bluuebunny/crossref_metadata_2025 huggingface dataset:
A Partial Picture of the Single-Cell Transcriptomics of Human IgA Nephropathy
Authors: Tang Rong , Meng Ting , Lin Wei , Shen Chanjuan , Ooi Joshua D. , Eggenhuizen Peter J. , Jin Peng , Ding Xiang , Chen Jinbiao , Tang Yangshuo , Xiao Zhou , Ao Xiang , Peng Weisheng , Zhou Qiaoling , Xiao Ping , Zhong Yong , Xiao Xiangcheng
Published: April 2021

The molecular mechanisms underlying renal damage of IgA nephropathy (IgAN) remain incompletely defined. Here, single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from IgAN and control subjects to define the transcriptomic landscape at single-cell resolution. We presented a comprehensive scRNA-seq analysis of human renal biopsies from IgAN. We showed for the first time that IgAN mesangial cells displayed increased expression of several novel genes including MALAT1, GADD45B, SOX4, and EDIL3, which were related to cell proliferation and matrix accumulation. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. Furthermore, we compared the results of 4 IgAN patients with the published scRNA-Seq data of healthy kidney tissues of three human donors in order to further validate the findings in our study. The results also verified that the overexpressed genes in tubule cells from IgAN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. The receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. IgAN patients with overt proteinuria displayed elevated genes participating in several signaling pathways compared with microproteinuria group. It needs to be mentioned that based on number of mesangial cells and other kidney cells analyzed in this study, the results of our study are preliminary and needs to be confirmed on larger number of cells from larger number of patients and controls in future studies. Therefore, these results offer new insight into pathogenesis and identify new therapeutic targets for IgAN.
Discovery and Validation of a Three-Cytokine Plasma Signature as a Biomarker for Diagnosis of Pediatric Tuberculosis
Authors: Kumar Nathella Pavan , Hissar Syed , Thiruvengadam Kannan , Banurekha Velayuthum V. , Suresh N. , Shankar Janani , S Elilarasi , N S Gomathi , S Kalpana , J Ganesh , M A Aravind , Baskaran Dhanaraj , Tripathy Srikanth , Swaminathan Soumya , Babu Subash
Published: April 2021

Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls (discovery cohort) and obtained a separate “validation” cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.
The Key Role of NAD+ in Anti-Tumor Immune Response: An Update
Authors: Morandi Fabio , Horenstein Alberto Leonardo , Malavasi Fabio
Published: April 2021

Nicotinamide adenine dinucleotide (NAD+) is an important molecule that functions as a co-enzyme in numerous metabolic processes. Generated both through de novo synthesis and via salvage pathways, NAD+ is the substrate for a variety of NAD+-consuming enzymes. Among them is CD38, a cell surface ecto-enzyme widely expressed on different types of cells and endowed with the function of cADP-ribose synthases/NAD+ glycohydrolase. Surface CD38 expression is increased in different hematological and solid tumors, where it cooperates with other ecto-enzymes to produce the immunosuppressive molecule adenosine (ADO). Few studies have explored the correlation of NAD+ levels with T-cell mediated anti-tumor response in preclinical models. We therefore discuss these novel findings, examining the possible contribution of NAD+ depletion, along with ADO production, in the immunosuppressive activities of CD38 in the context of human tumors. Lastly, we discuss the use of pharmacological inhibitors of CD38 and supplementation of different NAD+ precursors to increase NAD+ levels and to boost T cell responses. Such molecules may be employed as adjuvant therapies, in combination with standard treatments, for cancer patients.
The Role of the Gut-Liver Axis in Metabolic Dysfunction-Associated Fatty Liver Disease
Authors: Martín-Mateos Rosa , Albillos Agustín
Published: April 2021

The complex interplay between the gut microbiota, the intestinal barrier, the immune system and the liver is strongly influenced by environmental and genetic factors that can disrupt the homeostasis leading to disease. Among the modulable factors, diet has been identified as a key regulator of microbiota composition in patients with metabolic syndrome and related diseases, including the metabolic dysfunction-associated fatty liver disease (MAFLD). The altered microbiota disrupts the intestinal barrier at different levels inducing functional and structural changes at the mucus lining, the intercellular junctions on the epithelial layer, or at the recently characterized vascular barrier. Barrier disruption leads to an increased gut permeability to bacteria and derived products which challenge the immune system and promote inflammation. All these alterations contribute to the pathogenesis of MAFLD, and thus, therapeutic approaches targeting the gut-liver-axis are increasingly being explored. In addition, the specific changes induced in the intestinal flora may allow to characterize distinctive microbial signatures for non-invasive diagnosis, severity stratification and disease monitoring.
Case Report: Complete and Fast Recovery From Severe COVID-19 in a Pemphigus Patient Treated With Rituximab
Authors: Sinagra Jo Linda , Vedovelli Claudio , Binazzi Raffaella , Salemme Adele , Moro Francesco , Mazzanti Cinzia , Didona Biagio , Di Zenzo Giovanni
Published: April 2021

COVID-19 is characterized by a severe pulmonary disease due to severe acute respiratory syndrome (SARS)-CoV-2 infection. For clinicians involved in the management of patients with chronic autoimmune diseases the risk linked to the conditions itself and to drug-induced immunosuppression during the COVID-19 pandemic is a major topic. Pemphigus is a rare autoimmune blistering disease (AIBD) of the skin and mucous membranes caused by autoantibodies to desmosomal components, desmoglein 1 and 3. Among immunosuppressant therapies, rituximab (RTX) is considered a highly effective treatment with a favorable safety profile, but it induces a prolonged B-cell depletion that can lead to higher susceptibility to infections. For this reason, concerns about its use during the pandemic have been raised. We describe a case of a pemphigus patient in which RTX-induced B cell depletion led to the severe inflammatory phase, whereas corticosteroid treatment allowed a favorable outcome.
High Dimensional Imaging Mass Cytometry Panel to Visualize the Tumor Immune Microenvironment Contexture
Authors: Elaldi Roxane , Hemon Patrice , Petti Luciana , Cosson Estelle , Desrues Belinda , Sudaka Anne , Poissonnet Gilles , Van Obberghen-Schilling Ellen , Pers Jacques-Olivier , Braud Veronique M. , Anjuère Fabienne , Meghraoui-Kheddar Aïda
Published: April 2021

The integrative analysis of tumor immune microenvironment (TiME) components, their interactions and their microanatomical distribution is mandatory to better understand tumor progression. Imaging Mass Cytometry (IMC) is a high dimensional tissue imaging system which allows the comprehensive and multiparametric in situ exploration of tumor microenvironments at a single cell level. We describe here the design of a 39-antibody IMC panel for the staining of formalin-fixed paraffin-embedded human tumor sections. We also provide an optimized staining procedure and details of the experimental workflow. This panel deciphers the nature of immune cells, their functions and their interactions with tumor cells and cancer-associated fibroblasts as well as with other TiME structural components known to be associated with tumor progression like nerve fibers and tumor extracellular matrix proteins. This panel represents a valuable innovative and powerful tool for fundamental and clinical studies that could be used for the identification of prognostic biomarkers and mechanisms of resistance to current immunotherapies.
Adapting T Cell Receptor Ligand Discrimination Capability via LAT
Authors: Lo Wan-Lin , Weiss Arthur
Published: April 2021

Self- and non-self ligand discrimination is a core principle underlying T cell-mediated immunity. Mature αβ T cells can respond to a foreign peptide ligand presented by major histocompatibility complex molecules (pMHCs) on antigen presenting cells, on a background of continuously sensed self–pMHCs. How αβ T cells can properly balance high sensitivity and high specificity to foreign pMHCs, while surrounded by a sea of self-peptide ligands is not well understood. Such discrimination cannot be explained solely by the affinity parameters of T cell antigen receptor (TCR) and pMHC interaction. In this review, we will discuss how T cell ligand discrimination may be molecularly defined by events downstream of the TCR–pMHC interaction. We will discuss new evidence in support of the kinetic proofreading model of TCR ligand discrimination, and in particular how the kinetics of specific phosphorylation sites within the adaptor protein linker for activation of T cells (LAT) determine the outcome of TCR signaling. In addition, we will discuss emerging data regarding how some kinases, including ZAP-70 and LCK, may possess scaffolding functions to more efficiently direct their kinase activities.
Photosynthesis and Bio-Optical Properties of Fluorescent Mesophotic Corals
Authors: Ben-Zvi Or , Wangpraseurt Daniel , Bronstein Omri , Eyal Gal , Loya Yossi
Published: April 2021

Mesophotic coral ecosystems (MCEs) are light-dependent coral-associated communities found at 30–150 m depth. Corals inhabiting these deeper reefs are often acclimatized to a limited and blue-shifted light environment, enabling them to maintain the relationship with their photosynthetic algal symbionts (family Symbiodiniaceae) despite the seemingly suboptimal light conditions. Among others, fluorescent proteins produced by the coral host may play a role in the modulation of the quality and spectral distribution of irradiance within the coral tissue through wavelength transformation. Here we examined the bio-optical properties and photosynthetic performances of different fluorescence morphs of two mesophotic coral species Goniopora minor and Alveopora ocellata, in order to test the photosynthesis enhancement hypothesis proposed for coral fluorescence. The green morph of G. minor and the low fluorescence morph of A. ocellata exhibit, in their natural habitats, higher abundance. The morphs also presented different spectral reflectance and light attenuation within the tissue. Nevertheless, chlorophyll a fluorescence-based, and O2 evolution measurements, revealed only minor differences between the photosynthetic abilities of three fluorescence morphs of the coral G. minor and two fluorescence morphs of A. ocellata. The fluorescence morphs did not differ in their algal densities or chlorophyll concentrations and all corals harbored Symbiodiniaceae from the genus Cladocopium. Thus, despite the change in the internal light quantity and quality that corals and their symbionts experience, we found no evidence for the facilitation or enhancement of photosynthesis by wavelength transformation.
A Visitor of Tropical Waters: First Record of a Clymene Dolphin (Stenella clymene) Off the Patagonian Coast of Argentina, With Comments on Diet and Metazoan Parasites
Authors: Hernández-Orts Jesús S. , Hernández-Mena David I. , Pantoja Camila , Kuchta Roman , García Néstor A. , Crespo Enrique A. , Loizaga Rocío
Published: April 2021

The poorly known Clymene dolphin (Stenella clymene) is a small oceanic cetacean distributed in tropical and subtropical waters of the Atlantic Ocean. In this study, we report, for the first time, a vagrant individual of Clymene dolphin in Argentina (Rada Tilly) that represents the current southern-most record for this cetacean species. We provide a molecular identification of the dolphin, based on partial sequences of the mitochondrial cytochrome b gene, generated from DNA extracted from its metazoan parasites. Three prey species, namely Argentine hake, Patagonian squid and lobster krill were identified from hard pieces collected in the stomach. Seven metazoan parasite taxa (three in adult stage, one immature stage and three in larval stage) were identified using morphological and molecular data, i.e., the digenean Pholeter gastrophilus (new host record), the cestodes Tetrabothrius (Tetrabothrius) forsteri, Clistobothrium grimaldii unidentified phyllobothriid plerocercoids, the nematodes Anisakis pegreffii (new host record), Halocercus delphini and the acanthocephalan Corynosoma australe (new host record). Our study provides the first molecular exploration of the metazoan parasite diversity in delphinids from the southwestern Atlantic, and contributes significantly to understand the poorly known parasite fauna of the Clymene dolphin.
The Impact of Serum Anti-neutrophil Cytoplasmic Antibody on Clinical Characteristics and Outcomes in Pediatric-Onset Systemic Lupus Erythematosus Patients
Authors: Gau Chun-Chun , Tseng Min-Hua , Wu Chao-Yi , Yang Huang-Yu , Huang Jing-Long
Published: April 2021

Background:Systemic lupus erythematosus (SLE), an autoimmune disease, is characterized by the overproduction of autoantibodies. Anti-neutrophil cytoplasmic antibodies (ANCAs) have been recognized in SLE for decades. To date, their association with SLE disease activity, especially in pediatric-onset SLE (pSLE) patients, is limited.

Methods:We conducted a retrospective case-control study of pSLE patients with ANCAs from 2010 to 2020. Clinical characteristics, laboratory data, renal histological features, treatment and outcomes were analyzed.

Results:A total of 70 pediatric-onset SLE patients (9 ANCA-positive vs. 61 ANCA-negative) with a median age of 12.23 years (age ranging from 4 years to 18 years) at diagnosis were enrolled. Among patients with ANCAs, MPO-ANCA was found in seven and PR3-ANCA in two of those cases. Patients with ANCAs had a tendency to have hematuria compared with those without ANCAs (66 vs. 24.6%, respectively;p= 0.026). Of the 70 SLE patients, 8 with ANCAs and 44 without ANCAs underwent renal biopsies. Patients with ANCAs (25%, 2/8) were more likely to lack the typical full-house pattern in their renal immunofluorescence (IF) staining.

Conclusion:pSLE patients with ANCAs tend to have hematuria and an absence of typical IF histology. However, patients with and without ANCAs showed no difference in their clinical presentations and treatment outcomes.
Adverse Health-Related Quality of Life Outcome Despite Adequate Clinical Response to Treatment in Systemic Lupus Erythematosus
Authors: Gomez Alvaro , Qiu Victor , Cederlund Arvid , Borg Alexander , Lindblom Julius , Emamikia Sharzad , Enman Yvonne , Lampa Jon , Parodis Ioannis
Published: April 2021

Objective: To determine the prevalence of adverse health-related quality of life (HRQoL) outcomes in patients with SLE who achieved an adequate clinical response after a 52-week long standard therapy plus belimumab or placebo, and identify contributing factors.

Methods: We included patients who met the primary endpoint of the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials, i.e., SLE Responder Index 4 (total population: N = 760/1,684; placebo: N = 217/562; belimumab 1 mg/kg: N = 258/559; belimumab 10 mg/kg: N = 285/563). Adverse HRQoL outcomes were defined as SF-36 scale scores ≤ the 5th percentile derived from age- and sex-matched population-based norms, and FACIT-Fatigue scores <30. We investigated factors associated with adverse HRQoL outcomes using logistic regression analysis.

Results: We found clinically important diminutions of HRQoL in SLE patients compared with matched norms and high frequencies of adverse HRQoL outcomes, the highest in SF-36 general health (29.1%), followed by FACIT-Fatigue (25.8%) and SF-36 physical functioning (25.4%). Overall, frequencies were higher with increasing age. Black/African American and White/Caucasian patients reported higher frequencies than Asians and Indigenous Americans, while Hispanics experienced adverse HRQoL outcome less frequently than non-Hispanics. Established organ damage was associated with adverse physical but not mental HRQoL outcomes; particularly, damage in the cardiovascular (OR: 2.12; 95% CI: 1.07–4.21; P = 0.032) and musculoskeletal (OR: 1.41; 95% CI: 1.01–1.96; P = 0.041) domains was associated with adverse SF-36 physical component summary. Disease activity showed no impact on HRQoL outcomes. In multivariable logistic regression analysis, addition of belimumab to standard therapy was associated with lower frequencies of adverse SF-36 physical functioning (OR: 0.59; 95% CI: 0.39–0.91; P = 0.016) and FACIT-F (OR: 0.53; 95% CI: 0.34–0.81; P = 0.004).

Conclusions: Despite adequate clinical response to standard therapy plus belimumab or placebo, a substantial proportion of SLE patients still reported adverse HRQoL outcomes. While no impact was documented for disease activity, established organ damage contributed to adverse outcome within physical HRQoL aspects and add-on belimumab was shown to be protective against adverse physical functioning and severe fatigue.
Identification of an IRGP Signature to Predict Prognosis and Immunotherapeutic Efficiency in Bladder Cancer
Authors: Zhang Liang-Hao , Li Long-Qing , Zhan Yong-Hao , Zhu Zhao-Wei , Zhang Xue-Pei
Published: April 2021

Background

Identify immune-related gene pairs (IRGPs) signature related to the prognosis and immunotherapeutic efficiency for bladder cancer (BLCA) patients.

Materials and Methods

One RNA-seq dataset (The Cancer Genome Atlas Program) and two microarray datasets (GSE13507 and GSE31684) were included in this study. We defined these cohorts as training set to construct IRGPs and one immunotherapy microarray dataset as validation set. Identifying BLCA subclasses based on IRGPs by consensus clustering. The Lasso penalized Cox proportional hazards regression model was used to construct prognostic signature and potential molecular mechanisms were analyzed.

Results

This signature can accurately predict the overall survival of BLCA patients and was verified in the immunotherapy validation set. IRGP-signatures can be used as independent prognostic risk factor in various clinical subgroups. Use the CIBERSORT algorithm to assess the abundance of infiltrating immune cells in each sample, and combine the results of the gene set enrichment analysis of a single sample to explore the differences in the immune microenvironment between IRPG signature groups. According to the results of GSVA, GSEA, and CIBERSORT algorithm, we found that IRGP is strikingly positive correlated with tumor microenvironment (TME) stromal cells infiltration, indicating that the poor prognosis and immunotherapy might be caused partly by enrichment of stromal cells. Finally, the results from the TIDE analysis revealed that IRGP could efficiently predict the response of immunotherapy in BLCA.

Conclusion

The novel IRGP signature has a significant prognostic value for BLCA patients might facilitate personalized for immunotherapy.
Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines
Authors: Lim Kue Peng , Zainal Nur Syafinaz
Published: April 2021

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.
Kanamycin-Mediated Conformational Dynamics of Escherichia coli Outer Membrane Protein TolC
Authors: Pattanayak Biraja S. , Dehury Budheswar , Priyadarshinee Mamali , Jha Suman , Beuria Tushar K. , Soren Dhananjay , Mallick Bairagi C.
Published: April 2021

TolC is a member of the outer membrane efflux proteins (OEPs) family and acts as an exit duct to export proteins, antibiotics, and substrate molecules across the Escherichia coli cell membrane. Export of these molecules is evidenced to be brought about through the reversible interactions and binding of substrate-specific drug molecules or antibiotics with TolC and by being open for transport, which afterward leads to cross-resistance. Hence, the binding of kanamycin with TolC was monitored through molecular docking (MD), the structural fluctuations and conformational changes to the atomic level. The results were further supported from the steady-state fluorescence binding and isothermal titration calorimetry (ITC) studies. Binding of kanamycin with TolC resulted in a concentration dependent fluorescence intensity quenching with 7 nm blue shift. ITC binding data maintains a single binding site endothermic energetic curve with binding parameters indicating an entropy driven binding process. The confirmational changes resulting from this binding were monitored by a circular dichroism (CD) study, and the results showed insignificant changes in the α-helix and β-sheets secondary structure contents, but the tertiary structure shows inclusive changes in the presence of kanamycin. The experimental data substaintially correlates the RMSD, Rg, and RMSF results. The resulting conformational changes of the TolC-kanamycin complexation was stabilized through H-bonding and other interactions.
Development and Validation of a Nomogram Based on Motoric Cognitive Risk Syndrome for Cognitive Impairment
Authors: Liu Yong , Wei Kai , Cao Xinyi , Jiang Lijuan , Gu Nannan , Feng Lei , Li Chunbo
Published: April 2021

Objective

To develop and validate a prediction nomogram based on motoric cognitive risk syndrome for cognitive impairment in healthy older adults.

Methods

Using two longitudinal cohorts of participants (aged ≥ 60 years) with 4-year follow-up, we developed (n = 1,177) and validated (n = 2,076) a prediction nomogram. LASSO (least absolute shrinkage and selection operator) regression model and multivariable Cox regression analysis were used for variable selection and for developing the prediction model, respectively. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness.

Results

The individualized prediction nomogram was assessed based on the following: motoric cognitive risk syndrome, education, gender, baseline cognition, and age. The model showed good discrimination [Harrell’s concordance index (C-index) of 0.814; 95% confidence interval, 0.782–0.835] and good calibration. Comparable results were also seen in the validation cohort, which includes good discrimination (C-index, 0.772; 95% confidence interval, 0.776–0.818) and good calibration. Decision curve analysis demonstrated that the prediction nomogram was clinically useful.

Conclusion

This prediction nomogram provides a practical tool with all necessary predictors, which are accessible to practitioners. It can be used to estimate the risk of cognitive impairment in healthy older adults.
Serotoninergic Modulation of Phototactic Variability Underpins a Bet-Hedging Strategy in Drosophila melanogaster
Authors: Krams Indrikis A. , Krama Tatjana , Krams Ronalds , Trakimas Giedrius , Popovs Sergejs , Jõers Priit , Munkevics Maris , Elferts Didzis , Rantala Markus J. , Makņa Jānis , de Bivort Benjamin L.
Published: April 2021

When organisms’ environmental conditions vary unpredictably in time, it can be advantageous for individuals to hedge their phenotypic bets. It has been shown that a bet-hedging strategy possibly underlies the high inter-individual diversity of phototactic choice in Drosophila melanogaster. This study shows that fruit flies from a population living in a boreal and relatively unpredictable climate have more variable variable phototactic biases than fruit flies from a more stable tropical climate, consistent with bet-hedging theory. We experimentally show that phototactic variability of D. melanogaster is regulated by the neurotransmitter serotonin (5-HT), which acts as a suppressor of the variability of phototactic choices. When fed 5-HT precursor, boreal flies exhibited lower variability, and they were insensitive to 5-HT inhibitor. The opposite pattern was seen in the tropical flies. Thus, the reduction of 5-HT in fruit flies’ brains may be the mechanistic basis of an adaptive bet-hedging strategy in a less predictable boreal climate.
Non-Cell-Autonomous Regulation of Optic Nerve Regeneration by Amacrine Cells
Authors: Sergeeva Elena G. , Rosenberg Paul A. , Benowitz Larry I.
Published: April 2021

Visual information is conveyed from the eye to the brain through the axons of retinal ganglion cells (RGCs) that course through the optic nerve and synapse onto neurons in multiple subcortical visual relay areas. RGCs cannot regenerate their axons once they are damaged, similar to most mature neurons in the central nervous system (CNS), and soon undergo cell death. These phenomena of neurodegeneration and regenerative failure are widely viewed as being determined by cell-intrinsic mechanisms within RGCs or to be influenced by the extracellular environment, including glial or inflammatory cells. However, a new concept is emerging that the death or survival of RGCs and their ability to regenerate axons are also influenced by the complex circuitry of the retina and that the activation of a multicellular signaling cascade involving changes in inhibitory interneurons – the amacrine cells (AC) – contributes to the fate of RGCs. Here, we review our current understanding of the role that interneurons play in cell survival and axon regeneration after optic nerve injury.
Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis
Authors: Chen Shixue , Zhang Zhibo , Zheng Xuan , Tao Haitao , Zhang Sujie , Ma Junxun , Liu Zhefeng , Wang Jinliang , Qian Yuanyu , Cui Pengfei , Huang Di , Huang Ziwei , Wu Zhaozhen , Hu Yi
Published: April 2021

Background

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens.

Methods

Published articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata.

Results

A total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09–24.03), a median TTR of 2.05 months (m) (95%CI: 1.85–2.26), and a median DOR of 10.65 m (95%CI: 7.78–13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02–57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47–21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56–22.94]), while I+C (8.09 m [95%CI: 6.86–9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60–17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations.

Conclusions

PD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.
RETRACTED: Circular RNA hsa_circ_0013958 Functions as an Oncogenic Gene Through Modulating miR-532-3p/WEE1 Axis in Hepatocellular Carcinoma
Authors: Ma Tao , Ma Yue , Du Yongjun , Wei Zhongheng , Wang Jianchu , Jun Yufu , Xiao Fenqiang
Published: April 2021

Background

circ0013958 was identified as a biomarker, which can be used for the diagnosis and screening of lung cancer. However, the role of circ0013958 in hepatocellular carcinoma (HCC) remains unclear.

Methods

In our study, quantitative real-time polymerase chain reaction was performed to determine the levels of circ0013958 in HCC tissues and cell lines. EdU, CCK-8, transwell, flow cytometry and tumorigenesis assays were applied to assess the functions of circ0013958 in HCC in vitro and in vivo. Western blot assay was to detect the expression of WEE1. Luciferase reporter assay, bioinformatics analysis and rescue experiments were used to examine the interaction among circ0013958, miR-532-3p and WEE1.

Results

It revealed that circ0013958 was significantly up-regulated in HCC, which was positively correlated with poor prognosis of HCC patients. Circ0013958 promoted HCC cell proliferation and invasion, inhibited cell apoptosis in vitro, and promoted tumorigenesis in vivo. Circ0013958 acted as a miR-532-3p sponge to regulate WEE1 expression, thus promoting the progression of HCC.

Conclusions

Circ0013958 promotes HCC progression through miR-532-3p/WEE1 axis. Circ0013958 may serve as a potential diagnostic biomarker and therapeutic target of HCC.
The Role of Liquid Biopsy in Early Diagnosis of Lung Cancer
Authors: Freitas Cláudia , Sousa Catarina , Machado Francisco , Serino Mariana , Santos Vanessa , Cruz-Martins Natália , Teixeira Armando , Cunha António , Pereira Tania , Oliveira Hélder P. , Costa José Luís , Hespanhol Venceslau
Published: April 2021

Liquid biopsy is an emerging technology with a potential role in the screening and early detection of lung cancer. Several liquid biopsy-derived biomarkers have been identified and are currently under ongoing investigation. In this article, we review the available data on the use of circulating biomarkers for the early detection of lung cancer, focusing on the circulating tumor cells, circulating cell-free DNA, circulating micro-RNAs, tumor-derived exosomes, and tumor-educated platelets, providing an overview of future potential applicability in the clinical practice. While several biomarkers have shown exciting results, diagnostic performance and clinical applicability is still limited. The combination of different biomarkers, as well as their combination with other diagnostic tools show great promise, although further research is still required to define and validate the role of liquid biopsies in clinical practice.
Preoperative Assessment for Event-Free Survival With Hepatoblastoma in Pediatric Patients by Developing a CT-Based Radiomics Model
Authors: Jiang Yi , Sun Jingjing , Xia Yuwei , Cheng Yan , Xie Linjun , Guo Xia , Guo Yingkun
Published: April 2021

Objective: To explore a CT-based radiomics model for preoperative prediction of event-free survival (EFS) in patients with hepatoblastoma and to compare its performance with that of a clinicopathologic model.

Patients and Methods: Eighty-eight patients with histologically confirmed hepatoblastoma (mean age: 2.28 ± 2.72 years) were recruited from two institutions between 2002 and 2019 for this retrospective study. They were divided into a training cohort (65 patients from institution A) and a validation cohort (23 patients from institution B). Radiomics features were extracted manually from pretreatment CT images in the portal venous (PV) phase. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to construct a “radiomics signature” and radiomics score (Rad-score) for EFS prediction. Then, a nomogram incorporating the Rad-score, updated staging system, and significant variables of clinicopathologic risk (age, alpha-fetoprotein (AFP) level, histology subtype, tumor diameter) as the radiomic model, clinicopathologic model, and combined clinicopathologic-radiomic model were built for EFS estimation in the training cohort, the performance of which was assessed in an external-validation cohort with respect to clinical usefulness, discrimination, and calibration.

Results: Nine survival-relevant features were selected for a radiomics signature and Rad-score building. Multivariable analysis revealed that histology subtype (P = 0.01), PV (P = 0.001) invasion, and metastasis (P = 0.047) were independent risk factors of EFS. Patients were divided into low- and high-risk groups based on the Rad-score with a cutoff of 0.08 according to survival outcome. The radiomics signature-incorporated nomogram showed good performance (P < 0.001) for EFS estimation (C-Index: 0.810; 95% CI: 0.738–0.882), which was comparable with that of the clinicopathological model for EFS estimation (C-Index: 0.81 vs. 0.85). The radiomics-based nomogram failed to show incremental prognostic value compared with that using the clinicopathologic model. The combined model (radiomics signature plus clinicopathologic parameters) showed significant improvement in the discriminatory accuracy, along with good calibration and greater net clinical benefit, of EFS (C-Index: 0.88; 95% CI: 0.829–0.933).

Conclusion: The radiomics signature can be used as a prognostic indicator for EFS in patients with hepatoblastoma. A combination of the radiomics signature and clinicopathologic risk factors showed better performance in terms of EFS prediction in patients with hepatoblastoma, which enabled precise clinical decision-making.
Clinicopathological Features and Prognoses in Patients With Brain Metastases From Small-Cell Esophageal Carcinoma: A Retrospective Analysis of 18 Patients
Authors: Jiao Wenpeng , Lin Chi , Xiao Linlin , Zhang Xinyuan , Hu Mengzhu , Zhao Min , Wang Jun
Published: April 2021

Objective: This study aims to examine the clinical characteristics of patients with brain metastases (BM) from small-cell esophageal carcinoma (SCEC) and to explore the association of the corresponding factors with overall survival (OS).

Methods: The data of 18 patients with brain metastases from SCEC, diagnosed from January 1, 2006, to December 31, 2018, in the Fourth Hospital of Hebei Medical University were analyzed retrospectively.

Results: The 18 patients who were included in this study accounted for 6.7% of the patients with SCEC diagnosed from 2006 to 2018. Of the 18 patients, 8 (44.4%) were females. For the entire cohort, the median OS was 7 months, the 1-year OS was 22.2%, and the 2-year OS was 0%. For patients who received whole-brain radiotherapy (WBRT) and for those who did not (13 vs. 5), the median OS was 11.9 and 3 months, respectively, and the 1-year OS was 30.8 and 0%, respectively. When comparing diagnosis-specific Graded Prognostic Assessment (DS-GPA) scores of patients with BM from SCEC ranging from 2.5 to 4 and from 0 to 2, the median OS was 13.1 and 4 months, respectively, and the 1-year OS was 57.1 and 0%, respectively. In the univariable regression, patients who received WBRT had improved OS compared to those who did not (HR = 0.249, p = 0.018), and patients with a DS-GPA score of 2.5–4 were associated with improved OS compared with patients with a DS-GPA score of 0–2 (HR = 0.050, p = 0.005).

Conclusion: The incidence of brain metastases in patients with SCEC is low, but the prognosis in those patients is very poor. The DS-GPA score may be a prognostic factor of patients with BM from SCEC. Brain radiotherapy could improve the survival of these patients.
Case Report: MIS-C Temporarily Associated With COVID-19 Complicated by Reye's Syndrome
Authors: Pessoa Fabrício Silva , Lacerda Eliza Maria da Costa Brito , Gonçalves Valdênia Costa , Tanaka Barbara Neiva
Published: April 2021

We describe a 7-year-old child with multisystemic inflammatory syndrome that was temporarily associated with the novel coronavirus disease which evolved into serious illness, with coronary aneurysm, using human immunoglobulin and acetylsalicylic acid, in which clinical manifestations including hepatitis, convulsions, and coma were aggravated with Reye's syndrome. To date, there has been no report of the association of multisystemic inflammatory syndrome that is temporarily associated with the novel coronavirus disease and Reye's syndrome.
Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy
Authors: Kušíková Katarína , Feichtinger René Günther , Csillag Bernhard , Kalev Ognian Kostadinov , Weis Serge , Duba Hans-Christoph , Mayr Johannes Adalbert , Weis Denisa
Published: April 2021

Mitochondriopathies represent a wide spectrum of miscellaneous disorders with multisystem involvement, which are caused by various genetic changes. The establishment of the diagnosis of mitochondriopathy is often challenging. Recently, several mutations of the VARS2 gene encoding the mitochondrial valyl-tRNA synthetase were associated with early onset encephalomyopathies or encephalocardiomyopathies with major clinical features such as hypotonia, developmental delay, brain MRI changes, epilepsy, hypertrophic cardiomyopathy, and plasma lactate elevation. However, the correlation between genotype and phenotype still remains unclear. In this paper we present a male Caucasian patient with a recurrent c.1168G>A (p.Ala390Thr) and a new missense biallelic variant c.2758T>C (p.Tyr920His) in the VARS2 gene which were detected by whole exome sequencing (WES). VARS2 protein was reduced in the patient's muscle. A resulting defect of oxidative phosphorylation (OXPHOS) was proven by enzymatic assay, western blotting and immunohistochemistry from a homogenate of skeletal muscle tissue. Clinical signs of our patient included hyperlactatemia, hypertrophic cardiomyopathy (HCM) and pulmonary hypertension, which led to early death at the age of 47 days without any other known accompanying signs. The finding of novel variants in the VARS2 gene expands the spectrum of known mutations and phenotype presentation. Based on our findings we recommend to consider possible mitochondriopathy and to include the analysis of the VARS2 gene in the genetic diagnostic algorithm in cases with early manifesting and rapidly progressing HCM with hyperlactatemia.
Cardioprotective Roles of β-Hydroxybutyrate Against Doxorubicin Induced Cardiotoxicity
Authors: Liu Yihai , Wei Xuan , Wu Mingyue , Xu Jiamin , Xu Biao , Kang Lina
Published: April 2021

Background: β-Hydroxybutyrate (BHB) is produced by fatty acid oxidation in the liver under the fasting state and confirmed to play a cardioprotective role in ischemia and hypertensive settings. Doxorubicin (DOX) is an effective chemotherapeutic drug, but limited by serious irreversible cardiotoxicity. However, whether BHB can protect from DOX-induced cardiotoxicity remains unknown.

Methods and Results: C57BL/6 mice were intraperitoneally injected with DOX to induce cardiac toxicity and intragastrically administered into BHB for treatment. They were randomly divided into three groups, namely a sham group (Sham), a doxorubicin group (DOX), and a doxorubicin+β-Hydroxybutyrate group (DOX + BHB). Echocardiography and pathological staining were performed to evaluate cardiac function and fibrosis. H9c2 cardiomyocyte was treated with DOX or BHB for in vitro experiments. Cell apoptosis and ROS were determined by flow cytometry. BHB significantly restored DOX-induced cardiac function decline and partially prevented cardiac reverse remodeling, characterized by increased cell size and decreased fibrosis. In vitro, BHB treatment decreased cellular injury and apoptosis. Also, BHB alleviated oxidative stress level and increased mitochondrial membrane potential.

Conclusion: Our results suggested that BHB could protected from DOX-induced cardiotoxicity by inhibiting cell apoptosis and oxidative stress and maintaining mitochondrial membrane integrity.
Ficus erecta Thunb. Leaves Ameliorate Cognitive Deficit and Neuronal Damage in a Mouse Model of Amyloid-β-Induced Alzheimer’s Disease
Authors: Sohn Eunjin , Kim Yu Jin , Kim Joo-Hwan , Jeong Soo-Jin
Published: April 2021

Alzheimer’s disease (AD) pathogenesis is linked to amyloid plaque accumulation, neuronal loss, and brain inflammation. Ficus erecta Thunb. is a food and medicinal plant used to treat inflammatory diseases. Here, we investigated the neuroprotective effects of F. erecta Thunb. against cognitive deficit and neuronal damage in a mouse model of amyloid-β (Aβ)-induced AD. First, we confirmed the inhibitory effects of ethanol extracts of F. erecta (EEFE) leaves on Aβ aggregation in vivo and in vitro. Next, behavioral tests (passive avoidance task and Morris water maze test) revealed EEFE markedly improved cognitive impairment in Aβ-injected mice. Furthermore, EEFE reduced neuronal loss and the expression of neuronal nuclei (NeuN), a neuronal marker, in brain tissues of Aβ-injected mice. EEFE significantly reversed Aβ-induced suppression of cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression, indicating neuroprotection was mediated by the CREB/BDNF signaling. Moreover, EEFE significantly suppressed the inflammatory cytokines interleukin 1beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and expression of ionized calcium-binding adaptor molecule 1 (Iba-1), a marker of microglial activation, in brain tissues of Aβ-injected mice, suggesting anti-neuroinflammatory effects. Taken together, EEFE protects against cognitive deficit and neuronal damage in AD-like mice via activation of the CREB/BDNF signaling and upregulation of the inflammatory cytokines.
Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon
Authors: Hao Wenzhi , Wu Jiajia , Yuan Naijun , Gong Lian , Huang Junqing , Ma Qingyu , Zhu Huizheng , Gan Hua , Da Xiaoli , Deng Lijuan , Li Xiaojuan , Chen Jiaxu
Published: April 2021

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1β, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.
Guaiazulene Triggers ROS-Induced Apoptosis and Protective Autophagy in Non-small Cell Lung Cancer
Authors: Ye Qin , Zhou Li , Jin Ping , Li Lei , Zheng Shuwen , Huang Zhao , Liu Jiayang , Qin Siyuan , Liu Hao , Zou Bingwen , Xie Ke
Published: April 2021

Non-small cell lung cancer (NSCLC) is one of the most frequent cancers worldwide, yet effective treatment remains a clinical challenge. Guaiazulene (GYZ), a cosmetic color additive, has previously been characterized as a potential antitumor agent due to observed anticancer effects. However, the efficacy of GYZ in the treatment of NSCLC and the involved molecular mechanisms remain largely unknown. Here, we indicated a role for GYZ in the suppression of NSCLC both in vitro and in vivo via triggering reactive oxygen species (ROS)-induced apoptosis. Concomitantly, GYZ induced complete autophagic flux in NSCLC cells via inhibiting the Akt/mTOR signaling pathway, which displayed cytoprotective effect against GYZ-induced growth suppression. Accompanied with autophagy inhibition obviously enhanced the effects of GYZ. Notably, GYZ acts synergistically with paclitaxel in the suppression of NSCLC in vitro. Together, our results for the first time reported that GYZ suppressed the proliferation of NSCLC and suggested a potential strategy for inhibiting NSCLC growth by combinational use of GYZ and autophagy inhibitors.
Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy
Authors: Liu Hui-Min , Guo Chun-Ling , Zhang Yao-Fang , Chen Jian-Fang , Liang Zhi-Peng , Yang Lin-Hua , Ma Yan-Ping
Published: April 2021

Leonurine, an active natural alkaloid compound isolated from Herba leonuri, has been reported to exhibit promising anticancer activity in solid tumors. The aim of this study was to explore whether leonurine is able to inhibit chronic myeloid leukemia (CML) malignancy. Here, we found that leonurine dose dependently inhibited the proliferation, migration, colony formation and promoted apoptosis of CML cells. Furthermore, leonurine markedly reduced CML xenograft growth in vivo. Mechanically, leonurine upregulated SOCS5 expression, thus leading JAK2/STAT3 signaling suppression. Silencing of SOCS5 by its siRNA abrogated the effect of leonurine on CML cells, demonstrating that SOCS5 mediates the anti-leukemia effect of leonurine. Notably, we observed that miR-18a-5p was remarkably increased in CML cells. Treating CML cells with leonurine significantly decreased miR-18a-5p expression. Moreover, we found miR-18a-5p repressed SOCS5 by directly targeting its 3′-UTR. miR-18a-5p downregulation induced by leonurine reduced the biological activity of CML cells by relieving miR-18a-5p repression of SOCS5 expression. Taken together, leonurine exerts significant anti-leukemia efficacy in CML by regulating miR-18a-5p/SOCS5/JAK2/STAT3 axis.