieszka , Szczepańska-Sadowska Ewa , Żera Tymoteusz
Published: November 2021

Vasopressin (AVP) is a key neurohormone involved in the regulation of body functions. Due to its urine-concentrating effect in the kidneys, it is often referred to as antidiuretic hormone. Besides its antidiuretic renal effects, AVP is a potent neurohormone involved in the regulation of arterial blood pressure, sympathetic activity, baroreflex sensitivity, glucose homeostasis, release of glucocorticoids and catecholamines, stress response, anxiety, memory, and behavior. Vasopressin is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus and released into the circulation from the posterior lobe of the pituitary gland together with a C-terminal fragment of pro-vasopressin, known as copeptin. Additionally, vasopressinergic neurons project from the hypothalamus to the brainstem nuclei. Increased release of AVP into the circulation and elevated levels of its surrogate marker copeptin are found in pulmonary diseases, arterial hypertension, heart failure, obstructive sleep apnoea, severe infections, COVID-19 due to SARS-CoV-2 infection, and brain injuries. All these conditions are usually accompanied by respiratory disturbances. The main stimuli that trigger AVP release include hyperosmolality, hypovolemia, hypotension, hypoxia, hypoglycemia, strenuous exercise, and angiotensin II (Ang II) and the same stimuli are known to affect pulmonary ventilation. In this light, we hypothesize that increased AVP release and changes in ventilation are not coincidental, but that the neurohormone contributes to the regulation of the respiratory system by fine-tuning of breathing in order to restore homeostasis. We discuss evidence in support of this presumption. Specifically, vasopressinergic neurons innervate the brainstem nuclei involved in the control of respiration. Moreover, vasopressin V1a receptors (V1aRs) are expressed on neurons in the respiratory centers of the brainstem, in the circumventricular organs (CVOs) that lack a blood-brain barrier, and on the chemosensitive type I cells in the carotid bodies. Finally, peripheral and central administrations of AVP or antagonists of V1aRs increase/decrease phrenic nerve activity and pulmonary ventilation in a site-specific manner. Altogether, the findings discussed in this review strongly argue for the hypothesis that vasopressin affects ventilation both as a blood-borne neurohormone and as a neurotransmitter within the central nervous system.
Virchow’s Triad and the Role of Thrombosis in COVID-Related Stroke
Authors: Gonzalez-Gonzalez Francisco J. , Ziccardi Mary Rodriguez , McCauley Mark D.
Published: November 2021

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as a virally transmitted disease. Three months later, SARS-CoV-2 became one of the largest pandemics in recent times, causing more than 235 million cases globally, and accounting for at least 4.8 million deaths to date. SARS-COV-2 infection was initially classified as a respiratory tract infection, but later was recognized as a multisystemic disease compromising gastrointestinal, hematological, cardiac, and neurological systems. With this Review, we aim to describe the epidemiology, risk factors, mechanisms, and management of cerebrovascular events in patients infected with COVID-19. Neurological manifestations related to thromboembolic cerebrovascular events in patients infected with COVID-19 have been frequent and associated with poor prognosis in the majority of cases. A better understanding of the mechanisms of thrombosis and etiologies of this new disease process are necessary to determine how to prevent and treat patients to reduce their length of stay, morbidity, and mortality.
Research on the Influence Mechanism of Personal Initiative on Enterprise Emergency Management Ability
Authors: Li Shuang , Xu Feng , Xu Zhengquan , Kang Yuqing , Yang Qifeng
Published: November 2021

This study aims to explore the influence mechanism of personal initiative on the overall emergency management ability of enterprises so as to put forward effective measures to improve the emergency management ability. Based on social interaction theory and feature activation theory, the concepts of organizational support theory, executive power, and political skills were introduced to construct a corresponding theoretical model. We collected data through an online questionnaire to test this model via structural equation model analysis and regression analysis, with 208 participants of varying backgrounds. The results show that personal initiative can strengthen enterprise emergency management ability. The mediating effect of executive power between personal initiative and emergency management ability of enterprise has also been proved. In addition, the two adjustment variables of political skills and perceived organizational support both have a positive impact on the improvement of personal initiative and execution. Therefore, in order to improve the enterprise emergency management ability, it is suggested that enterprises should give full play to the personal initiative and improve the individual and overall executive power. The conclusion of this paper can provide new methodological support for improving emergency management ability.
The Future of Coaching: A Conceptual Framework for the Coaching Sector From Personal Craft to Scientific Process and the Implications for Practice and Research
Authors: Passmore Jonathan , Evans-Krimme Rosie
Published: November 2021

This conceptual paper explores the development of coaching, as an expression of applied positive psychology. It argues that coaching is a positive psychology dialogue which has probably existed since the emergence of sophisticated forms of language, but only in the past few 1000years, has evidence emerged of its use as a deliberate practice to enhance learning. In the past 50years, this dialectic tool has been professionalised, through the emergence of professional bodies, and the introduction of formal training and certification. In considering the development of the coaching industry, we have used Rostow’s model of sector development to reflect on future possible pathways and the changes in the coaching industry with the clothing sector, to understand possible futures. We have offered a five-stage model to conceptualise this pathway of development. Using this insight, we have further reviewed past research and predicted future pathways for coaching research, based on a new ten-phase model of coaching research.
Visual and Verbal Processes in Right-Left Confusion: Psychometric and Experimental Approaches
Authors: Tagami Ubuka , Imaizumi Shu
Published: November 2021

Errors in discriminating right from left, termed right-left confusion, reflect a failure in translating visuospatial perceptions into verbal representation of right or left (i.e., visuo-verbal process). There may also be verbo-visual process, where verbal cues are translated into visual representations of space. To quantify these two processes underlying right-left confusion, Study 1 investigated the factor structure of the Right-Left Confusability Scale, which assesses daily experiences of right-left confusion. Exploratory factor analysis suggested that these two processes and another factor reflecting mental rotation underlie right-left confusion. Study 2 examined correlations between the (sub)scale scores and performance on orientation judgment tasks reflecting visuo-verbal and verbo-visual processes. Overall, self-reported measures were not associated with the behavioral performances presumably reflecting the two processes. These results suggest that the cognitive mechanisms underlying right-left confusion can be classified into visuo-verbal and verbo-visual processes and mental rotation, although their psychometric and behavioral indices might be distinct. Further studies may develop better assessments of right-left confusion reflecting these processes.