bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrodermal Activity Is Sensitive to Sleep Deprivation but Does Not Moderate the Effect of Total Sleep Deprivation on Affect
Authors: Kurinec Courtney A. , Stenson Anthony R. , Hinson John M. , Whitney Paul , Van Dongen Hans P. A.
Published: July 2022

Emotion is characterized by dimensions of affective valence and arousal, either or both of which may be altered by sleep loss, thereby contributing to impaired regulatory functioning. Controlled laboratory studies of total sleep deprivation (TSD) generally show alterations in physiological arousal and affective state, but the relationship of affect and emotion with physiological arousal during TSD has not been well characterized. Established methods for examining physiological arousal include electrodermal activity (EDA) measures such as non-specific skin conductance responses (NSSCR) and skin conductance level (SCL). These measures are robust physiological markers of sympathetic arousal and have been linked to changes in experienced emotion. To explore the link between physiological arousal and affect during sleep deprivation, we investigated individuals’ EDA under TSD and its relationship to self-reported affect. We also investigated the relationship of EDA to two other measures known to be particularly sensitive to the arousal-decreasing effects of TSD, i.e., self-reported sleepiness and performance on a vigilant attention task. Data were drawn from three previously published laboratory experiments where participants were randomly assigned to either well-rested control (WRC) or 38 h of TSD. In this data set, comprising one of the largest samples ever used in an investigation of TSD and EDA (N = 193 with 74 WRC and 119 TSD), we found the expected impairing effects of TSD on self-reported affect and sleepiness and on vigilant attention. Furthermore, we found that NSSCR, but not SCL, were sensitive to TSD, with significant systematic inter-individual differences. Across individuals, the change in frequency of NSSCR during TSD was not predictive of the effect of TSD on affect, sleepiness, or vigilant attention, nor was it related to these outcomes during the rested baseline. Our findings indicate that while physiological arousal, as measured by EDA, may be useful for assessing TSD-related changes in non-specific arousal at the group level, it is not associated with individuals’ self-reported affect at rest nor their change in affect during TSD. This suggests that an essential aspect of the relationship between physiological arousal and self-reported affect is not well captured by EDA as measured by NSSCR.
Patterns of Gray and White Matter Volume Alterations in Patients With Post-Traumatic Anosmia: A Voxel-Based Morphometry Study
Authors: Gao Xing , Su Baihan , Sun Zhifu , Xu Lei , Wei Yongxiang , Wu Dawei
Published: July 2022

Objective

Traumatic brain injury is one of the major causes of human olfactory dysfunction and leads to brain structure alterations, mainly in the cortical olfactory regions. Our study aimed to investigate volume changes in the gray matter (GM) and white matter (WM) in patients with post-traumatic anosmia and then to explore the relationship between GM volume and olfactory function.

Methods

Ethics committee approved prospective studies which included 22 patients with post-traumatic anosmia and 18 age- and gender-matched healthy volunteers. Olfactory function was assessed using the Sniffin' Sticks. High-resolution 3-dimensional T1 MRIs of the participants were acquired on a 3T scanner and the data were collected for voxel-based morphometry (VBM) analysis. Furthermore, the GM and WM volumes of the whole brain regions were compared and correlated with olfactory function.

Results

The analysis revealed significant GM volume reduction in the orbitofrontal cortex (OFC), gyrus rectus (GR), olfactory cortex, insula, parahippocampal, temporal pole, and cerebellum (all P < 0.001) in patients. Besides, WM volume loss was also found in the OFC, GR, and insula (all P < 0.001) in patients. All WM atrophy areas were connected to areas of GM volume loss spatially. Correlation analysis showed the olfactory scores were significantly positively correlated with the GM volume of the occipital cortex (P < 0.001, and PFWE < 0.05), while no significant correlation was found between the Sniffin' Sticks test scores and the WM volume in patients.

Conclusion

The reduction of GM and WM volume in olfactory-related regions was responsible for olfactory dysfunction in post-traumatic patients. The occipital cortex may play a compensation mechanism to maintain the residual olfactory function. To our knowledge, we report here for the first time on white matter volume alterations specifically in post-traumatic patients with anosmia.
Associations of White Matter and Basal Ganglia Microstructure to Cognitive Fatigue Rate in Multiple Sclerosis
Authors: Román Cristina A. F. , Wylie Glenn R. , DeLuca John , Yao Bing
Published: July 2022

Fatigue, including cognitive fatigue, is one of the most debilitating symptoms reported by persons with multiple sclerosis (pwMS). Cognitive fatigue has been associated with disruptions in striato-thalamo-cortical and frontal networks, but what remains unknown is how therateat which pwMS become fatigued over time relates to microstructural properties within the brain. The current study aims to fill this gap in knowledge by investigating how cognitive fatigue rate relates to white matter and basal ganglia microstructure in a sample of 62 persons with relapsing-remitting MS. Participants rated their level of cognitive fatigue at baseline and after each block (x7) of a within-scanner cognitive fatigue inducing task. The slope of the regression line of all eight fatigue ratings was designated as “cognitive fatigue rate.” Diffusional kurtosis imaging maps were processed using tract-based spatial statistics and regional analyses (i.e., basal ganglia) and associated with cognitive fatigue rate. Results showed cognitive fatigue rate to be related to several white matter tracts, with many having been associated with basal ganglia connectivity or the previously proposed “fatigue network.” In addition, cognitive fatigue rate was associated with the microstructure within the putamen, though this did not survive multiple comparisons correction. Our approach of using cognitive fatigue rate, rather than trait fatigue, brings us closer to understanding how brain pathology may be impacting the experience of fatigue in the moment, which is crucial for developing interventions. These results hold promise for continuing to unpack the complex construct that is cognitive fatigue.
Right Frontal Theta: Is It a Response Biomarker for Ketamine’s Therapeutic Action in Anxiety Disorders?
Authors: Shadli Shabah M. , Delany Robert G. , Glue Paul , McNaughton Neil
Published: July 2022

Anxiety disorders are the most prevalent mental disorders in the world, creating huge economic burdens on health systems and impairing the quality of life for those affected. Recently, ketamine has emerged as an effective anxiolytic even in cases resistant to conventional treatments (TR); but its therapeutic mechanism is unknown. Previous data suggest that ketamine anxiety therapy is mediated by reduced right frontal electroencephalogram (EEG) theta power measured during relaxation. Here we test for a similar theta reduction between population-sample, presumed treatment-sensitive, (TS) anxiety patients and healthy controls. Patients with TS DSM-5 anxiety disorder and healthy controls provided EEG during 10 min of relaxation and completed anxiety-related questionnaires. Frontal delta, theta, alpha1, alpha2, beta, and gamma power, Higuchi’s fractal dimension (HFD) and frontal alpha asymmetry (FAA) values were extracted to match ketamine testing; and we predicted that the controls would have less theta power at F4, relative to the TS anxious patients, and no differences in HFD or FAA. We provide graphical comparisons of our frontal band power patient-control differences with previously published post-pre ketamine TR differences. As predicted, theta power at F4 was significantly lower in controls than patients and FAA was not significantly different. However, HFD was unexpectedly reduced at lateral sites. Gamma power did not increase between controls and patients suggesting that the increased gamma produced by ketamine relates to dissociation rather than therapy. Although preliminary, and indirect, our results suggest that the anxiolytic action of ketamine is mediated through reduced right frontal theta power.
Modulation of GABAergic Synaptic Transmission by NMDA Receptors in the Dorsal Horn of the Spinal Cord
Authors: Leonardon Benjamin , Cathenaut Lou , Vial-Markiewicz Louise , Hugel Sylvain , Schlichter Rémy , Inquimbert Perrine
Published: July 2022

The dorsal horn (DH) of the spinal cord is an important structure involved in the integration of nociceptive messages. Plastic changes in the properties of neuronal networks in the DH underlie the development of analgesia as well as of hyperalgesia and allodynia in acute and chronic pain states. Two key mechanisms are involved in these chronic pain states: increased electrical activities and glutamate release leading to the recruitment of NMDAr and plastic changes in the synaptic inhibition. Although: (1) the balance between excitation and inhibition is known to play a critical role in the spinal network; and (2) plastic changes in spinal excitation and inhibition have been studied separately, the relationship between these two mechanisms has not been investigated in detail. In the present work, we addressed the role of NMDA receptors in the modulation of GABAergic synaptic transmission in the DH network. Using tight-seal whole-cell recordings on adult mice DH neurons, we characterized the effect of NMDAr activation on inhibitory synaptic transmission and more especially on the GABAergic one. Our results show that, in a subset of neurons recorded in lamina II, NMDAr activation facilitates spontaneous and miniature GABAergic synaptic transmission with a target specificity on GABAergic interneurons. In contrast, NMDA reduced the mean amplitude of evoked GABAergic IPSCs. These results show that NMDAr modulate GABAergic transmission by a presynaptic mechanism of action. Using a pharmacological approach, we investigated the composition of NMDAr involved in this modulation of GABAergic synaptic transmission. We found that the NMDA-induced facilitation was mediated by the activation of NMDAr containing GluN2C/D subunits. Altogether, our results bring new insights on nociceptive information processing in the spinal cord network and plastic changes in synaptic inhibition that could underlie the development and maintenance of chronic pain.
Exercise Outcomes in Childhood Obesity-Related Inflammation and Oxidative Status
Authors: Estébanez Brisamar , Huang Chun-Jung , Rivera-Viloria Marta , González-Gallego Javier , Cuevas María J.
Published: July 2022

Childhood obesity is identified as one of the major public health issues to increase the risk for cardiometabolic diseases and related complications in adulthood. The literature has supported inflammation and oxidative stress as the primary underlying mechanisms involved in the pathogenesis of obesity-related diseases. Epidemiological evidence consistently shows the benefits of physical activity in the improvement of obesity-mediated inflammation and oxidative stress status. In this narrative mini-review, the available scientific evidence on the potential effects of exercise in alleviating these susceptibilities in childhood obesity will be assessed.
Staphylococcus epidermidis’ Overload During Suckling Impacts the Immune Development in Rats
Authors: Morales-Ferré Carla , Franch Àngels , Castell Margarida , Olivares Mónica , Rodríguez-Lagunas María J. , Pérez-Cano Francisco J.
Published: July 2022

Mastitis is an inflammation of the mammary gland occurring in 3–33% of the breastfeeding mothers. The majority of mastitis cases have an infectious etiology. More than 75% of infectious mastitis are caused by Staphylococcus epidermidis and Staphylococcus aureus and involves breast milk microbiota alteration, which, may have an impact in lactating infant. The aim of this study was to analyze in rats during the suckling period and later in life the impact of a high and a low overload of Staphylococcus epidermidis, similarly as it occurs during the clinical and the subclinical mastitis, respectively. From days 2 to 21 of life, suckling rats were daily supplemented with low (Ls group) or high (Hs group) dose of S. epidermidis. Body weight and fecal humidity were periodically recorded. On days 21 and 42 of life, morphometry, hematological variables, intestinal gene expression, immunoglobulin (Ig) and cytokine profile and spleen cells’ phenotype were measured. Although no differences were found in body weight, Ls and Hs groups showed higher body length and lower fecal humidity. Both doses induced small changes in lymphocytes subpopulations, reduced the plasma levels of Ig and delayed the Th1/Th2 balance causing a bias toward the Th2 response. No changes were found in cytokine concentration. The low dose affected the Tc cells intestinal homing pattern whereas the high dose had an impact on the hematological variables causing leukocytosis and lymphocytosis and also influenced the intestinal barrier maturation. In conclusion, both interventions with Staphylococcus epidermidis overload during suckling, affects the immune system development in short and long term.
Effects of Zymosan on Short-Chain Fatty Acid and Gas Production in in vitro Fermentation Models of the Human Intestinal Microbiota
Authors: Pi Xionge , Yu Zaichun , Yang Xiaoxia , Du Zhi , Liu Wei
Published: July 2022

In this study, the effects of zymosan (HG, hydrolyzed glucan) on the structure and metabolism of fecal microbiota in Chinese healthy people was investigated by an in vitro simulated intestinal microecology fermentation model. We found that HG significantly regulated fecal microbiota composition, including the increase of Bifidobacterium, Faecalibacterium, Prevotella and the decrease of Escherichia-Shigella. Moreover, HG significantly increased the total production of short chain fatty acids (SCFAs) and gases, in which the production of Acetic acid, Propionic acid, CO2, and H2 significantly increased while the production of Isovaleric acid and NH3 significantly decreased. Additionally, the supplement of HG showed certain differences in the regulation of microbiota from four groups. HG significantly increased the relative abundance of Bifidobacterium and significantly decreased the relative abundance of Escherichia-Shigella excluding the older men group. Meanwhile, and the relative abundance of Lactobacillus was significantly increased in young populations. And the relative abundance of Bacteroides was significantly decreased only in the young women. Furthermore, HG significantly increased H2 concentration only in older men. These findings suggest that HG, as a new generation of prebiotics, could regulate the structure of fecal microbiota and its metabolites in a better direction, but when HG participates in precision nutrition formula, it may be necessary to consider the differences in the utilization of different populations.
Bioactive-Chemical Quality Markers Revealed: An Integrated Strategy for Quality Control of Chicory
Authors: Li Yaolei , Ju Shanshan , Lin Zhijian , Wu Hao , Wang Yu , Jin Hongyu , Ma Shuangcheng , Zhang Bing
Published: July 2022

As a miraculous Xinjiang Uyghur customary traditional Chinese medicine (TCM), Chicory (Cichorium glandulosum Boiss.et Huet and Cichorium intybus L.) has been found to have therapeutic potential for metabolic diseases in recent years. Although it is widely used as an ethnic medicine, there is still a lack of targeted quality control indicators in quality standards. Hence, this study was conducted to further develop a strategy to reveal bioactive-chemical quality markers based on the existing foundation. First, through the comparative screening of fingerprint profiles of a large amount of Cichorium glandulosum Boiss.et Huet and Cichorium intybus L., superiority components were found to be potential indicators of chemical quantitative properties for the roots and above-ground parts. The results of content determination showed that their contents differed among different species and parts. Second, the potential dominant components were further confirmed using network pharmacology and molecular docking techniques. Again, the results of RAW264.7 cells and L02 cells experiments showed that chicory acid and lactucin were the main components that could reflect the anti-inflammatory and uric acid-lowering potential of chicory. Finally, under this strategy, this study reveals that cichoric acid and lactucin have the properties of quality markers and quality control of chicory. In a word, this work contributes to the quality control, standard improvement, and rational clinical use of chicory.
Anti-cancer Potential of Polysaccharide Extracted From Polygonatum sibiricum on HepG2 Cells via Cell Cycle Arrest and Apoptosis
Authors: Li Mo , Liu Yumeng , Zhang Henan , Liu Yanfeng , Wang Weiming , You Shengbo , Hu Xinyu , Song Meijun , Wu Rina , Wu Junrui
Published: July 2022

Polygonatum sibiricum is one of the most widely used traditional Chinese medicine in China. Polygonatum sibiricum polysaccharide (PSP) is the main functional component of Polygonatum sibiricum. In this study, a water-soluble polysaccharide (PSP-1) was first isolated from Polygonatum sibiricum with a molecular weight of 38.65 kDa. Structural analysis was performed via methylation and FT-IR spectroscopy analyses, which in combination with NMR spectroscopy, revealed that PSP-1 has a → 4-α-D-Glcp-1 → backbone with the substitution at O-6 with the β-D-Glcp-1 → residues. Furthermore, PSP-1 exhibited potent and concentration-dependent anticancer effects, inducing HepG2 cell apoptosis and arresting the cell cycle at the G1 phase. Moreover, PSP-1 also decreased the mitochondrial membrane potential, damaged the nucleus of HepG2 cells, and increased the activity of caspase-9 and−3 in the intrinsic apoptotic pathways to induce HepG2 cell apoptosis. To conclude, PSP-1 might be a good candidate for the treatment of liver cancer, and this work provides important information for understanding the relationship between structure and antitumor activity of PSP-1, which is relevant for the treatment of hepatocellular carcinoma in clinic.
Pyroptosis-Related lncRNA Prognostic Model for Renal Cancer Contributes to Immunodiagnosis and Immunotherapy
Authors: Zhou Xuan , Yao Liangyu , Zhou Xiang , Cong Rong , Luan Jiaochen , Wei Xiyi , Zhang Xu , Song Ninghong
Published: July 2022

Background

Renal clear cell cancer (ccRCC) is one of the most common cancers in humans. Thus, we aimed to construct a risk model to predict the prognosis of ccRCC effectively.

Methods

We downloaded RNA sequencing (RNA-seq) data and clinical information of 539 kidney renal clear cell carcinoma (KIRC) patients and 72 normal humans from The Cancer Genome Atlas (TCGA) database and divided the data into training and testing groups randomly. Pyroptosis-related lncRNAs (PRLs) were obtained through Pearson correlation between pyroptosis genes and all lncRNAs (p < 0.05, coeff > 0.3). Univariate and multivariate Cox regression analyses were then performed to select suitable lncRNAs. Next, a novel signature was constructed and evaluated by survival analysis and ROC analysis. The same observation applies to the testing group to validate the value of the signature. By gene set enrichment analysis (GSEA), we predicted the underlying signaling pathway. Furthermore, we calculated immune cell infiltration, immune checkpoint, the T-cell receptor/B-cell receptor (TCR/BCR), SNV, and Tumor Immune Dysfunction and Exclusion (TIDE) scores in TCGA database. We also validated our model with an immunotherapy cohort. Finally, the expression of PRLs was validated by quantitative PCR (qPCR).

Results

We constructed a prognostic signature composed of six key lncRNAs (U62317.1, MIR193BHG, LINC02027, AC121338.2, AC005785.1, AC156455.1), which significantly predict different overall survival (OS) rates. The efficiency was demonstrated using the receiver operating characteristic (ROC) curve. The signature was observed to be an independent prognostic factor in cohorts. In addition, we found the PRLs promote the tumor progression via immune-related pathways revealed in GSEA. Furthermore, the TCR, BCR, and SNV data were retrieved to screen immune features, and immune cell scores were calculated to measure the effect of the immune microenvironment on the risk model, indicating that high- and low-risk scores have different immune statuses. The TIDE algorithm was then used to predict the immune checkpoint blockade (ICB) response of our model, and subclass mapping was used to verify our model in another immunotherapy cohort data. Finally, qPCR validates the PRLs in cell lines.

Conclusion

This study provided a new risk model to evaluate ccRCC and may be pyroptosis-related therapeutic targets in the clinic.
Myeloid-Derived Suppressor Cells as Key Players and Promising Therapy Targets in Prostate Cancer
Authors: Siemińska Izabela , Baran Jarek
Published: July 2022

Prostate cancer (PC) is the second most often diagnosed malignancy in men and one of the major causes of cancer death worldwide. Despite genetic predispositions, environmental factors, including a high-fat diet, obesity, a sedentary lifestyle, infections of the prostate, and exposure to chemicals or ionizing radiation, play a crucial role in PC development. Moreover, due to a lack of, or insufficient T-cell infiltration and its immunosuppressive microenvironment, PC is frequently classified as a “cold” tumor. This is related to the absence of tumor-associated antigens, the lack of T-cell activation and their homing into the tumor bed, and the presence of immunological cells with regulatory functions, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg), and tumor-associated macrophages (TAMs). All of them, by a variety of means, hamper anti-tumor immune response in the tumor microenvironment (TME), stimulating tumor growth and the formation of metastases. Therefore, they emerge as potential anti-cancer therapy targets. This article is focused on the function and role of MDSCs in the initiation and progression of PC. Clinical trials directly targeting this cell population or affecting its biological functions, thus limiting its pro-tumorigenic activity, are also presented.
Glia Maturation Factor β as a Novel Independent Prognostic Biomarker and Potential Therapeutic Target of Kidney Renal Clear Cell Carcinoma
Authors: Zhu Tong , Wang Tianyu , Feng Zijun , Gao Furong , Zhang Jieping , Jin Caixia , Tian Haibin , Xu Jingying , Chen Hao , Ou Qingjian , Wang Juan , Xu Guotong , Lu Lixia
Published: July 2022

Kidney renal clear cell carcinoma (KIRC) has the highest mortality rate and potential for invasion among renal cancers. The diagnosis and treatment of KIRC are becoming challenging because of its diverse pathogenic mechanisms. Glia (GMFB) is a highly conserved growth and differentiation factor for glia cells and neurons, and it is closely associated with neurodegenerative diseases. However, its role in KIRC remains unknown. The present study integrated bioinformatics approaches with suitable meta-analyses to determine the position of GMFB in KIRC. There was a significant decrease in Gmfb expression in KIRC kidneys compared with normal controls. Gmfb expression was negatively associated with pathologic stage, T and M stages, and histologic grade. Univariate and multivariate analyses showed that elevated Gmfb expression was an independent factor for a favorable prognosis. Furthermore, the nomogram verified that Gmfb is a low-risk factor for KIRC. Knockdown of Gmfb in Caki-2 cells increased viability and decreased p21 and p27 levels. Overexpression of Gmfb inhibited Caki-2 cell proliferation, migration, and invasion and decreased mitochondrial membrane potential. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses considering Gmfb co-expressed differentially expressed genes (DEGs) showed that collecting duct acid secretion and mineral absorption ranked were the most important upregulated and downregulated DEGs, respectively. The upregulated hub genes for DEGs were mainly involved in nucleosome assembly, nucleosome organization, and chromatin assembly, and the downregulated hub genes were primarily associated with keratinization. The ratio of tumor-infiltrating immune cells in KIRC tissues was evaluated using CIBERSORTx. The results showed that the Gmfb expression was significantly positively correlated with macrophage M2 cells and mast resting cell infiltration levels and negatively correlated with T follicular helper, T regulatory, and B plasma cell infiltration levels. The former cell types were associated with a beneficial outcome, while the latter had a worse outcome in patients with KIRC. In summary, this study identified GMFB as a novel independent biomarker and therapeutic target for KIRC, and it provides a helpful and distinct individualized treatment strategy for KIRC with a combination of molecular targets and tumor microenvironment.
The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma
Authors: Yang Ran , Zhan Yong , Li Yi , Dai Shu-Yang , He Shi-Wei , Ye Chun-Jing , Meng Ling-Du , Chen De-Qian , Dong Chen-Bin , Chen Lian , Chen Gong , Dong Kui-Ran , Li Kai , Zheng Shan , Li Jun , Yao Wei , Dong Rui
Published: July 2022

Sialoblastoma (SBL) is an infrequent embryonal malignant tumor originating from the salivary gland, resembling primitive salivary gland anlage, whereas hepatoblastoma (HB) is the most common pediatric liver malignancy. The simultaneous occurrence of both tumors is extremely rare. Here we reported a case of a 6-month-old infant diagnosed with synchronous SBL and HB. The patient received neoadjuvant chemotherapy followed by surgical resection. Fresh tissues of both tumors were collected before and after chemotherapy, which were further profiled by whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). WES analysis revealed potential somatic driver mutation PIK3CA p.Glu454Lys for SBL and canonical mutation CTNNB1 p.Ser45Pro for HB. No shared somatic variants or common copy number alterations were found between SBL and HB primary tumor samples. Though scRNA-seq, single-cell atlases were constructed for both tumors. SBL may recapitulate a pre-acinar stage in the development of salivary gland, including basaloid, duct-like, myoepithelial-like, and cycling phenotypes. In the meantime, HB was composed of tumor cells resembling different stages of the liver, including hepatocyte-like, hepatic progenitor-like, and hepatoblast-like cells. After chemotherapy, both tumors were induced into a more mature phenotype. In terms of transcriptional signatures, SBL and HB showed enhanced expression of epithelial markers KRT8, KRT18, and essential embryo development genes SDC1, MDK, indicating the disruption of normal embryo epithelium development. Finally, heterozygous deleterious germline mutation BLM and FANCI were identified which could predispose the patient to higher cancer risk. It partially explained the reason for the co-occurrence of SBL and HB. Taken together, we provided valuable resources for deciphering cellular heterogeneity and adaptive change of tumor cells after chemotherapy for synchronous SBL and HB, providing insights into the mechanisms leading to synchronous pediatric tumors.
Identification and Validation of Immune-Related Long Non-Coding RNA Signature for Predicting Immunotherapeutic Response and Prognosis in NSCLC Patients Treated With Immunotherapy
Authors: Ma Jianli , Zhang Minghui , Yu Jinming
Published: July 2022

Background

Numerous studies have reported that long non-coding RNAs (lncRNAs) play important roles in immune-related pathways in cancer. However, immune-related lncRNAs and their roles in predicting immunotherapeutic response and prognosis of non-small cell lung cancer (NSCLC) patients treated with immunotherapy remain largely unexplored.

Methods

Transcriptomic data from NSCLC patients were used to identify novel lncRNAs by a custom pipeline. ImmuCellAI was utilized to calculate the infiltration score of immune cells. The marker genes of immunotherapeutic response-related (ITR)-immune cells were used to identify immune-related (IR)-lncRNAs. A co-expression network was constructed to determine their functions. LASSO and multivariate Cox analyses were performed on the training set to construct an immunotherapeutic response and immune-related (ITIR)-lncRNA signature for predicting the immunotherapeutic response and prognosis of NSCLC. Four independent datasets involving NSCLC and melanoma patients were used to validate the ITIR-lncRNA signature.

Results

In total, 7,693 novel lncRNAs were identified for NSCLC. By comparing responders with non-responders, 154 ITR-lncRNAs were identified. Based on the correlation between the marker genes of ITR-immune cells and lncRNAs, 39 ITIR-lncRNAs were identified. A co-expression network was constructed and the potential functions of 38 ITIR-lncRNAs were annotated, most of which were related to immune/inflammatory-related pathways. Single-cell RNA-seq analysis was performed to confirm the functional prediction results of an ITIR-lncRNA, LINC01272. Four-ITIR-lncRNA signature was identified and verified for predicting the immunotherapeutic response and prognosis of NSCLC. Compared with non-responders, responders had a lower risk score in both NSCLC datasets (P<0.05). NSCLC patients in the high-risk group had significantly shorter PFS/OS time than those in the low-risk group in the training and testing sets (P<0.05). The AUC value was 1 of responsiveness in the training set. In melanoma validation datasets, patients in the high-risk group also had significantly shorter OS/PFS time than those in the low-risk group (P<0.05). The ITIR-lncRNA signature was an independent prognostic factor (P<0.001).

Conclusion

Thousands of novel lncRNAs in NSCLC were identified and characterized. In total, 39 ITIR-lncRNAs were identified, 38 of which were functionally annotated. Four ITIR-lncRNAs were identified as a novel ITIR-lncRNA signature for predicting the immunotherapeutic response and prognosis in NSCLC patients treated with immunotherapy.
Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates
Authors: Wang Xiao-Jun , Gao Jing , Yu Qin , Zhang Min , Hu Wei-Dong
Published: July 2022

Background

The competing endogenous RNA (ceRNA) network-mediated regulatory mechanisms in small cell lung cancer (SCLC) remain largely unknown. This study aimed to integrate multi-omics profiles, including the transcriptome, regulome, genome and pharmacogenome profiles, to elucidate prioritised ceRNA characteristics, pathways and drug candidates in SCLC.

Method

We determined the plasma messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) expression levels using whole-transcriptome sequencing technology in our SCLC plasma cohort. Significantly expressed plasma mRNAs were then overlapped with the Gene Expression Omnibus (GEO) tissue mRNA data (GSE 40275, SCLC tissue cohort). Next, we applied a multistep multi-omics (transcriptome, regulome, genome and pharmacogenome) integration analysis to first construct the network and then to identify the lncRNA/circRNA-miRNA-mRNA ceRNA characteristics, genomic alterations, pathways and drug candidates in SCLC.

Results

The multi-omics integration-based prioritisation of SCLC ceRNA regulatory networks consisted of downregulated mRNAs (CSF3R/GAA), lncRNAs (AC005005.4-201/DLX6-AS1-201/NEAT1-203) and circRNAs (hsa_HLA-B_1/hsa_VEGFC_8) as well as upregulated miRNAs (hsa-miR-4525/hsa-miR-6747-3p). lncRNAs (lncRNA-AC005005.4-201 and NEAT1-203) and circRNAs (circRNA-hsa_HLA-B_1 and hsa_VEGFC_8) may regulate the inhibited effects of hsa-miR-6747-3p for CSF3R expression in SCLC, while lncRNA-DLX6-AS1-201 or circRNA-hsa_HLA-B_1 may neutralise the negative regulation of hsa-miR-4525 for GAA in SCLC. CSF3R and GAA were present in the genomic alteration, and further identified as targets of FavId and Trastuzumab deruxtecan, respectively. In the SCLC-associated pathway analysis, CSF3R was involved in the autophagy pathways, while GAA was involved in the glucose metabolism pathways.

Conclusions

We identified potential lncRNA/cirRNA-miRNA-mRNA ceRNA regulatory mechanisms, pathways and promising drug candidates in SCLC, providing novel potential diagnostics and therapeutic targets in SCLC.
C12orf59 Promotes Esophageal Squamous Cell Carcinoma Progression via YAP-Mediated Epithelial-Mesenchymal Transition
Authors: Xu Chunhua , Lin Shan , Lu Yanxin , Mao Longyi , Li Shi , Li Zesong
Published: July 2022

C12orf59 is a novel gene widely expressed in diverse normal human tissues. Aberrant expression of C12orf59, which is involved in tumor progression, has been reported in a few types of cancer. However, its expression and biological function in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that the mRNA and protein levels of C12orf59 were prominently higher in both tumor tissues and most ESCC cell lines. Functionally, C12orf59 overexpression promoted ESCC cell proliferation, migration and invasion, whereas C12orf59 depletion worked oppositely. Mechanistically, C12orf59 exerted its oncogenic function through the induction of epithelial-mesenchymal transition (EMT) of ESCC cells, which relied on Yes-associated protein (YAP) dephosphorylation and nuclear translocation. Constitutively active YAP further facilitated cell migration, invasion and EMT induced by enforced C12orf59 overexpression. On the contrary, increased cell motility and EMT caused by enforced C12orf59 overexpression were dramatically repressed upon YAP inactivation by verteporfin. Thus, we conclude that YAP activation driven by C12orf59 contributes to the malignancy of ESCC through EMT and that targeting drugs for C12orf59 combined with YAP inhibitor may be a potential therapeutic strategy for ESCC.
The Value of Circulating Tumor Cells in the Prognosis and Treatment of Pancreatic Cancer
Authors: Luo Kai , Wang Xiangkun , Zhang Xudong , Liu Zhongyuan , Huang Shuai , Li Renfeng
Published: July 2022

In the past few decades, tumor diagnosis and treatment theory have developed in a variety of directions. The number of people dying from pancreatic cancer increases while the mortality rate of other common tumors decreases. Traditional imaging methods show the boundaries of pancreatic tumor, but they are not sufficient to judge early micrometastasis. Although carcinoembryonic antigen (CEA) and carbohydrate antigen19-9 (CA19-9) have the obvious advantages of simplicity and minimal invasiveness, these biomarkers obviously lack sensitivity and specificity. Circulating tumor cells (CTCs) have attracted attention as a non-invasive, dynamic, and real-time liquid biopsy technique for analyzing tumor characteristics. With the continuous development of new CTCs enrichment technologies, substantial progress has been made in the basic research of CTCs clinical application prospects. In many metastatic cancers, CTCs have been studied as an independent prognostic factor. This article reviews the research progress of CTCs in the treatment and prognosis of pancreatic cancer.
Cyclophilin D: Guardian or Executioner for Tumor Cells?
Authors: Zhang Ling , Liu Yi , Zhou Rou , He Baoyu , Wang Wenjun , Zhang Bin
Published: July 2022

Cyclophilin D (CypD) is a peptide-proline cis-trans isomerase (PPIase) distributed in the mitochondrial matrix. CypD regulates the opening of the mitochondrial permeability conversion pore (mPTP) and mitochondrial bioenergetics through PPIase activity or interaction with multiple binding partners in mitochondria. CypD initially attracted attention due to its regulation of mPTP overopening-mediated cell death. However, recent studies on the effects of CypD on tumors have shown conflicting results. Although CypD has been proven to promote the aerobic glycolysis in tumor cells, its regulation of malignant characteristics such as the survival, invasion and drug resistance of tumor cells remains controversial. Here, we elaborate the main biological functions of CypD and its relationships with tumor progression identified in recent years, focusing on the dual role of CypD in tumors.
Case Report: Successful Treatment With Anti-C5 Monoclonal Antibody in a Japanese Adolescent Who Developed Thrombotic Microangiopathy After Autologous Bone Marrow Transplantation for Malignant Lymphoma
Authors: Shimizu Shoichi , Morohashi Tamaki , Kanezawa Koji , Yagasaki Hiroshi , Takahashi Shori , Morioka Ichiro
Published: July 2022

Background

Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of bone marrow transplantation (BMT). Recently, abnormalities in the complement system have been identified in the pathogenesis of TA-TMA, and there are series of reports stating that anti-C5 monoclonal antibody (eculizumab) is effective in patients with high levels of the membrane attack complex (C5b-9).

Case Presentation

A 12-year-old boy underwent autologous BMT after receiving high-dose chemotherapy for malignant lymphoma. The patient was engrafted on day 19 after transplantation; however, hemolytic anemia and non-immune thrombocytopenia persisted, and haptoglobin decreased on day 46. Moreover, on day 83, the patient developed pulmonary hemorrhage, hypertension, severe proteinuria, hematuria, and acute kidney injury (AKI). Pulmonary bleeding stopped with daily platelet transfusion and hemostatic agents, but reappeared on day 100. Based on the presence of destruction of red blood cells, elevated lactate dehydrogenase levels, negative direct and indirect Coombs tests, normal ADAMTS13 levels, hemolytic anemia, non-immune thrombocytopenia, and AKI, the patient was diagnosed with systemic TA-TMA and we initiated plasma exchange (PE) and continuous hemodialysis for AKI. High C5b-9 levels were identified at the start of the series of PE, therefore we decided to administer eculizumab. After three courses of eculizumab, no pulmonary hemorrhage was observed, and anemia, thrombocytopenia, renal dysfunction, hematuria, and proteinuria all tended to improve. Three years after transplantation, the patient is alive and does not require eculizumab.

Discussion

Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage C5 and the formation of C5b-9. In this case, TA-TMA could not be controlled with PE alone. We therefore decided to use eculizumab relatively early based on the high C5b-9 level and could resolve the momentum of TA-TMA.

Conclusion

In previous reports, TA-TMA typically occurred in early post-allogeneic BMT of patients with lymphoma or in post-autologous BMT of patients with neuroblastoma and was treated with eculizumab. We here reported that eculizumab could be successful treatment for TA-TMA in post-autologous BMT of patient with lymphoma.
Entrustable Professional Activities for Chinese Standardized Residency Training in Pediatric Intensive Care Medicine
Authors: Yun Zhang , Jing Liu , Junfei Chen , Wenjing Zhang , Jinxiang Wu , Tong Yue , Aijun Zhang
Published: July 2022

Background

Entrustable professional activities (EPAs) were first introduced by Olle ten Cate in 2005. Since then, hundreds of applications in medical research have been reported worldwide. However, few studies discuss the use of EPAs for residency training in pediatric intensive care medicine. We conducted a pilot study of EPA for pediatric intensive care medicine to evaluate the use of EPAs in this subspecialty.

Materials and Methods

A cross-sectional study was implemented in pediatric intensive care medicine standardized residency training at the Qilu Hospital of Shandong University. An electronic survey assessing EPA performance using eight scales composed of 15 categories were distributed among residents and directors.

Results

A total of 217 director-assessment and 44 residents’ self-assessment questionnaires were collected, both demonstrating a rising trend in scores across postgraduate years. There were significant differences in PGY1-vs.-PGY2 and PGY1-vs.-PGY3 director-assessment scores, while there were no differences in PGY2-vs.-PGY3 scores. PGY had a significant effect on the score of each EPA, while position significantly affected the scores of all EPAs except for EPA1 (Admit a patient) and EPA2 (Select and interpret auxiliary examinations). Gender only significantly affected the scores of EPA6 (Report a case), EPA12 (Perform health education), and EPA13 (Inform bad news).

Conclusion

This study indicates that EPA assessments have a certain discriminating capability among different PGYs in Chinese standardized residency training in pediatric intensive care medicine. Postgraduate year, gender, and resident position affected EPA scores to a certain extent. Given the inconsistency between resident-assessed and director-assessed scores, an improved feedback program is needed in the future.
Introducing the Concept of Exercise Holidays for Human Spaceflight - What Can We Learn From the Recovery of Bed Rest Passive Control Groups
Authors: Ekman Robert , Green David A. , Scott Jonathon P. R. , Huerta Lluch Roger , Weber Tobias , Herssens Nolan
Published: July 2022

In an attempt to counteract microgravity-induced deconditioning during spaceflight, exercise has been performed in various forms on the International Space Station (ISS). Despite significant consumption of time and resources by daily exercise, including around one third of astronauts’ energy expenditure, deconditioning—to variable extents—are observed. However, in future Artemis/Lunar Gateway missions, greater constraints will mean that the current high volume and diversity of ISS in-flight exercise will be impractical. Thus, investigating both moreeffectiveandefficientmulti-systems countermeasure approaches taking into account the novel mission profiles and the associated health and safety risks will be required, while also reducing resource requirements. One potential approach is to reduce mission exercise volume by the introduction of exercise-free periods, or “exercise holidays”. Thus, we hypothesise that by evaluating the ‘recovery’ of the no-intervention control group of head-down-tilt bed rest (HDTBR) campaigns of differing durations, we may be able to define the relationship between unloading duration and the dynamics of functional recovery—of interest to future spaceflight operations within and beyond Low Earth Orbit (LEO)—including preliminary evaluation of the concept of exercise holidays. Hence, the aim of this literature study is to collect and investigate the post-HDTBR recovery dynamics of current operationally relevant anthropometric outcomes and physiological systems (skeletal, muscular, and cardiovascular) of the passive control groups of HDTBR campaigns, mimicking a period of ‘exercise holidays’, thereby providing a preliminary evaluation of the concept of ‘exercise holidays’ for spaceflight, within and beyond LEO. The main findings were that, although a high degree of paucity and inconsistency of reported recovery data is present within the 18 included studies, data suggests that recovery of current operationally relevant outcomes following HDTBR without exercise—and even without targeted rehabilitation during the recovery period—could be timely and does not lead to persistent decrements differing from those experienced following spaceflight. Thus, evaluation of potential exercise holidays concepts within future HDTBR campaigns is warranted, filling current knowledge gaps prior to its potential implementation in human spaceflight exploration missions.
Characterization of Salivary Secreted Proteins That Induce Cell Death From Riptortus pedestris (Fabricius) and Their Roles in Insect-Plant Interactions
Authors: Dong Yumei , Huang Xingge , Yang Yuxia , Li Jifen , Zhang Meiqian , Shen Hui , Ren Yanrong , Li Xinyu , Tian Jiale , Shen Danyu , Dou Daolong , Xia Ai
Published: July 2022

Riptortus pedestris (Fabricius) is a polyphagous hemipteran crop pest that mainly feeds on the leguminous plants, resulting in shriveled and dimpled seeds. With recent several outbreaks in the Huang-Huai-Hai region of China, as well as in South Korea and Japan, this species has caused enormous economic losses to soybean crops. In the present study, we found that R. pedestris feeding results in local lesions at the infestation sites. To identify the key effectors that induce plant damage during feeding, the salivary glands of R. pedestris were dissected for transcriptome sequencing, and 200 putative secreted proteins were transiently expressed in N. benthamiana. Among them, three intracellular effectors (RP191, RP246, and RP302) and one apoplastic effector (RP309) were identified as necrosis-inducing proteins (NIPs), which also triggered the reactive oxidative burst. Yeast signal sequence trap and qRT-PCR analysis suggested that these proteins might be secreted into plant tissue during R. pedestris infestation. Pathogenicity assays revealed that RP191, 246, and 302 promote Phytophthora capsici infection or induce Spodoptera litura feeding by inhibiting plant immunity. RP302 is localized to the cytoplasm and nuclei, while RP191 and 246 are endoplasmic reticulum (ER) resident proteins. RP309 stimulates the expression of PTI marker genes, and its induced cell death depends on co-receptors NbBAK1 and NbSOBIR1, indicating that it is a HAMP. Bioinformatics analysis demonstrated that four NIPs are recently evolved effectors and only conserved in the Pentatomidae. In this study, saliva-secreted proteins were used as the starting point to preliminarily analyze the harm mechanism of R. pedestris, which might provide a new idea and theoretical basis for this species control.
Overexpression of TaSNAC4-3D in Common Wheat (Triticum aestivum L.) Negatively Regulates Drought Tolerance
Authors: Ma Jianhui , Zhang Mengqi , Lv Wenming , Tang Xiaoxiao , Zhao Dongyang , Wang Li , Li Chunxi , Jiang Lina
Published: July 2022

The development and production of bread wheat (Triticum aestivum L.) are widely affected by drought stress worldwide. Many NAC transcription factors (TFs) of stress-associated group (SNAC) are functionally proven to regulate drought tolerance. In this study, we identified 41 TaSNACs that were classified into 14 groups, and the expression of TaSNAC4-3D was induced in the leaf tissue via osmotic or abscisic acid (ABA) treatment. TaSNAC4-3D was localized to the nucleus through the transient expression assay, and the C-terminal region exhibited transcriptional activity via transactivation assays. TaSNAC4-3D was overexpressed in common wheat. The wheat plants with TaSNAC4-3D overexpression was more sensitive to drought stress compared with wild-type (WT) plants. The water loss rate showed no difference between transgenic lines and WT plants. However, drought stress increased H2O2 and O2– accumulation and promoted programmed cell death (PCD) in the leaf tissue of TaSNAC4-3D overexpression lines compared with WT plants. RNA-seq analysis was performed under well-watered and drought conditions, and four strong potential target genes, encoding senescence regulators, were identified by analyzing their promoters containing the NAC recognition sequence (NACRS). Based on these results, our findings revealed that TaSNAC4-3D negatively regulates drought tolerance by inducing oxidative damage in bread wheat.