bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice
Authors: Insuela Daniella Bianchi Reis , Ferrero Maximiliano Ruben , Gonçalves-de-Albuquerque Cassiano Felippe , Chaves Amanda da Silva , da Silva Adriano Yagho Oliveira , Castro-Faria-Neto Hugo Caire , Simões Rafael Loureiro , Barja-Fidalgo Thereza Christina , Silva Patricia Machado Rodrigues e , Martins Marco Aurélio , Silva Adriana Ribeiro , Carvalho Vinicius Frias
Published: July 2021

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxisin vitrowas tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLPin vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophilsin vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxisin vitrowas reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophilsin vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophilsin vitro. Human neutrophil chemotaxis and adherence to endothelial cellsin vitrowere inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.
Combination Therapy With Anti-PD-1 or PD-1 Antibody Alone in Asian Pediatric Patients With Relapsed or Refractory Cancer
Authors: Que Yi , Wang Juan , Zhu Jia , Li Na , Huang Junting , Lu Suying , Sun Feifei , Zhang Lian , Zhen Zijun , Zhang Li , Cai Ruiqing , Guo Haixia , Sun Xiaofei , Zhang Yizhuo
Published: July 2021

There is limited experience of PD-1 antibody combined with other therapies in children. We aimed to explore the antitumor activity and safety of PD-1 antibody monotherapy or combination with other regimens in relapsed or refractory pediatric cancer. This is a retrospective-case study conducted in two Chinese expert centers. The primary objective of this study was to describe the overall response rate (ORR) and disease control rate (DCR). Secondary objectives included characterizing toxicities. Of the 22 pediatric patients with cancer who received PD-1 inhibitors, the median follow-up for all patients after the commencement of PD-1 therapy with or without other regimens was 12.3 months (0 - 43 months). PD-1 antibody monotherapy demonstrated antitumor activity in a population of pediatric patients with Hodgkin lymphoma (HL), with an objective response rate (ORR) and disease control rate (DCR) of 83.3% (3CR and 2PR) and 100%, respectively. However, no objective response was observed in patients with melanoma or Burkitt lymphoma evaluated in this study. We reviewed responses for patients with chemotherapy, decitabine or everolimus combination therapies with PD-1 antibodies, and found that PD-1 antibody combined with decitabine showed potential efficacy in pediatric patients with advanced embryonal rhabdomyosarcoma and lymphoepitheliomatoid-like carcinoma. There were no severe treatment-related adverse events (TRAEs) directly attributed to PD-1 antibody monotherapy in Asian pediatric patients with lower incidence of hematologic toxicity and nonhematologic toxicity. The Grade ≥3 TRAEs were attributed to the combination chemotherapy.
The Effect of Tetanus-Diphtheria-Acellular-Pertussis Immunization During Pregnancy on Infant Antibody Responses: Individual-Participant Data Meta-Analysis
Authors: Abu-Raya Bahaa , Maertens Kirsten , Munoz Flor M. , Zimmermann Petra , Curtis Nigel , Halperin Scott A. , Rots Nynke , Barug Daan , Holder Beth , Kampmann Beate , Leuridan Elke , Sadarangani Manish
Published: July 2021

Background

Immunization with tetanus-diphtheria-acellular pertussis (Tdap) vaccine in pregnancy is increasingly recommended. We determined the effect of Tdap immunization in pregnancy on infants’ vaccine responses.

Methods

Individual-participant data meta-analysis of ten studies (n=1884) investigating infants’ antibody response to routine immunizations following Tdap immunization in pregnancy was performed. Geometric mean ratios (GMRs) of antigen-specific immunoglobulin G (IgG) levels were calculated using mixed-effects models. Seroprotection rates were compared using chi-squared tests.

Results

Infants of Tdap-immunized women had significantly lower IgG against pertussis toxin (GMR 0.65; 95%CI 0.57-0.74), filamentous haemagglutinin (FHA) (0.68; 0.53-0.87), pertactin (0.65; 0.58-0.72) and fimbria 2/3 (FIM2/3) (0.41; 0.32-0.52) after primary immunization, compared with infants of unimmunized women. These lower levels persisted after booster immunization for FHA (0.72; 0.61-0.84) and FIM2/3 (0.53; 0.29-0.96). After primary immunization, infants of Tdap-immunized women had lower seroprotection rates against diphtheria (90% [843/973] vs 98% [566/579]; p<0.001) and invasive pneumococcal disease (IPD) caused by 5 Streptococcus pneumoniae (SPN) serotypes (SPN5, SPN6B, SPN9V, SPN19A, SPN23F), and higher seroprotection rates against Haemophilus influenzae type b (short-term and long-term seroprotection rates, 86%[471/547] vs 76%[188/247] and 62%[337/547] vs 49%(121/247), respectively, all p=0.001). After booster immunization, seroprotection rates against diphtheria and tetanus were 99% (286/288) and (618/619) in infants of Tdap-immunized women, respectively.

Conclusions

Infants of Tdap-immunized women in pregnancy had lower IgG levels against pertussis, diphtheria and some SPN serotypes after their immunization compared with infants of unimmunized women. Enhanced surveillance of pertussis, diphtheria and IPD in infants is needed to determine the clinical significance of these findings.

Systematic Review Registration

CRD42017079171.
Low Growth Hormone Levels Predict Poor Outcome of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure
Authors: Wu Daxian , Zhang Lingjian , Ma Shanshan , Zhao Yalei , Chen Ronggao , Zhang Fen , Liu Qiuhong , Xu Xiaowei , Xie Zhongyang
Published: July 2021

Background and Aims: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) remains a serious entity with high mortality. Growth hormone (GH) is related to the liver metabolism and regeneration. The present study aimed to explore the changes and prognostic efficacy of GH on the outcome of HBV-ACLF.

Methods: A prospective cohort of 124 patients and a cross-sectional cohort of 142 subjects were enrolled. GH and insulin-like growth factor-1(IGF-1) were detected by ELISA. Thirty-day survival was collected and the association between GH and the 30-day mortality of HBV-ACLF was analyzed.

Results: The mean age of the whole prospective cohort was 46.61 ± 12.71 years, and 19 (15.3%) patients were female. The median (IQR) of GH levels in non-survivors were 1106.55 (674.25, 1922.4) pg/ml, which were significantly lower than in survivors (p < 0.001). In the cross-sectional cohort, GH level was significantly higher in liver cirrhosis - acute decompensation (LC-AD) group than liver cirrhosis (LC) group (p < 0.001) while IGF-1 decreased significantly in LC, LC-AD, ACLF groups than health control (HC) and chronic Hepatitis B (CHB) groups (p < 0.001). The area under the receiver operating characteristic curve (AUROC) of GH for predicting 30-day mortality was 0.793. We built a new prognostic model, namely MELD-GH, which showed better predictive efficacy than Child-Pugh, MELD, CLIF-SOFA, and CLIF-C ACLF scores.

Conclusions: Low GH predicted the poor outcome of HBV-ACLF patients. GH and IGF-1 levels were differently distributed among HC, CHB, LC, LC-AD, and ACLF patients. MELD-GH had better predictive accuracy when compared to Child-Pugh, MELD, CLIF-SOFA, and CLIF-C ACLF scores.
Big Data, Data Science, and Causal Inference: A Primer for Clinicians
Authors: Raita Yoshihiko , Camargo Carlos A. , Liang Liming , Hasegawa Kohei
Published: July 2021

Clinicians handle a growing amount of clinical, biometric, and biomarker data. In this “big data” era, there is an emerging faith that the answer to all clinical and scientific questions reside in “big data” and that data will transform medicine into precision medicine. However, data by themselves are useless. It is the algorithms encoding causal reasoning and domain (e.g., clinical and biological) knowledge that prove transformative. The recent introduction of (health) data science presents an opportunity to re-think this data-centric view. For example, while precision medicine seeks to provide the right prevention and treatment strategy to the right patients at the right time, its realization cannot be achieved by algorithms that operate exclusively in data-driven prediction modes, as do most machine learning algorithms. Better understanding of data science and its tasks is vital to interpret findings and translate new discoveries into clinical practice. In this review, we first discuss the principles and major tasks of data science by organizing it into three defining tasks: (1) association and prediction, (2) intervention, and (3) counterfactual causal inference. Second, we review commonly-used data science tools with examples in the medical literature. Lastly, we outline current challenges and future directions in the fields of medicine, elaborating on how data science can enhance clinical effectiveness and inform medical practice. As machine learning algorithms become ubiquitous tools to handle quantitatively “big data,” their integration with causal reasoning and domain knowledge is instrumental to qualitatively transform medicine, which will, in turn, improve health outcomes of patients.
The Pepper Mitogen-Activated Protein Kinase CaMAPK7 Acts as a Positive Regulator in Response to Ralstonia solanacearum Infection
Authors: Shi Lanping , Zhang Kan , Xie Linjing , Yang Mingxing , Xie Baixue , He Shuilin , Liu Zhiqin
Published: July 2021

Mitogen-activated protein kinase (MAPK) pathways play a vital role in multiple plant processes, including growth, development, and stress signaling, but their involvement in response toRalstonia solanacearumis poorly understood, particularly in pepper plants. Herein,CaMAPK7was identified from the pepper genome and functionally analyzed. The accumulations ofCaMAPK7transcripts and promoter activities were both significantly induced in response toR. solanacearumstrain FJC100301 infection, and exogenously applied phytohormones, including methyl jasmonate (MeJA), brassinolide (BR), salicylic acid (SA), and ethephon (ETN), were decreased by abscisic acid (ABA) treatment. Virus-induced gene silencing (VIGS) ofCaMAPK7significantly enhanced the susceptibility of pepper plants to infection byR. solanacearumand downregulated the defense-related marker genes, includingCaDEF1,CaPO2,CaSAR82A, andCaWRKY40. In contrast, the ectopic overexpression ofCaMAPK7in transgenic tobacco enhanced resistance toR. solanacearumand upregulated the defense-associated marker genes, includingNtHSR201,NtHSR203,NtPR4,PR1a/c,NtPR1b,NtCAT1, andNtACC. Furthermore, transient overexpression ofCaMAPK7in pepper leaves triggered intensive hypersensitive response (HR)-like cell death, H2O2accumulation, and enriched CaWRKY40 at the promoters of its target genes and drove their transcript accumulations, includingCaDEF1,CaPO2, andCaSAR82A. Taken together, these data indicate thatR. solanacearuminfection induced the expression ofCaMAPK7, which indirectly modifies the binding of CaWRKY40 to its downstream targets, includingCaDEF1,CaPO2, andCaSAR82A, ultimately leading to the activation of pepper immunity againstR. solanacearum. The protein that responds to CaMAPK7 in pepper plants should be isolated in the future to build a signaling bridge between CaMAPK7 and CaWRKY40.
Tobacco Smoking Increases Methylation of Polypyrimidine Tract Binding Protein 1 Promoter in Intracranial Aneurysms
Authors: Wang Zhepei , Zhou Shengjun , Zhao Jikuang , Nie Sheng , Sun Jie , Gao Xiang , Lenahan Cameron , Lin Zhiqin , Huang Yi , Chen Gao
Published: July 2021

DNA methylation at the gene promoter region is reportedly involved in the development of intracranial aneurysm (IA). This study aims to investigate the methylation levels of polypyrimidine tract-binding protein 1 (PTBP1) in IA, as well as its potential to predict IA. Forty-eight patients with IA and 48 age- and sex-matched healthy controls were recruited into this study. Methylation levels of CpG sites were determined via bisulfite pyrosequencing. The PTBP1 levels in the blood were determined using a real-time quantitative reverse transcription-polymerase chain reaction test. Significant differences were found between IAs and controls in CpG1 (p = 0.001), CpG2 (p < 0.001), CpG3 (p = 0.037), CpG4 (p = 0.003), CpG5 (p = 0.006), CpG6 (p = 0.02), and mean methylation (p < 0.001). The mRNA level of PTBP1 in the blood was much lower in IAs compared with controls (p = 0.002), and the PTBP1 expression was significantly associated with DNA methylation promoter levels in individuals (r = −0.73, p < 0.0001). In addition, stratification analysis comparing smokers and non-smokers revealed that tobacco smokers had significantly higher levels of DNA methylation in PTBP1 than non-smokers (p = 0.002). However, no statistical difference in PTBP1 methylation was found between ruptured and unruptured IA groups (p > 0.05). The ROC analyses of curves revealed that PTBP1 methylation may be a predictor of IA regardless of sex (both sexes, area under curve (AUC) = 0.78, p < 0.0001; male, AUC = 0.76, p = 0.002; female, AUC = 0.79, p < 0.0001). These findings suggest that long-term tobacco smoke exposure led to DNA methylation in the promoter region of the PTBP1 gene, which further decreased PTBP1 gene expression and participated in the pathogenesis of IA. The methylation of PTBP1 may be a potential predictive marker for the occurrence of IA.
Anterior Cingulate Cortex Activity During Rest Is Related to Alterations in Pain Perception in Aging
Authors: Terrasa Juan L. , Montoya Pedro , Sitges Carolina , van der Meulen Marian , Anton Fernand , González-Roldán Ana M.
Published: July 2021

Alterations in the affective component of pain perception are related to the development of chronic pain and may contribute to the increased vulnerability to pain observed in aging. The present study analyzed age-related changes in resting-state brain activity and their possible relation to an increased pain perception in older adults. For this purpose, we compared EEG current source density and fMRI functional-connectivity at rest in older (n = 20, 66.21 ± 3.08 years) and younger adults (n = 21, 20.71 ± 2.30 years) and correlated those brain activity parameters with pain intensity and unpleasantness ratings elicited by painful stimulation. We found an age-related increase in beta2 and beta3 activity in temporal, frontal, and limbic areas, and a decrease in alpha activity in frontal areas. Moreover, older participants displayed increased functional connectivity in the anterior cingulate cortex (ACC) and the insula with precentral and postcentral gyrus. Finally, ACC beta3 activity was positively correlated with pain intensity and unpleasantness ratings in older, and ACC-precentral/postcentral gyrus connectivity was positively correlated with unpleasantness ratings in older and younger participants. These results reveal that ACC resting-state hyperactivity is a stable trait of brain aging and may underlie their characteristic altered pain perception.
Latent Sex Differences in CaMKII-nNOS Signaling That Underlie Antidepressant-Like Effects of Yueju-Ganmaidazao Decoction in the Hippocampus
Authors: Yin Ying , Qian Shiyu , Chen Yifan , Sun Yan , Li Yuqiao , Yu Yongfei , Li Jianqing , Wu Zhangjie , Yu Xinlang , Ge Rui , Han Jia , Sun Dongdong , Wu Haoxin , Liu Lanying , Xue Wenda , Wang Wei
Published: July 2021

Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.
Feel-Good Requirements: Neurophysiological and Psychological Design Criteria of Affective Touch for (Assistive) Robots
Authors: Ege Cansev Mehmet , Nordheimer Daniel , Andrea Kirchner Elsa , Beckerle Philipp
Published: July 2021

Previous research has shown the value of the sense of embodiment, i.e., being able to integrate objects into one's bodily self-representation, and its connection to (assistive) robotics. Especially, tactile interfaces seem essential to integrate assistive robots into one's body model. Beyond functional feedback, such as tactile force sensing, the human sense of touch comprises specialized nerves for affective signals, which transmit positive sensations during slow and low-force tactile stimulations. Since these signals are extremely relevant for body experience as well as social and emotional contacts but scarcely considered in recent assistive devices, this review provides a requirement analysis to consider affective touch in engineering design. By analyzing quantitative and qualitative information from engineering, cognitive psychology, and neuroscienctific research, requirements are gathered and structured. The resulting requirements comprise technical data such as desired motion or force/torque patterns and an evaluation of potential stimulation modalities as well as their relations to overall user experience, e.g., pleasantness and realism of the sensations. This review systematically considers the very specific characteristics of affective touch and the corresponding parts of the neural system to define design goals and criteria. Based on the analysis, design recommendations for interfaces mediating affective touch are derived. This includes a consideration of biological principles and human perception thresholds which are complemented by an analysis of technical possibilities. Finally, we outline which psychological factors can be satisfied by the mediation of affective touch to increase acceptance of assistive devices and outline demands for further research and development.
Development of a Prognostic Five-Gene Signature for Diffuse Lower-Grade Glioma Patients
Authors: Zhang Qiang , Liu Wenhao , Luo Shun-Bin , Xie Fu-Chen , Liu Xiao-Jun , Xu Ren-Ai , Chen Lixi , Su Zhilin
Published: July 2021

Background: Diffuse lower-grade gliomas (LGGs) are infiltrative and heterogeneous neoplasms. Gene signature including multiple protein-coding genes (PCGs) is widely used as a tumor marker. This study aimed to construct a multi-PCG signature to predict survival for LGG patients.

Methods: LGG data including PCG expression profiles and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Survival analysis, receiver operating characteristic (ROC) analysis, and random survival forest algorithm (RSFVH) were used to identify the prognostic PCG signature.

Results: From the training (n = 524) and test (n = 431) datasets, a five-PCG signature which can classify LGG patients into low- or high-risk group with a significantly different overall survival (log rank P < 0.001) was screened out and validated. In terms of prognosis predictive performance, the five-PCG signature is stronger than other clinical variables and IDH mutation status. Moreover, the five-PCG signature could further divide radiotherapy patients into two different risk groups. GO and KEGG analysis found that PCGs in the prognostic five-PCG signature were mainly enriched in cell cycle, apoptosis, DNA replication pathways.

Conclusions: The new five-PCG signature is a reliable prognostic marker for LGG patients and has a good prospect in clinical application.
How Action Shapes Body Ownership Momentarily and Throughout the Lifespan
Authors: Liesner Marvin , Hinz Nina-Alisa , Kunde Wilfried
Published: July 2021

Objects which a human agent controls by efferent activities (such as real or virtual tools) can be perceived by the agent as belonging to his or her body. This suggests that what an agent counts as “body” is plastic, depending on what she or he controls. Yet there are possible limitations for such momentary plasticity. One of these limitations is that sensations stemming from the body (e.g., proprioception) and sensations stemming from objects outside the body (e.g., vision) are not integrated if they do not sufficiently “match”. What “matches” and what does not is conceivably determined by long–term experience with the perceptual changes that body movements typically produce. Children have accumulated less sensorimotor experience than adults have. Consequently, they express higher flexibility to integrate body-internal and body-external signals, independent of their “match” as suggested by rubber hand illusion studies. However, children’s motor performance in tool use is more affected by mismatching body-internal and body-external action effects than that of adults, possibly because of less developed means to overcome such mismatches. We review research on perception-action interactions, multisensory integration, and developmental psychology to build bridges between these research fields. By doing so, we account for the flexibility of the sense of body ownership for actively controlled events and its development through ontogeny. This gives us the opportunity to validate the suggested mechanisms for generating ownership by investigating their effects in still developing and incomplete stages in children. We suggest testable predictions for future studies investigating both body ownership and motor skills throughout the lifespan.
Altered Effective Connectivity of Children and Young Adults With Unilateral Amblyopia: A Resting-State Functional Magnetic Resonance Imaging Study
Authors: Dai Peishan , Zhou Xiaoyan , Ou Yilin , Xiong Tong , Zhang Jinlong , Chen Zailiang , Zou Beiji , Wei Xin , Wu Ying , Xiao Manyi
Published: July 2021

The altered functional connectivity (FC) in amblyopia has been investigated by many studies, but the specific causality of brain connectivity needs to be explored further to understand the brain activity of amblyopia. We investigated whether the effective connectivity (EC) of children and young adults with amblyopia was altered. The subjects included 16 children and young adults with left eye amblyopia and 17 healthy controls (HCs). The abnormalities between the left/right primary visual cortex (PVC) and the other brain regions were investigated in a voxel-wise manner using the Granger causality analysis (GCA). According to the EC results in the HCs and the distribution of visual pathways, 12 regions of interest (ROIs) were selected to construct an EC network. The alteration of the EC network of the children and young adults with amblyopia was analyzed. In the voxel-wise manner analysis, amblyopia showed significantly decreased EC between the left/right of the PVC and the left middle frontal gyrus/left inferior frontal gyrus compared with the HCs. In the EC network analysis, compared with the HCs, amblyopia showed significantly decreased EC from the left calcarine fissure, posterior cingulate gyrus, left lingual gyrus, right lingual gyrus, and right fusiform gyrus to the right calcarine fissure. Amblyopia also showed significantly decreased EC from the right inferior frontal gyrus and right lingual gyrus to the left superior temporal gyrus compared with the HCs in the EC network analysis. The results may indicate that amblyopia altered the visual feedforward and feedback pathway, and amblyopia may have a greater relevance with the feedback pathway than the feedforward pathway. Amblyopia may also correlate with the feedforward of the third visual pathway.
Orofacial Neuropathic Pain-Basic Research and Their Clinical Relevancies
Authors: Shinoda Masamichi , Imamura Yoshiki , Hayashi Yoshinori , Noma Noboru , Okada-Ogawa Akiko , Hitomi Suzuro , Iwata Koichi
Published: July 2021

Trigeminal nerve injury is known to cause severe persistent pain in the orofacial region. This pain is difficult to diagnose and treat. Recently, many animal studies have reported that rewiring of the peripheral and central nervous systems, non-neuronal cell activation, and up- and down-regulation of various molecules in non-neuronal cells are involved in the development of this pain following trigeminal nerve injury. However, there are many unknown mechanisms underlying the persistent orofacial pain associated with trigeminal nerve injury. In this review, we address recent animal data regarding the involvement of various molecules in the communication of neuronal and non-neuronal cells and examine the possible involvement of ascending pathways in processing pathological orofacial pain. We also address the clinical observations of persistent orofacial pain associated with trigeminal nerve injury and clinical approaches to their diagnosis and treatment.
Prediction Along a Developmental Perspective in Psychiatry: How Far Might We Go?
Authors: Nees Frauke , Deserno Lorenz , Holz Nathalie E. , Romanos Marcel , Banaschewski Tobias
Published: July 2021

Most mental disorders originate in childhood, and once symptoms present, a variety of psychosocial and cognitive maladjustments may arise. Although early childhood problems are generally associated with later mental health impairments and psychopathology, pluripotent transdiagnostic trajectories may manifest. Possible predictors range from behavioral and neurobiological mechanisms, genetic predispositions, environmental and social factors, and psychopathological comorbidity. They may manifest in altered neurodevelopmental trajectories and need to be validated capitalizing on large-scale multi-modal epidemiological longitudinal cohorts. Moreover, clinical and etiological variability between patients with the same disorders represents a major obstacle to develop effective treatments. Hence, in order to achieve stratification of patient samples opening the avenue of adapting and optimizing treatment for the individual, there is a need to integrate data from multi-dimensionally phenotyped clinical cohorts and cross-validate them with epidemiological cohort data. In the present review, we discuss these aspects in the context of externalizing and internalizing disorders summarizing the current state of knowledge, obstacles, and pitfalls. Although a large number of studies have already increased our understanding on neuropsychobiological mechanisms of mental disorders, it became also clear that this knowledge might only be the tip of the Eisberg and that a large proportion still remains unknown. We discuss prediction strategies and how the integration of different factors and methods may provide useful contributions to research and at the same time may inform prevention and intervention.
Aberrant Non-Coding RNA Expressed in Gastric Cancer and Its Diagnostic Value
Authors: Yu Zhilong , Rong ZeYin , Sheng Jinxin , Luo Zai , Zhang Jianming , Li Tengfei , Zhu Zhonglin , Fu Zhongmao , Qiu Zhengjun , Huang Chen
Published: July 2021

Gastric cancer (GC) is one of the digestive tract malignancies with high invasion and mortality rates. Recent studies have reported that non-coding RNAs (ncRNAs) seem to play a crucial part in many tumors. Due to their high stability, ncRNAs may used as novel biomarkers to predict the occurrence and prognosis of GC. Here, we measured miRNA, lncRNA and cirRNA expression profiles of GC patients by using microarray and RNA-sequencing data from tissue samples. The diagnosis prediction model based on the ncRNA signatures and clinical features was evaluated by circulating and tissue validation and ROC analysis. Nine miRNAs and eight lncRNAs were obtained from the microarray analysis. Six miRNAs (miR-550a-5p, miRNA-936, miR-1306-3p, miR-3185, miR-6083, miR-6792-3p) and three lncRNAs (lnc-MB21D1-3:5, lnc-PSCA-4:2 and lnc-ABCC5-2:1) were abnormally expressed in circulating and tissue samples compared with normal control (NC), which was closely related to clinical pathology and survival time of GC patients; circRNA sequencing and qRT-PCR revealed four circRNAs (circASHL2, circCCDC9, circNHSL1 and cirMLLT10) were abnormally expressed in GC tissues and parts of them were negative relationship with their predicted binding miRNAs. These ncRNAs might act as promising molecular markers for the diagnosis and prognosis of gastric cancer.
Preoperative Radiomics Analysis of 1p/19q Status in WHO Grade II Gliomas
Authors: Fan Ziwen , Sun Zhiyan , Fang Shengyu , Li Yiming , Liu Xing , Liang Yucha , Liu Yukun , Zhou Chunyao , Zhu Qiang , Zhang Hong , Li Tianshi , Li Shaowu , Jiang Tao , Wang Yinyan , Wang Lei
Published: July 2021

Purpose

The present study aimed to preoperatively predict the status of 1p/19q based on radiomics analysis in patients with World Health Organization (WHO) grade II gliomas.

Methods

This retrospective study enrolled 157 patients with WHO grade II gliomas (76 patients with astrocytomas with mutant IDH, 16 patients with astrocytomas with wild-type IDH, and 65 patients with oligodendrogliomas with mutant IDH and 1p/19q codeletion). Radiomic features were extracted from magnetic resonance images, including T1-weighted, T2-weighted, and contrast T1-weighted images. Elastic net and support vector machines with radial basis function kernel were applied in nested 10-fold cross-validation loops to predict the 1p/19q status. Receiver operating characteristic analysis and precision-recall analysis were used to evaluate the model performance. Student’s t-tests were then used to compare the posterior probabilities of 1p/19q co-deletion prediction in the group with different 1p/19q status.

Results

Six valuable radiomic features, along with age, were selected with the nested 10-fold cross-validation loops. Five features showed significant difference in patients with different 1p/19q status. The area under curve and accuracy of the predictive model were 0.8079 (95% confidence interval, 0.733–0.8755) and 0.758 (0.6879–0.8217), respectively, and the F1-score of the precision-recall curve achieved 0.6667 (0.5201–0.7705). The posterior probabilities in the 1p/19q co-deletion group were significantly different from the non-deletion group.

Conclusion

Combined radiomics analysis and machine learning showed potential clinical utility in the preoperative prediction of 1p/19q status, which can aid in making customized neurosurgery plans and glioma management strategies before postoperative pathology.
Circular RNA circ-MMP11 Contributes to Lapatinib Resistance of Breast Cancer Cells by Regulating the miR-153-3p/ANLN Axis
Authors: Wu Xiaoli , Ren Yi , Yao Rong , Zhou Leilei , Fan Ruihua
Published: July 2021

Background

Drug-resistance is a major obstacle to the treatment of breast cancer. Circular RNA (circRNA) circ-MMP11 has been reported to be promoting the progression of breast cancer. This study is designed to explore the role and mechanism of circ-MMP11 in lapatinib resistance in breast cancer.

Methods

Circ-MMP11, microRNA-153-3p (miR-153-3p), and Anillin (ANLN) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, number of colonies, apoptosis, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. Exosomes were exerted and detected by differential centrifugation and a transmission electron microscope. The protein levels of CD63, CD9, and ANLN were assessed by western blot assay. The binding relationship between miR-153-3p and circ-MMP11 or ANLN was predicted by circinteractome or starbase, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. The biological role of circ-MMP11 on breast cancer tumor growth and drug resistance was detected by the xenograft tumor model in vivo.

Results

Circ-MMP11 and ANLN were highly expressed, and miR-153-3p was decreased in LR breast cancer tissues and cells. Circ-MMP11 could be transported by exosomes. Furthermore, circ-MMP11 knockdown promoted lapatinib sensitivity by repressing cell viability, colony number, migration, invasion, and boosting apoptosis in LR breast cancer cells. Circ-MMP11 deficiency improved the drug sensitivity of breast cancer in vivo. Mechanically, circ-MMP11 could regulate ANLN expression through sponging miR-153-3p.

Conclusion

Circ-MMP11 could be transferred by exosomes in breast cancer cells. And circ-MMP11 functioned as a sponge of miR-153-3p to regulate ANLN expression, thereby promoting lapatinib resistance in breast cancer cells, providing therapeutic targets for the treatment of breast cancer.
Cucurbitacin B Inhibits Cell Proliferation by Regulating X-Inactive Specific Transcript Expression in Tongue Cancer
Authors: Tao Boqiang , Wang Dongxu , Yang Shuo , Liu Yingkun , Wu Han , Li Zhanjun , Chang Lu , Yang Zhijing , Liu Weiwei
Published: July 2021

Cucurbitacin B (CuB), a natural product, has anti-tumor effects on various cancers. In order to investigate the expression of long non-coding RNAs (lncRNA), we carried out RNA sequencing (RNA-seq) and quantitative PCR (qPCR). The data indicated that CAL27 and SCC9 tongue squamous cell carcinoma (TSCC) cells had reduced expression of X-inactive specific transcript (XIST) after CuB treatment. Moreover, our results showed increased expression of XIST in human tongue cancer. In this study, CuB treatment inhibited proliferation, migration and invasion of SCC9 cells, and induced cellular apoptosis. Interestingly, knockdown of XIST led to inhibition of cell proliferation and induced apoptosis in vitro. In addition, reduced expression of XIST suppressed cell migration and invasion. MicroRNA 29b (miR-29b) was identified as a direct target of XIST. Previous reports indicated that miR-29b regulates p53 protein. Our results suggest that increased expression of miR-29b induces cell apoptosis through p53 protein. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) system validated the role of XIST knockout in tumor development in vivo. Together, these results suggest that CuB exerts significant anti-cancer activity by regulating expression of XIST via miR-29b.
Pulmonary Functional Imaging for Lung Adenocarcinoma: Combined MRI Assessment Based on IVIM-DWI and OE-UTE-MRI
Authors: Liu Hui , Zheng Liyun , Shi Gaofeng , Xu Qian , Wang Qi , Zhu Hongshan , Feng Hui , Wang Lijia , Zhang Ning , Xue Meng , Dai Yongming
Published: July 2021

Purpose

The goal of current study was to introduce noninvasive and reproducible MRI methods for in vivo functional assessment of lung adenocarcinoma (LUAD).

Methods

Forty-four patients with pathologically confirmed LUAD were included in this study. All the lesions were classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IA). The IA lesions were further divided into five subtype patterns, including acinar, lepidic, papillary, micropapillary and solid. Tumors were grouped depending on predominant subtype: low grade (AIS, MIA or lepidic predominant), intermediate grade (papillary or acinar predominant) and high grade (micropapillary, or solid predominant). Spirometry was performed according to American Thoracic Society guidelines. For each patient, Intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) analysis and oxygen-enhanced MRI (OE-MRI) analysis were performed. Spearman’s test was used to assess the relationship between a) whole lung mean percent signal enhancement (PSE) and pulmonary function tests (PFTs) parameters; b) IVIM-derived parameters and PFTs parameters; c) tumor mean PSE and IVIM-derived parameters. Kruskal -Wallis tests were applied to test the difference of tumor mean PSE and IVIM-derived parameters between different histological tumor grades. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic performance.

Results

Whole lung mean PSE was significantly positively correlated with PFTs parameters (r = 0.40 ~ 0.44, P < 0.05). f value derived from IVIM-DWI was significantly negatively correlated with PFTs parameters (r = -0.38 ~ -0.47, P < 0.05). Both tumor mean PSE (P = 0.030 < 0.05) and f (P = 0.022 < 0.05) could differentiate different histological grades. f was negatively correlated with tumor mean PSE (r = -0.61, P < 0.001). For the diagnostic performance, the combination of tumor mean PSE and f outperformed than using tumor mean PSE or f alone in both sensitivity and area under the ROC curve.

Conclusions

The combined measurement of OE-MRI and IVIM-DWI may serve as a promising method for the noninvasive and non-radiation evaluation of pulmonary function. Quantitative analyses achieved by OE-MRI and IVIM-DWI offer an approach of the classification of LUAD subtypes.
HNRNPH1 Is a Novel Regulator Of Cellular Proliferation and Disease Progression in Chronic Myeloid Leukemia
Authors: Liu Menghan , Yang Lin , Liu Xiaojun , Nie Ziyuan , Zhang Xiaoyan , Lu Yaqiong , Pan Yuxia , Wang Xingzhe , Luo Jianmin
Published: July 2021

RNA binding proteins act as essential modulators in cancers by regulating biological cellular processes. Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), as a key member of the heterogeneous nuclear ribonucleoproteins family, is frequently upregulated in multiple cancer cells and involved in tumorigenesis. However, the function of HNRNPH1 in chronic myeloid leukemia (CML) remains unclear. In the present study, we revealed that HNRNPH1 expression level was upregulated in CML patients and cell lines. Moreover, the higher level of HNRNPH1 was correlated with disease progression of CML. In vivo and in vitro experiments showed that knockdown of HNRNPH1 inhibited cell proliferation and promoted cell apoptosis in CML cells. Importantly, knockdown of HNRNPH1 in CML cells enhanced sensitivity to imatinib. Mechanically, HNRNPH1 could bind to the mRNA of PTPN6 and negatively regulated its expression. PTPN6 mediated the regulation between HNRNPH1 and PI3K/AKT activation. Furthermore, the HNRNPH1–PTPN6–PI3K/AKT axis played a critical role in CML tumorigenesis and development. The present study first investigated the deregulated HNRNPH1–PTPN6–PI3K/AKT axis moderated cell growth and apoptosis in CML cells, whereby targeting this pathway may be a therapeutic CML treatment.
NEK7 Promotes Pancreatic Cancer Progression And Its Expression Is Correlated With Poor Prognosis
Authors: Yan Zilong , Qu Jianhua , Li Zhangfu , Yi Jing , Su Yanze , Lin Qirui , Yu Guangyin , Lin Zewei , Yin Weihua , Lu Fengmin , Liu Jikui
Published: July 2021

The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is still dismal. Elucidation of associated genomic alteration may provide effective therapeutic strategies for PDAC treatment. NIMA-related protein kinase 7 is widely expressed in various tumors, including breast cancer, colorectal cancer and lung cancer, and promotes the proliferation of liver cancer cells in vitro and in vivo. We investigated the protein expression level of NEK7 in tumor tissues and adjacent normal tissues using immunohistochemistry of 90 patients with PADC. Meanwhile, the RNA expression level of NEK7 was examined using database-based bioinformatic analysis. Correlation and significance of NEK7 expression with patient clinicopathological features and prognosis were examined. Cell proliferation, cell adhesion, migration and invasion capabilities were measured following downregulation of NEK7 expression. 3D tumor organoids of pancreatic cancer were established and splenic xenografted into nude mice, then liver metastatic ability of NEK7 was evaluated in following 4 weeks. We observed NEK7 expression was upregulated in tumor tissues compared to normal tissues at both RNA and protein levels using bioinformatic analysis and immunohistochemistry analysis in PDAC. NEK7 expression was undetectable in normal pancreatic ducts; NEK7 was overexpressed in primary tumor of PDAC; NEK7 expression was highly correlated with advanced T stage, poorly differentiated histological grade invasive ductal carcinoma, and lymphatic invasion. Meanwhile, patients with higher NEK7 expression accompanied by worse survival outcome. Moreover, NEK7 promoted migration, invasion, adhesion, proliferation and liver metastatic ability of pancreatic cancer cells. Taken together, our data indicate that NEK7 promotes pancreatic cancer progression and it may be a potential marker for PDAC prognosis.
The Changes of T-Wave Amplitude and QT Interval Between the Supine and Orthostatic Electrocardiogram in Children With Dilated Cardiomyopathy
Authors: Tan Cheng , Yi Xiuying , Chen Ying , Wang Shuangshuang , Ji Qing , Li Fang , Wang Yuwen , Zou Runmei , Wang Cheng
Published: July 2021

Objectives: Electrocardiogram (ECG) can be affected by autonomic nerves with body position changes. The study aims to explore the ECG changes of children with dilated cardiomyopathy (DCM) when their posture changes.

Materials and methods: Sixty-four children diagnosed with DCM were recruited as research group and 55 healthy children as control group. T-wave amplitude and QT interval in ECG were recorded, and their differences between supine and orthostatic ECG were compared in both groups. Subsequently, the children with DCM were followed up and the differences before and after treatment compared.

Results: ① Comparisons in differences: Differences of T-wave amplitude in lead II and III, aVF, and V5 and differences of QT interval in lead II, aVL, aVF, and V5 were lower in the research group than in the control group. ② Logistic regression analysis and diagnostic test evaluation: The differences of T-wave amplitude in lead III and QT interval in lead aVL may have predictive value for DCM diagnosis. When their values were 0.00 mV and 30 ms, respectively, the sensitivity and specificity of the combined index were 37.5 and 83.6%. ③ Follow-up: In the response group, the T-wave amplitude difference in lead aVR increased and the difference of QT interval in lead V6 decreased after treatment. In the non-response group, there was no difference before and after treatment. When the combined index of the differences of T-wave amplitude difference in lead aVR and QT interval difference in lead V6, respectively, were −0.05 mV and 5 ms, the sensitivity and specificity of estimating the prognosis of DCM were 44.4 and 83.3%.

Conclusions: The differences of T-wave amplitude and QT interval may have a certain value to estimate DCM diagnosis and prognosis.
Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population
Authors: Khan Niaz Muhammad , Hussain Basharat , Zheng Chenqing , Khan Ayaz , Masoud Muhammad Shareef , Gu Qingquan , Qiu Linhui , Malik Naveed Altaf , Qasim Muhammad , Tariq Muhammad , Chang Junlei
Published: July 2021

Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering andin silicoanalysis identified three known mutations inASPM, a MCPH5-associated gene. The founder mutation p.Trp1326*was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244*and p.Arg1019*were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm ofASPMand expanded the Pakistani MCPH cohort.