bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Clinical Responses to Tislelizumab as a First-Line Therapy for Primary Hepatocellular Carcinoma With B-Cell Indolent Lymphoma
Authors: Li Qijun , Dong Yong , Pan Yubin , Tang Honglin , Li Da
Published: March 2021

Background

As an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin’s lymphoma (NHL) is rare, especially in the treatment of ICIs.

Case presentation

A 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment.

Conclusion

Tislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.
Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension
Authors: Li Min , Riddle Suzette , Kumar Sushil , Poczobutt Joanna , McKeon B. Alexandre , Frid Maria G. , Ostaff Maureen , Reisz Julie A. , Nemkov Travis , Fini Mehdi A. , Laux Aya , Hu Cheng-Jun , El Kasmi Karim C. , D’Alessandro Angelo , Brown R. Dale , Zhang Hui , Stenmark Kurt R.
Published: March 2021

The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.
Increased Circulating T Follicular Helper Cells Induced via IL-12/21 in Patients With Acute on Chronic Hepatitis B Liver Failure
Authors: Du Bingying , Teng Jiaming , Yin Rongkun , Tian Yuanyuan , Jiang Tingwang , Du Yanan , Cai Wei
Published: March 2021

Objectives

T Follicular helper (Tfh) cells, recognized as a distinct CD4+ T cell subset, mediate the development of long-lived humoral immunity via B cell activation/differentiation. Tfh cells play an important role during hepatic viral infection, but its role in hepatitis B virus-related acute on chronic liver failure (HBV-ACLF) remains to be explored.

Materials and Methods

The frequency of Tfh cells, serum pro-inflammatory cytokine (IL-12, IL-21, IL-17 and TNF) levels and IgG/M levels were investigated in HBV-ACLF (n = 36), serious chronic hepatitis B (n = 21), moderate chronic hepatitis B patients (n = 32) and healthy control (HC) subjects (n = 10).

Results

Circulating Tfh cells were significantly increased in HBV-ACLF patients compared to other groups, correlating well with MELD score. However, the frequency of Tfh cells decreased in ameliorated HBV-ACLF patients. Furthermore, serum IL-12 and IL-21 levels were higher in HBV-ACLF patients, compared to other groups. Naïve CD4+ T cells from HC subjects differentiate into Tfh cells following treatment with HBV-ACLF patients’ serum, a process that can be blocked by IL-12/21 neutralizing antibodies. Tfh cells induced by HBV-ACLF patient’s serum promoted the proliferation and IgG production of B cells in vitro. Moreover, circulating CD19+ B cells, serum and liver IgG/M levels were significantly higher in HBV-ACLF patients, compared to other groups.

Conclusions

Our data demonstrated that there was a high frequency of Tfh cells and high levels of serum IL-12/21 in HBV-ACLF patients. Naïve CD4+ T cells differentiate into Tfh cells in the presence of HBV-ACLF patients’ serum rich in IL-12/21, which can be blocked by neutralizing IL-12/21 antibodies. These data may provide useful insights for both clinical and basic research in the treatment of HBV-ACLF.
Serum Heparin-Binding Protein as a Potential Biomarker to Distinguish Adult-Onset Still’s Disease From Sepsis
Authors: Tian Rui , Chen Xia , Yang Chengde , Teng Jialin , Qu Hongping , Liu Hong-Lei
Published: March 2021

Adult-onset Still’s disease (AOSD) is a systemic, multifactorial, autoinflammatory disease for which the etiopathogenesis is not well understood. Given the similarities in clinical and laboratory features between this disease and sepsis, and the differences in treatment strategies for these two diseases, specific diagnostic markers are crucial for the correct diagnosis and management of AOSD. Previous studies have shown plasma heparin-binding protein (HBP) is a promising potential biomarker for AOSD; thus, this study aimed to detect serum HBP levels in patients with AOSD or sepsis to assess its potential as a biomarker for differential diagnosis. We found that serum HBP levels were significantly higher in patients with active AOSD than that in those with inactive AOSD. Patients with sepsis had higher serum HBP levels compared with those who had active or inactive AOSD. We calculated the area under the receiver operating characteristic (ROC) curve to assess whether HBP could be used to differentiate active from inactive AOSD; this was 0.811 with sensitivity 0.650, specificity 0.811, and cutoff HBP value of 35.59 ng/ml. The area under the ROC curve for HBP as a biomarker to differentiate AOSD from sepsis was 0.653, with sensitivity 0.759, and specificity 0.552, and cutoff HBP value of 65.1 ng/ml. Taken together, the results of our study suggest that serum HBP could be a useful diagnostic biomarker to evaluate disease activity in patients with AOSD, and to differentiate AOSD from sepsis.
γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde
Authors: Li Yunxuan , Zhang Yixi , Zeng Xun
Published: March 2021

γδ T cells are distributed in various lymphoid and nonlymphoid tissues, and act as early responders in many conditions. Previous studies have proven their significant roles in infection, cancer, autoimmune diseases and tissue maintenance. Recently, accumulating researches have highlighted the crosstalk between γδ T cells and nervous systems. In these reports, γδ T cells maintain some physiological functions of central nervous system by secreting interleukin (IL) 17, and neurons like nociceptors can in turn regulate the activity of γδ T cells. Moreover, γδ T cells are involved in neuroinflammation such as stroke and multiple sclerosis. This review illustrates the relationship between γδ T cells and nervous systems in physiological and pathological conditions.
A Family Affair: Addressing the Challenges of Factor H and the Related Proteins
Authors: Poppelaars Felix , Goicoechea de Jorge Elena , Jongerius Ilse , Baeumner Antje J. , Steiner Mark-Steven , Józsi Mihály , Toonen Erik J. M. , Pauly Diana ,   the SciFiMed consortium
Published: March 2021

Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement dysregulation: the human Factor H (FH) family. This group of proteins consists of FH, Factor H-like protein 1 and five Factor H-related proteins. The FH family has been linked to infectious, vascular, eye, kidney and autoimmune diseases. In contrast to FH, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive. In this perspective review, we address the major challenges ahead in this emerging area, including 1) the controversies about the functional roles of the FH protein family, 2) the discrepancies in quantification of the FH protein family, 3) the unmet needs for validated tools and 4) limitations of animal models. Next, we also discuss the opportunities that exist for the immunology community. A strong multidisciplinary approach is required to solve these obstacles and is only possible through interdisciplinary collaboration between biologists, chemists, geneticists and physicians. We position this review in light of our own perspective, as principal investigators of the SciFiMed Consortium, a consortium aiming to create a comprehensive analytical system for the quantitative and functional assessment of the entire FH protein family.
Sodium-Dependent Phosphate Transporter Protein 1 Is Involved in the Active Uptake of Inorganic Phosphate in Nephrocytes of the Kidney and the Translocation of Pi Into the Tubular Epithelial Cells in the Outer Mantle of the Giant Clam, Tridacna squamosa
Authors: Ip Yuen K. , Boo Mel V. , Poo Jeslyn S. T. , Wong Wai P. , Chew Shit F.
Published: March 2021

Giant clams display light-enhanced inorganic phosphate (Pi) absorption, but how the absorbed Pi is translocated to the symbiotic dinoflagellates living extracellularly in a tubular system is unknown. They can accumulate Pi in the kidney, but the transport mechanism remains enigmatic. This study aimed to elucidate the possible functions of sodium-dependent phosphate transporter protein 1-homolog (PiT1-like), which co-transport Na+ and H2PO4–, in these two processes. The complete cDNA coding sequence of PiT1-like, which comprised 1,665 bp and encoded 553 amino acids (59.3 kDa), was obtained from the fluted giant clam, Tridacna squamosa. In the kidney, PiT1-like was localized in the plasma membrane of nephrocytes, and could therefore absorb Pi from the hemolymph. As the gene and protein expression levels of PiT1-like were up-regulated in the kidney during illumination, PiT1-like could probably increase the removal of Pi from the hemolymph during light-enhanced Pi uptake. In the ctenidial epithelial cells, PiT1-like had a basolateral localization and its expression was also light-dependent. It might function in Pi sensing and the absorption of Pi from the hemolymph when Pi was limiting. In the outer mantle, PiT1-like was localized in the basolateral membrane of epithelial cells forming the tertiary tubules. It displayed light-enhanced expression levels, indicating that the host could increase the translocation of Pi from the hemolymph into the tubular epithelial cells and subsequently into the luminal fluid to support increased Pi metabolism in the photosynthesizing dinoflagellates. Taken together, the accumulation of Pi in the kidney of giant clams might be unrelated to limiting the availability of Pi to the symbionts to regulate their population.
Antiviral Activity of Interferon Alpha-Inducible Protein 27 Against Hepatitis B Virus Gene Expression and Replication
Authors: Ullah Hafiz , Sajid Muhammad , Yan Kun , Feng Jiangpeng , He Miao , Shereen Muhammad Adnan , Li Qiaohong , Xu Tianmo , Hao Ruidong , Guo Deyin , Chen Yu , Zhou Limin , Zhou Li
Published: March 2021

Despite the availability of effective vaccines, hepatitis B virus (HBV) is still a major health issue, and approximately 350 million people have been chronically infected with HBV throughout the world. Interferons (IFNs) are the key molecules in the innate immune response that restrict several kinds of viral infections via the induction of hundreds of IFN-stimulated genes (ISGs). The objective of this study was to confirm if interferon alpha-inducible protein 27 (IFI27) as an ISG could inhibit HBV gene expression and DNA replication both in cell culture and in a mouse model. In human hepatoma cells, IFI27 was highly induced by the stimulation of IFN-alpha (IFN-α), and it potentiated the anti-HBV activity. The overexpression of IFI27 inhibited, while its silencing enhanced the HBV replication in HepG2 cell. However, the knocking out of IFI27 in HepG2 cells robustly increases the formation of viral DNA, RNA, and proteins. Detailed mechanistic analysis of the HBV genome showed that a sequence [nucleotide (nt) 1715–1815] of the EnhII/Cp promoter was solely responsible for viral inhibition. Similarly, the hydrodynamic injection of IFI27 expression constructs along with the HBV genome into mice resulted in a significant reduction in viral gene expression and DNA replication. In summary, our studies suggested that IFI27 contributed a vital role in HBV gene expression and replication and IFI27 may be a potential antiviral agent for the treatment of HBV.
Management and Prognosis of Interstitial Lung Disease With Lung Cancer (ILD-LC): A Real-World Cohort From Three Medical Centers in China
Authors: Xiaohong Xie , Liqiang Wang , Na Li , Xinqing Lin , Yinyin Qin , Ming Liu , Ming Ouyang , Qian Han , Qun Luo , Shiyue Li , Chunyan Li , Xiaoqian Wang , Shuanying Yang , Wei Huang , Mei Liu , Ping Wang , Chengzhi Zhou
Published: March 2021

Background and Objective

Interstitial lung disease with lung cancer (ILD-LC) is rare and its management has not been fully described. This study aimed to investigate the management and prognosis of ILD-LC patients in China.

Methods

The present analysis is a retrospective real-world cohort study. Clinical data of ILD-LC patients were obtained from 3 hospitals in China. The overall survival (OS) of patients was analyzed. Univariate and multivariate regression analyses were performed.

Results

One hundred eighty-four ILD-LC patients included were biased toward male (85.3%), smokers (75.5%), idiopathic pulmonary fibrosis (IPF) (58.2%) patients with comorbidities (67.9%) and ECOG-PS score of 1 (65.2%). Most patients were advanced peripheral non-small cell lung cancer. The initial anti-cancer regimen for ILD-LC is mainly chemotherapy, and patients with early-stage LC prefer surgery. In the anti-cancer cohort, the number of ILD-LC patients who underwent the 2nd and 3rd or more anti-cancer regimens were 78 (55.7%) and 32 (22.8%), respectively. In the non-anticancer cohort, the median OS was 3.5 months. In the early-stage cohort, the median OS was 14.2 months in the systematic therapy group; however, the median OS was not reached in the surgery group. In the advanced-stage cohort with systematic therapy, the median OS was 7.2 months. Interstitial pneumonia (IIP) and anti-angiogenesis were associated with OS in the univariate analysis, whereas anti-angiogenesis was an independent protective factor for advanced LC with ILD.

Conclusion

Patients with ILD-LC have very poor prognosis. Appropriate anti-tumor treatment can prolong the survival time of patients who can tolerate it. Targeted therapy and immunotherapy are alternative treatments for LC patients with mild ILD. For ILD patients with advanced LC, antiangiogenic regimens significantly improve the prognosis of the disease.
Gray Matter Atrophy in Amnestic Mild Cognitive Impairment: A Voxel-Based Meta-Analysis
Authors: Zhang Jinhuan , Liu Yongfeng , Lan Kai , Huang Xingxian , He Yuhai , Yang Fuxia , Li Jiaying , Hu Qingmao , Xu Jinping , Yu Haibo
Published: March 2021

Background: Voxel-based morphometry (VBM) has been widely used to investigate structural alterations in amnesia mild cognitive impairment (aMCI). However, inconsistent results have hindered our understanding of the exact neuropathology related to aMCI.

Objectives: Our aim was to systematically review the literature reporting VBM on aMCI to elucidate consistent gray matter alterations, their functional characterization, and corresponding co-activation patterns.

Methods: The PubMed, Web of Science, and EMBASE databases were searched for VBM studies on aMCI published from inception up to June 2020. Peak coordinates were extracted from clusters that showed significant gray matter differences between aMCI patients and healthy controls (HC). Meta-analysis was performed using seed-based d mapping with the permutation of subject images (SDM-PSI), a newly improved meta-analytic method. Functional characterization and task-based co-activation patterns using the BrainMap database were performed on significant clusters to explore their functional roles. Finally, VBM was performed based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to further support the findings.

Results: A total of 31 studies with 681 aMCI patients and 837 HC were included in this systematic review. The aMCI group showed significant gray matter atrophy in the left amygdala and right hippocampus, which was consistent with results from the ADNI dataset. Functional characterization revealed that these regions were mainly associated with emotion, cognition, and perception. Further, meta-regression analysis demonstrated that gray matter atrophy in the left inferior frontal gyrus and the left angular gyrus was significantly associated with cognitive impairment in the aMCI group.

Conclusions: The findings of gray matter atrophy in the left amygdala and right hippocampus are highly consistent and robust, and not only offer a better understanding of the underlying neuropathology but also provide accurate potential biomarkers for aMCI.
Deep Learning-Based Classification of GAD67-Positive Neurons Without the Immunosignal
Authors: Yamashiro Kotaro , Liu Jiayan , Matsumoto Nobuyoshi , Ikegaya Yuji
Published: March 2021

Excitatory neurons and GABAergic interneurons constitute neural circuits and play important roles in information processing. In certain brain regions, such as the neocortex and the hippocampus, there are fewer interneurons than excitatory neurons. Interneurons have been quantified via immunohistochemistry, for example, for GAD67, an isoform of glutamic acid decarboxylase. Additionally, the expression level of other proteins varies among cell types. For example, NeuN, a commonly used marker protein for postmitotic neurons, is expressed differently across brain regions and cell classes. Thus, we asked whether GAD67-immunopositive neurons can be detected using the immunofluorescence signals of NeuN and the fluorescence signals of Nissl substances. To address this question, we stained neurons in layers 2/3 of the primary somatosensory cortex (S1) and the primary motor cortex (M1) of mice and manually labeled the neurons as either cell type using GAD67 immunosignals. We then sought to detect GAD67-positive neurons without GAD67 immunosignals using a custom-made deep learning-based algorithm. Using this deep learning-based model, we succeeded in the binary classification of the neurons using Nissl and NeuN signals without referring to the GAD67 signals. Furthermore, we confirmed that our deep learning-based method surpassed classic machine-learning methods in terms of binary classification performance. Combined with the visualization of the hidden layer of our deep learning algorithm, our model provides a new platform for identifying unbiased criteria for cell-type classification.
Transcriptome Analysis of NPFR Neurons Reveals a Connection Between Proteome Diversity and Social Behavior
Authors: Ryvkin Julia , Bentzur Assa , Shmueli Anat , Tannenbaum Miriam , Shallom Omri , Dokarker Shiran , Benichou Jennifer I. C. , Levi Mali , Shohat-Ophir Galit
Published: March 2021

Social behaviors are mediated by the activity of highly complex neuronal networks, the function of which is shaped by their transcriptomic and proteomic content. Contemporary advances in neurogenetics, genomics, and tools for automated behavior analysis make it possible to functionally connect the transcriptome profile of candidate neurons to their role in regulating behavior. In this study we usedDrosophila melanogasterto explore the molecular signature of neurons expressing receptor for neuropeptide F (NPF), the fly homolog of neuropeptide Y (NPY). By comparing the transcription profile of NPFR neurons to those of nine other populations of neurons, we discovered that NPFR neurons exhibit a unique transcriptome, enriched with receptors for various neuropeptides and neuromodulators, as well as with genes known to regulate behavioral processes, such as learning and memory. By manipulating RNA editing and protein ubiquitination programs specifically in NPFR neurons, we demonstrate that the proper expression of their unique transcriptome and proteome is required to suppress male courtship and certain features of social group interaction. Our results highlight the importance of transcriptome and proteome diversity in the regulation of complex behaviors and pave the path for future dissection of the spatiotemporal regulation of genes within highly complex tissues, such as the brain.
Approach-Avoidance Decisions Under Threat: The Role of Autonomic Psychophysiological States
Authors: Livermore James J. A. , Klaassen Felix H. , Bramson Bob , Hulsman Anneloes M. , Meijer Sjoerd W. , Held Leslie , Klumpers Floris , de Voogd Lycia D. , Roelofs Karin
Published: March 2021

Acutely challenging or threatening situations frequently require approach-avoidance decisions. Acute threat triggers fast autonomic changes that prepare the body to freeze, fight or flee. However, such autonomic changes may also influence subsequent instrumental approach-avoidance decisions. Since defensive bodily states are often not considered in value-based decision-making models, it remains unclear how they influence the decision-making process. Here, we aim to bridge this gap by discussing the existing literature on the potential role of threat-induced bodily states on decision making and provide a new neurocomputational framework explaining how these effects can facilitate or bias approach-avoid decisions under threat. Theoretical accounts have stated that threat-induced parasympathetic activity is involved in information gathering and decision making. Parasympathetic dominance over sympathetic activity is particularly seen during threat-anticipatory freezing, an evolutionarily conserved response to threat demonstrated across species and characterized by immobility and bradycardia. Although this state of freezing has been linked to altered information processing and action preparation, a full theoretical treatment of the interactions with value-based decision making has not yet been achieved. Our neural framework, which we term the Threat State/Value Integration (TSI) Model, will illustrate how threat-induced bodily states may impact valuation of competing incentives at three stages of the decision-making process, namely at threat evaluation, integration of rewards and threats, and action initiation. Additionally, because altered parasympathetic activity and decision biases have been shown in anxious populations, we will end with discussing how biases in this system can lead to characteristic patterns of avoidance seen in anxiety-related disorders, motivating future pre-clinical and clinical research.
Atrophy in the Left Amygdala Predicted Drug Responses in Idiopathic Generalized Epilepsy Patients With Tonic–Clonic Seizures
Authors: Li Xin , Wang Zhongyuan , Chen Qian , Wang Xiaoyun , Qing Zhao , Zhang Wen , Lu Jiaming , Wang Junxia , Zhang Xin , Liu Jiani , Wang Zhengge , Li Baoxin , Zhang Bing
Published: March 2021

We aimed to determine the alterations in the subcortical structures of patients with idiopathic generalized epilepsy with tonic–clonic seizures (IGE-GTCS) via MRI volumetry and vertex-based shape analysis and to evaluate the relationships between MRI measures and drug responses. In a follow-up sample of 48 patients with IGE-GTCS and 48 matched normal controls (NCs), high-resolution 3D T1WI was performed at baseline. After 1 year of follow-up, 31 patients were classified as seizure free (SF) and 17 as drug resistant (DR). The volumes of subcortical structures were extracted, and vertex-based shape analysis was performed using FSL-Integrated Registration and Segmentation Toolbox (FSL-FIRST). Comparisons among groups were calculated adjusting for covariates [age, sex, and intracranial volume (ICV)]. Analysis of the relationships among imaging biomarkers along with frequency and duration was assessed using partial correlations. The differential imaging indicators were used as features in a linear support vector machine (LSVM). The DR group displayed significant regional atrophy in the volume of the left amygdala compared with NCs (p = 0.004, false discovery rate corrected) and SF patients (p = 0.029, uncorrected). Meanwhile, vertex-based shape analysis showed focal inward deformation in the basolateral subregion of the left amygdala in DR compared with the results for SF and NC (p < 0.05, FWE corrected). There were significant correlations between the volume changes and seizure frequency (r = −0.324, p = 0.030) and between shape (r = −0.438, p = 0.003) changes and seizure frequency. Moreover, the volume of the left thalamus in the DR group was significantly correlated with seizure frequency (r = −0.689, p = 0.006). The SVM results revealed areas under the receiver operating characteristic curve of 0.82, 0.68, and 0.88 for the classification between SF and DR, between SF and NC, and between DR and NC, respectively. This study indicates the presence of focal atrophy in the basolateral region of the left amygdala in patients with IGE drug resistance; this finding may help predict drug responses and suggests a potential therapeutic target.
Galvanic Vestibular Stimulation Produces Cross-Modal Improvements in Visual Thresholds
Authors: Voros Jamie L. , Sherman Sage O. , Rise Rachel , Kryuchkov Alexander , Stine Ponder , Anderson Allison P. , Clark Torin K.
Published: March 2021

Background

Stochastic resonance (SR) refers to a faint signal being enhanced with the addition of white noise. Previous studies have found that vestibular perceptual thresholds are lowered with noisy galvanic vestibular stimulation (i.e., “in-channel” SR). Auditory white noise has been shown to improve tactile and visual thresholds, suggesting “cross-modal” SR.

Objective

We investigated galvanic vestibular white noise (nGVS) (n = 9 subjects) to determine the cross-modal effects on visual and auditory thresholds.

Methods

We measured auditory and visual perceptual thresholds of human subjects across a swath of different nGVS levels in order to determine if some individual-subject determined best nGVS level elicited a reduction in thresholds as compared the no noise condition (sham).

Results

We found improvement in visual thresholds (by an average of 18%, p = 0.014). Subjects with higher (worse) visual thresholds with no stimulation (sham) improved more than those with lower thresholds (p = 0.04). Auditory thresholds were unchanged by vestibular stimulation.

Conclusion

These results are the first demonstration of cross-modal improvement with galvanic vestibular stimulation, indicating galvanic vestibular white noise can produce cross-modal improvements in some sensory channels, but not all.
Radiomics Analysis Based on Contrast-Enhanced MRI for Prediction of Therapeutic Response to Transarterial Chemoembolization in Hepatocellular Carcinoma
Authors: Zhao Ying , Wang Nan , Wu Jingjun , Zhang Qinhe , Lin Tao , Yao Yu , Chen Zhebin , Wang Man , Sheng Liuji , Liu Jinghong , Song Qingwei , Wang Feng , An Xiangbo , Guo Yan , Li Xin , Wu Tingfan , Liu Ai Lian
Published: March 2021

Purpose

To investigate the role of contrast-enhanced magnetic resonance imaging (CE-MRI) radiomics for pretherapeutic prediction of the response to transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).

Methods

One hundred and twenty-two HCC patients (objective response, n = 63; non-response, n = 59) who received CE-MRI examination before initial TACE were retrospectively recruited and randomly divided into a training cohort (n = 85) and a validation cohort (n = 37). All HCCs were manually segmented on arterial, venous and delayed phases of CE-MRI, and total 2367 radiomics features were extracted. Radiomics models were constructed based on each phase and their combination using logistic regression algorithm. A clinical-radiological model was built based on independent risk factors identified by univariate and multivariate logistic regression analyses. A combined model incorporating the radiomics score and selected clinical-radiological predictors was constructed, and the combined model was presented as a nomogram. Prediction models were evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis.

Results

Among all radiomics models, the three-phase radiomics model exhibited better performance in the training cohort with an area under the curve (AUC) of 0.838 (95% confidence interval (CI), 0.753 - 0.922), which was verified in the validation cohort (AUC, 0.833; 95% CI, 0.691 - 0.975). The combined model that integrated the three-phase radiomics score and clinical-radiological risk factors (total bilirubin, tumor shape, and tumor encapsulation) showed excellent calibration and predictive capability in the training and validation cohorts with AUCs of 0.878 (95% CI, 0.806 - 0.950) and 0.833 (95% CI, 0.687 - 0.979), respectively, and showed better predictive ability (P = 0.003) compared with the clinical-radiological model (AUC, 0.744; 95% CI, 0.642 - 0.846) in the training cohort. A nomogram based on the combined model achieved good clinical utility in predicting the treatment efficacy of TACE.

Conclusion

CE-MRI radiomics analysis may serve as a promising and noninvasive tool to predict therapeutic response to TACE in HCC, which will facilitate the individualized follow-up and further therapeutic strategies guidance in HCC patients.
Characterizing the Genomic Landscape of Brain Glioma With Circulating Tumor DNA From Tumor In Situ Fluid
Authors: Sheng Zhiyuan , Yu Jinliang , Deng Kaiyuan , Andrade-Barazarte Hugo , Zemmar Ajmal , Li Sijia , Li Nianxuan , Yan Zhaoyue , Chen Zhongcan , Sun Yong , Hernesniemi Juha , Bu Xingyao
Published: March 2021

Tumor in situ fluid (TISF) refers to the fluid at the local surgical cavity. We evaluated the feasibility of TISF-derived circulating tumor DNA (ctDNA) characterizing the genomic landscape for glioma. This retrospective study included TISF and tumor samples from 10 patients with glioma, we extracted cell-free DNA (cfDNA) from the TISF and then performed deep sequencing on that. And we compared genomic alterations between TISF and tumor tissue. Results showed that the concentration of cfDNA fragments from the patients for TISF ranged from 7.2 to 1,397 ng/ml. At least one tumor-specific mutation was identified in all 10 patients (100%). Further analysis of TISF ctDNA revealed a broad spectrum of genetic mutations, which have been reported to have clinical relevance. The analysis of concordance between TISF and tumor tissue reflected the spatiotemporal heterogeneity of glioma. Collectively, TISF ctDNA was a powerfully potential source for characterizing the genomic landscape of glioma, which provided new possibilities for precision medicine in patients with glioma.
The Biomarker Potential of Caveolin-1 in Penile Cancer
Authors: Panic Andrej , Reis Henning , Wittka Alina , Darr Christopher , Hadaschik Boris , Jendrossek Verena , Klein Diana
Published: March 2021

Various types of human cancers were characterized by an altered expression of epithelial or stromal caveolin-1 (CAV1). However, the clinical significance of CAV1 expression in penile cancer remains largely unknown. Here the expression patterns of CAV1 were analyzed in a retrospective cohort (n=43) of penile squamous cell carcinomas (SCC). Upon penile cancer progression, significantly increased CAV1-levels were determined within the malignant epithelium, whereas within the tumor stroma, namely the fibroblastic tumor compartment harboring activated and/or cancer associated fibroblasts, CAV1 levels significantly decline. Concerning the clinicopathological significance of CAV1 expression in penile cancer as well as respective epithelial-stromal CAV1 distributions, high expression within the tumor cells as well as low expression of CAV1 within the stromal compartment were correlated with decreased overall survival of penile cancer patients. Herein, CAV1 expressions and distributions at advanced penile cancer stages were independent of the immunohistochemically proven tumor protein p53 status. In contrast, less differentiated p16-positive tumor epithelia (indicative for human papilloma virus infection) were characterized by significantly decreased CAV1 levels. Conclusively, we provide further and new evidence that the characteristic shift in stromal‐epithelial CAV1 being functionally relevant to tumor progression even occurs in penile SCC.
Computational Image Analysis Identifies Histopathological Image Features Associated With Somatic Mutations and Patient Survival in Gastric Adenocarcinoma
Authors: Cheng Jun , Liu Yuting , Huang Wei , Hong Wenhui , Wang Lingling , Zhan Xiaohui , Han Zhi , Ni Dong , Huang Kun , Zhang Jie
Published: March 2021

Computational analysis of histopathological images can identify sub-visual objective image features that may not be visually distinguishable by human eyes, and hence provides better modeling of disease phenotypes. This study aims to investigate whether specific image features are associated with somatic mutations and patient survival in gastric adenocarcinoma (sample size = 310). An automated image analysis pipeline was developed to extract quantitative morphological features from H&E stained whole-slide images. We found that four frequently somatically mutated genes (TP53, ARID1A, OBSCN, and PIK3CA) were significantly associated with tumor morphological changes. A prognostic model built on the image features significantly stratified patients into low-risk and high-risk groups (log-rank test p-value = 2.6e-4). Multivariable Cox regression showed the model predicted risk index was an additional prognostic factor besides tumor grade and stage. Gene ontology enrichment analysis showed that the genes whose expressions mostly correlated with the contributing features in the prognostic model were enriched on biological processes such as cell cycle and muscle contraction. These results demonstrate that histopathological image features can reflect underlying somatic mutations and identify high-risk patients that may benefit from more precise treatment regimens. Both the image features and pipeline are highly interpretable to enable translational applications.
Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases
Authors: Wang Kun , Liu Ming , Wang Hong-Wei , Jin Ke-Min , Yan Xiao-Luan , Bao Quan , Xu Da , Wang Li-Jun , Liu Wei , Wang Yan-Yan , Li Juan , Liu Li-Juan , Zhang Xiao-Yu , Yang Chun-He , Jin Ge , Xing Bao-Cai
Published: March 2021

Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21–68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.
Association Between Digoxin Use and Cancer Incidence: A Propensity Score-Matched Cohort Study With Competing Risk Analysis
Authors: Tai Chi-Jung , Yang Yi-Hsin , Tseng Tzyy-Guey , Chang Fang-Rong , Wang Hui-Chun
Published: March 2021

Background: Previous studies neglected death as a critical competing risk while estimating the cancer risk for digoxin users. Therefore, the current study aims to assess the effectiveness of digoxin on cancer prevention by competing risk analysis.

Methods: We performed a population-based retrospective cohort study using the Taiwan National Health Insurance Research database between 1998 and 2010. After one-to-one propensity score-matching from 36,160 patients with defined criteria, we enrolled 758 patients both in digoxin and β-blocker group for further analysis.

Results: The results showed that the digoxin group had higher all-cause mortality than the β-blocker group in the 4- year (10.4 vs. 4.9%) and 8 years (13.6 vs. 7.0%) follow-up. The subdistribution HR of cancer incidence in the digoxin group compared to the β-blocker group was 1.99 (95% confidence interval [CI]: 1.22–3.01) and 1.46 (95% CI: 1.01–2.15) in the 4 years and 8 years follow-up, respectively.

Conclusions: The result of our study showed the usage of digoxin has no benefit in cancer prevention compared with β-blocker. The possibility of β-blocker as a new drug candidate for cancer prevention needs further clinical evaluation. The current study also emphasized the necessity of competing risk analysis applying to similar clinical researches.
Abacavir Increases Purinergic P2X7 Receptor Activation by ATP: Does a Pro-inflammatory Synergism Underlie Its Cardiovascular Toxicity?
Authors: Collado-Díaz Víctor , Martinez-Cuesta Maria Ángeles , Blanch-Ruiz Maria Amparo , Sánchez-López Ainhoa , García-Martínez Patricia , Peris José E , Usach Iris , Ivorra Maria Dolores , Lacetera Alessandra , Martín-Santamaría Sonsoles , Esplugues Juan V. , Alvarez Angeles
Published: March 2021

The cardiovascular toxicity of Abacavir is related to its purinergic structure. Purinergic P2X7-receptors (P2X7R), characterized by activation by high concentrations of ATP and with high plasticity, seem implicated. We appraise the nature of the interplay between Abacavir and P2X7R in generating vascular inflammation. The effects of Abacavir on leukocyte-endothelium interactions were compared with those of its metabolite carbovir triphosphate (CBV-TP) or ATP in the presence of apyrase (ATP-ase) or A804598 (P2X7R-antagonist). CBV-TP and ATP levels were evaluated by HPLC, while binding of Abacavir, CBV-TP and ATP to P2X7R was assessed by radioligand and docking studies. Hypersensitivity studies explored a potential allosteric action of Abacavir. Clinical concentrations of Abacavir (20 µmol/L) induced leukocyte-endothelial cell interactions by specifically activating P2X7R, but the drug did not show affinity for the P2X7R ATP-binding site (site 1). CBV-TP levels were undetectable in Abacavir-treated cells, while those of ATP were unaltered. The effects of Abacavir were Apyrase-dependent, implying dependence on endogenous ATP. Exogenous ATP induced a profile of proinflammatory actions similar to Abacavir, but was not entirely P2X7R-dependent. Docking calculations suggested ATP-binding to sites 1 and 2, and Abacavir-binding only to allosteric site 2. A combination of concentrations of Abacavir (1 µmol/L) and ATP (0.1 µmol/L) that had no effect when administered separately induced leukocyte-endothelium interactions mediated by P2X7R and involving Connexin43 channels. Therefore, Abacavir acts as a positive allosteric modulator of P2X7R, turning low concentrations of endogenous ATP themselves incapable of stimulating P2X7R into a functional proinflammatory agonist of the receptor.
Treatment Outcomes of Extensively Drug-Resistant Tuberculosis in Pakistan: A Countrywide Retrospective Record Review
Authors: Abubakar Muhammad , Ahmad Nafees , Ghafoor Abdul , Latif Abdullah , Ahmad Izaz , Atif Muhammad , Saleem Fahad , Khan Shereen , Khan Amjad , Khan Amer Hayat
Published: March 2021

Background: The current study is conducted with the aim to the fill the gap of information regarding treatment outcomes and variables associated with unsuccessful outcome among XDR-TB patients from Pakistan.

Methods: A total of 404 culture confirmed XDR-TB patients who received treatment between 1st May 2010 and June 30, 2017 at 27 treatment centers all over Pakistan were retrospectively followed until their treatment outcomes were reported. A p-value <0.05 reflected a statistical significant association.

Results: The patients had a mean age 32.9 ± 14.1 years. The overall treatment success rate was 40.6% (95% confidence interval [CI]:35.80–45.60%). A total of 155 (38.4%) patients were declared cured, 9 (2.2%) completed treatment, 149 (36.9%) died, 60 (14.9%) failed treatment and 31 (7.7%) were lost to follow up (LTFU). The results of the multivariate binary logistic regression analysis revealed that the patients’ age of >60 years (OR = 4.69, 95%CI:1.57–15.57) and receiving high dose isoniazid (OR = 2.36, 95%CI:1.14–4.85) had statistically significant positive association with death, whereas baseline body weight >40 kg (OR = 0.43, 95%CI:0.25–0.73) and sputum culture conversion in the initial two months of treatment (OR = 0.33, 95%CI:0.19–0.58) had statistically significant negative association with death. Moreover, male gender had statistically significant positive association (OR = 1.92, 95%CI:1.04–3.54) with LTFU.

Conclusion: The treatment success rate (40.6%) of XDR-TB patients in Pakistan was poor. Providing special attention and enhanced clinical management to patients with identified risk factors for death and LTFU in the current cohort may improve the treatment outcomes.
The Placebo and Nocebo Responses in Clinical Trials in Inflammatory Bowel Diseases
Authors: Enck Paul , Klosterhalfen Sibylle
Published: March 2021

Placebo and nocebo responses are mostly discussed in clinical trials with functional bowel disorders. Much less has been investigated and is known in gastrointestinal diseases beyond irritable bowel syndrome (IBS), especially in inflammatory bowel diseases (IBD). For the purpose of this review, we screened the Journal of Interdisciplinary Placebo Studies (JIPS) database with approximately 4,500 genuine placebo research articles and identified nine meta-analyses covering more than 135 randomized and placebo-controlled trials (RCTs) with more than 10,000 patients with Crohn´s disease (CD) and another five meta-analyses with 150 RCTs and more than 10,000 patients with ulcerative colitis (UC). Only three discussed nocebo effects, especially in the context of clinical use of biosimilars to treat inflammation. The articles were critically analyzed with respect to the size of the placebo response in CD and UC, its effects on clinical improvement versus maintenance of remission, and mediators and moderators of the response identified. Finally, we discussed and compared the differences and similarities of the placebo responses in IBD and IBS and the nocebo effect in switching from biologics to biosimilars in IBD management.
Diuretic Action of Apelin-13 Mediated by Inhibiting cAMP/PKA/sPRR Pathway
Authors: Chen Yanting , Xu Chuanming , Hu Jiajia , Deng Mokan , Qiu Qixiang , Mo Shiqi , Du Yanhua , Yang Tianxin
Published: March 2021

Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron. During water deprivation (WD), the urine concentrating capability was impaired by an apelin peptide, apelin-13, accompanied by the suppression of the protein expression of aquaporin 2 (AQP2), NKCC2, PRR/sPRR, renin and nuclear β-catenin levels in the kidney. The upregulated expression of AQP2 or PRR/sPRR both induced by AVP and 8-Br-cAMP was blocked by apelin-13, PKA inhibitor (H89), or β-catenin inhibitor (ICG001). Interestingly, the blockage of apelin-13 on AVP-induced AQP2 protein expression was reversed by exogenous sPRR. Together, the present study has defined the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/sPRR pathway in the CD as the molecular target of the diuretic action of apelin.
A New Method for Detecting Myocardial Ischemia Based on ECG T-Wave Area Curve (TWAC)
Authors: Li Ronghua , Zhao Xiaoye , Gong Yinglan , Zhang Jucheng , Dong Ruiqing , Xia Ling
Published: March 2021

In recent years, coronary heart disease (CHD) has become one of the main diseases that endanger human health, with a high mortality and disability rate. Myocardial ischemia (MI) is the main symptom in the development of CHD. Continuous and severe myocardial ischemia will lead to myocardial infarction. The clinical manifestations of MI are mainly the changes of ST-T segment of ECG, that is, ST segment and T wave. Nearly one third of patients with CHD, however, has no obvious ECG changes. In this paper, a new method for detecting MI based on the T-wave area curve (TWAC) was proposed. Through observation and analysis of clinical data, it was found that there exist significant correlation between the morphology of TWAC and MI. The TWAC morphology of normal subject is smooth and gentle, while the TWAC morphology of patients with coronary stenosis is mostly jagged, and the curve becomes more severe with more severe stenosis. The preliminary test results show that the sensitivity, specificity, and accuracy of the proposed method for detecting MI are 84.3, 83.6, and 84%, respectively. This study shows that the TWAC based approach may be an effective method for detecting MI, especially for the CHD patients with no obvious ECG changes.