bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of LncRNA SNHG14 as a biomarker of clinicopathological and prognosis value in human cancers: A meta-analysis and bioinformatics analysis
Authors: Liu Bin , Lu Tingting , Wang Yongfeng , Zhang Guangming , Fu Liangyin , Yu Miao , Yang Kehu , Cai Hui
Published: October 2022

Background: SNGH14 is a newly discovered long non-coding RNA (lncRNA) highly associated with tumorigenesis. However, whether the level of SNHG14 is related to the prognosis of patients with different cancer types is unclear.

Methods: PubMed, Web of Science, Cochrane Library, and Embase were searched to identify eligible studies from inception to November 2021. The odds ratio (OR) and 95% confidence interval (CI) were utilized to analyze dichotomous variables, while the hazard ratio (HR) and 95% CI were used for survival outcomes. We also included trial sequential analysis (TSA) to assess whether the current evidence was sufficiently conclusive. Stata 15.0 and TSA 0.9 software were used for data analyses.

Results: A total of 21 studies involving 1,080 patients, mainly from China, were included. Our results revealed that high SNHG14 expression was associated significantly with poor overall survival (OS) [HR = 1.39; 95% CI: (1.06–1.83); p = 0.017]. In addition, elevated SNHG14 expression was related to tumor size (> 3.5 cm) [OR = 1.60; 95% CI: (1.20–2.14); p = 0.001], TNM staging [OR = 0.54; 95% CI: (0.40–0.71); p < 0.001], lymph node metastasis [OR = 1.86; 95% CI: (1.35–2.55); p < 0.001], differentiation grade [OR = 1.95; 95% CI: (1.36–2.80); p < 0.001], and distant metastasis [OR = 2.44; 95% CI: (1.30–4.58); p = 0.005]. However, no significant difference was observed between age [OR = 0.98; 95% CI: (0.72–1.35); p = 0.915] and gender [OR = 0.98; 95% CI: (0.72–1.35); p = 0.915] from the enhanced expression of SNHG14.

Conclusion: The current study revealed that overexpression of SNGH14 is associated with low OS rate and clinicopathological characteristics. SNGH14 can be a novel tumor marker that aids in tumor diagnosis, thereby improving patient prognosis.
Clinical neutrophil-associated genes as reliable predictors of hepatocellular carcinoma
Authors: Song Lishan , Xu Chaojie , Zhang Tong , Chen Shengyang , Hu Shuiquan , Cheng Bingbing , Tong Hao , Li Xiaoyong
Published: October 2022

Background: Growing evidence suggests that infiltrating neutrophils are key players in hepatocellular carcinoma (HCC) tumor progression. However, a comprehensive analysis of the biological roles of neutrophil infiltration and related genes in clinical outcomes and immunotherapy is lacking.

Methods: HCC samples were obtained from the TCGA and GEO databases. The CIBERSORT algorithm was used to reveal the TIME landscape. Gene modules significantly associated with neutrophils were found using weighted gene co-expression network analysis (WGCNA), a “dynamic tree-cut” algorithm, and Pearson correlation analysis. Genes were screened using Cox regression analysis and LASSO and prognostic value validation was performed using Kaplan-Meier curves and receiver operating characteristic (ROC) curves. Risk scores (RS) were calculated and nomograms were constructed incorporating clinical variables. Gene set variation analysis (GSVA) was used to calculate signaling pathway activity. Immunophenoscore (IPS) was used to analyze differences in immunotherapy among samples with different risk scores. Finally, the relationship between RS and drug sensitivity was explored using the pRRophetic algorithm.

Results: 10530 genes in 424 samples (50 normal samples, 374 tumor samples) were obtained from the TCGA database. Using WGCNA, the “MEbrown” gene module was most associated with neutrophils. Nine genes with prognostic value in HCC (PDLIM3, KLF2, ROR2, PGF, EFNB1, PDZD4, PLN, PCDH17, DOK5) were finally screened. Prognostic nomograms based on RS, gender, tumor grade, clinical stage, T, N, and M stages were constructed. The nomogram performed well after calibration curve validation. There is an intrinsic link between risk score and TMB and TIME. Samples with different risk scores differed in different signaling pathway activity, immunopharmaceutical treatment and chemotherapy sensitivity.

Conclusion: In conclusion, a comprehensive analysis of neutrophil-related prognostic features will help in prognostic prediction and advance individualized treatment.
Bet v 1-displaying elastin-like polypeptide nanoparticles induce a strong humoral and weak CD4+ T-cell response against Bet v 1 in a murine immunogenicity model
Authors: van Strien Jolinde , Warmenhoven Hans , Logiantara Adrian , Makurat Max , Aglas Lorenz , Bethanis Athanasios , Leboux Romain , van Rijt Leonie , MacKay J. Andrew , van Schijndel Johannes W. , Schneider Gregory , Olsthoorn René , Jiskoot Wim , van Ree Ronald , Kros Alexander
Published: October 2022

There is growing concern about the toxicity of colloidal aluminum salts used as adjuvants in subcutaneous allergen immunotherapy (SCIT). Therefore, alternative adjuvants and delivery systems are being explored to replace alum in SCIT. We applied micellar elastin-like polypeptides (ELPs), a type of self-assembling protein, to replace alum as vaccine adjuvant in birch pollen SCIT. ELP and an ELP-Bet v 1 fusion protein were expressed inE. coliand purified by immuno-affinity chromatography and inverse-transition cycling (ITC). Nanoparticles self-assembled from ELP and a 9:1 ELP/ELP-Bet v 1 mixture were characterized by using dynamic light scattering and atomic force microscopy. Allergenicity was assessed by measuring mediator release from rat basophilic leukemia cells transformed with the human FcϵR1 and sensitized with sera derived from human birch pollen allergic patients. Humoral and T-cell immunity were investigated by immunizing naïve mice with the ELP/ELP-Bet v 1 nanoparticles or alum-adsorbed Bet v 1, both containing 36 µg Bet v 1. ELP and ELP/ELP-Bet v 1 self-assembled at 37°C into spherically shaped micelles with a diameter of ~45 nm. ELP conjugation made Bet v 1 hypo-allergenic (10-fold). Compared to alum-adsorbed Bet v 1, ELP/ELP-Bet v 1 nanoparticles induced stronger IgG responses with an earlier onset. Additionally, ELP/ELP-Bet v 1 did not induce Th2 skewing cytokines and IgE. The hypoallergenic character and strong humoral immune response in the absence of a Th2-skewing T-cell response make ELP-based nanoparticles a promising candidate to replace alum in SCIT.
The bridge of the gut–joint axis: Gut microbial metabolites in rheumatoid arthritis
Authors: Xu Xiaoyu , Wang Miao , Wang Zikang , Chen Qian , Chen Xixuan , Xu Yingyue , Dai Min , Wu Bin , Li Yanping
Published: October 2022

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint destruction, synovitis, and pannus formation. Gut microbiota dysbiosis may exert direct pathogenic effects on gut homeostasis. It may trigger the host’s innate immune system and activate the “gut–joint axis”, which exacerbates the RA. However, although the importance of the gut microbiota in the development and progression of RA is widely recognized, the mechanisms regulating the interactions between the gut microbiota and the host immune system remain incompletely defined. In this review, we discuss the role of gut microbiota-derived biological mediators, such as short-chain fatty acids, bile acids, and tryptophan metabolites, in maintaining intestinal barrier integrity, immune balance and bone destruction in RA patients as the bridge of the gut–joint axis.
NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies
Authors: Moltrasio Chiara , Romagnuolo Maurizio , Marzano Angelo Valerio
Published: October 2022

The NLRP3 inflammasome is one of the NOD-like receptor family members with the most functional characterization and acts as a key player in innate immune system, participating in several physiological processes including, among others, the modulation of the immune system response and the coordination of host defences. Activation of the inflammasome is a crucial signaling mechanism that promotes both an acute and a chronic inflammatory response, which can accelerate the production of pro-inflammatory cytokines, mainly Interleukin (IL)-1β and IL-18, leading to an exacerbated inflammatory network. Cryopyrin associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder, clinically characterized by cutaneous and systemic, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients, in which an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies. During recent years, two new hereditary NLRP3-related disorders have been described, deafness autosomal dominant 34 (DFN34) and keratitis fugax hereditaria (KFH), with an exclusive cochlear- and anterior eye- restricted autoinflammation, respectively, and caused by mutations in NLRP3 gene, thus expanding the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases. Several crucial mechanisms involved in the control of activation and regulation of the NLRP3 inflammasome have been identified and researchers took advantage of this to develop novel target therapies with a significant improvement of clinical signs and symptoms of NLRP3-associated diseases. This review provides a broad overview of NLRP3 inflammasome biology with particular emphasis on CAPS, whose clinical, genetic, and therapeutic aspects will be explored in depth. The latest evidence on two “new” diseases, DFN34 and KFH, caused by mutations in NLRP3 is also described.
Cytokine levels associated with favorable clinical outcome in the CAPSID randomized trial of convalescent plasma in patients with severe COVID-19
Authors: Körper Sixten , Schrezenmeier Eva Vanessa , Rincon-Arevalo Hector , Grüner Beate , Zickler Daniel , Weiss Manfred , Wiesmann Thomas , Zacharowski Kai , Kalbhenn Johannes , Bentz Martin , Dollinger Matthias M. , Paul Gregor , Lepper Philipp M. , Ernst Lucas , Wulf Hinnerk , Zinn Sebastian , Appl Thomas , Jahrsdörfer Bernd , Rojewski Markus , Lotfi Ramin , Dörner Thomas , Jungwirth Bettina , Seifried Erhard , Fürst Daniel , Schrezenmeier Hubert
Published: October 2022

Objectives

To determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP).

Methods

Patients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models.

Results

The majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models.

Conclusion

This analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.
Self-reactivity of CD8 T-cell clones determines their differentiation status rather than their responsiveness in infections
Authors: Paprckova Darina , Niederlova Veronika , Moudra Alena , Drobek Ales , Pribikova Michaela , Janusova Sarka , Schober Kilian , Neuwirth Ales , Michalik Juraj , Huranova Martina , Horkova Veronika , Cesnekova Michaela , Simova Michaela , Prochazka Jan , Balounova Jana , Busch Dirk H. , Sedlacek Radislav , Schwarzer Martin , Stepanek Ondrej
Published: October 2022

Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8+ T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8+ T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.
Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
Authors: Maldonado-Pérez Noelia , Tristán-Manzano María , Justicia-Lirio Pedro , Martínez-Planes Elena , Muñoz Pilar , Pavlovic Kristina , Cortijo-Gutiérrez Marina , Blanco-Benítez Carlos , Castella María , Juan Manel , Wenes Mathias , Romero Pedro , Molina-Estévez Francisco J. , Marañón Concepción , Herrera Concha , Benabdellah Karim , Martin Francisco
Published: October 2022

Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies. However, the generation of patient-specific CAR-T products delays treatment and precludes standardization. Allogeneic off-the-shelf CAR-T cells are an alternative to simplify this complex and time-consuming process. Here we investigated safety and efficacy of knocking out the TCR molecule in ARI-0001 CAR-T cells, a second generation αCD19 CAR approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) under the Hospital Exemption for treatment of patients older than 25 years with Relapsed/Refractory acute B cell lymphoblastic leukemia (B-ALL). We first analyzed the efficacy and safety issues that arise during disruption of the TCR gene using CRISPR/Cas9. We have shown that edition of TRAC locus in T cells using CRISPR as ribonuleorproteins allows a highly efficient TCR disruption (over 80%) without significant alterations on T cells phenotype and with an increased percentage of energetic mitochondria. However, we also found that efficient TCRKO can lead to on-target large and medium size deletions, indicating a potential safety risk of this procedure that needs monitoring. Importantly, TCR edition of ARI-0001 efficiently prevented allogeneic responses and did not detectably alter their phenotype, while maintaining a similar anti-tumor activity ex vivo and in vivo compared to unedited ARI-0001 CAR-T cells. In summary, we showed here that, although there are still some risks of genotoxicity due to genome editing, disruption of the TCR is a feasible strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We propose to further validate this protocol for the treatment of patients that do not fit the requirements for standard autologous CAR-T cells administration.
Self-sampling to identify pathogens and inflammatory markers in patients with acute sore throat: Feasibility study
Authors: Lown Mark , Miles Elizabeth A. , Fisk Helena L. , Smith Kirsten A. , Muller Ingrid , Maund Emma , Rogers Kirsty , Becque Taeko , Hayward Gail , Moore Michael , Little Paul , Glogowska Margaret , Hay Alastair D. , Stuart Beth , Mantzourani Efi , Butler Chris , Bostock Jennifer , Davies Firoza , Dickerson Ian , Thompson Natalie , Francis Nick
Published: October 2022

Introduction

Sore throat is a common reason for overuse of antibiotics. The value of inflammatory or biomarkers in throat swab or saliva samples in predicting benefit from antibiotics is unknown.

Methods

We used the ‘person-based approach’ to develop an online tool to support self-swabbing and recruited adults and children with sore throats through participating general practices and social media. Participants took bacterial and viral swabs and a saliva sponge swab and passive drool sample. Bacterial swabs were cultured for streptococcus (Group A, B, C, F and G). The viral swab and saliva samples were tested using a routine respiratory panel PCR and Covid-19 PCR testing. We used remaining viral swab and saliva sample volume for biomarker analysis using a panel of 13 biomarkers.

Results

We recruited 11 asymptomatic participants and 45 symptomatic participants. From 45 symptomatic participants, bacterial throat swab, viral throat swab, saliva sponge and saliva drool samples were returned by 41/45 (91.1%), 43/45 (95.6%), 43/45 (95.6%) and 43/45 (95.6%) participants respectively. Three saliva sponge and 6 saliva drool samples were of insufficient quantity. Two adult participants had positive bacterial swabs. Six participants had a virus detected from at least one sample (swab or saliva). All of the biomarkers assessed were detectable from all samples where there was sufficient volume for testing. For most biomarkers we found higher concentrations in the saliva samples. Due to low numbers, we were not able to compare biomarker concentrations in those who did and did not have a bacterial pathogen detected. We found no evidence of a difference between biomarker concentrations between the symptomatic and asymptomatic participants but the distributions were wide.

Conclusions

We have demonstrated that it is feasible for patients with sore throat to self-swab and provide saliva samples for pathogen and biomarker analysis. Typical bacterial and viral pathogens were detected but at low prevalence rates. Further work is needed to determine if measuring biomarkers using oropharyngeal samples can help to differentiate between viral and bacterial pathogens in patients classified as medium or high risk using clinical scores, in order to better guide antibiotic prescribing and reduce inappropriate prescriptions.
Costimulators expressed on human endothelial cells modulate antigen-dependent recruitment of circulating T lymphocytes
Authors: Manes Thomas D. , Wang Vivian , Pober Jordan S.
Published: October 2022

Endothelial cells (ECs) can present antigens to circulating effector memory T cells (TEM) and to regulatory T cells (T regs), triggering antigen-specific extravasation at specific sites where foreign antigens are introduced, e.g. by infection or transplantation. We model human antigen-induced transendothelial migration (TEM) using presentation of superantigen by cultured human dermal microvascular (HDM)ECs to isolated resting human peripheral blood T cell subpopulations or to T effector cells activatedin vitro. T cell receptor (TCR)-mediated cytokine synthesis, a common assay of T cell activation by antigen, is modulated by antigen-independent signals provided by various positive or negative costimulator proteins (the latter known as checkpoint inhibitors) expressed by antigen presenting cells, including ECs. We report here that some EC-expressed costimulators also modulate TCR-TEM, but effects differ between TEM and cytokine production and among some T cell types. Blocking EC LFA-3 interactions with TEMCD2 boosts TEM but reduces cytokine production. Blocking EC ICOS-L interactions with TEMCD28 (but not ICOS) reduces both responses but these involve distinct CD28-induced signals. Activated CD4+ T effector cells no longer undergo TCR-TEM. Engagement of T cell CD28 by EC ICOS-L increases TCR-TEM by activated CD8 effectors while engagement of OX40 promotes TCR-TEM by activated CD4 T regs. B7-H3 mostly affects TEM of resting TEMand some checkpoint inhibitors affect cytokine synthesis or TEM depending upon subtype. Our data suggest that blockade or mimicry of costimulators/checkpoint inhibitorsin vivo, clinically used to modulate immune responses, may act in part by modulating T cell homing.
Turning up a new pattern: Identification of cancer-associated fibroblast-related clusters in TNBC
Authors: Xie Jindong , Zheng Shaoquan , Zou Yutian , Tang Yuhui , Tian Wenwen , Wong Chau-Wei , Wu Song , Ou Xueqi , Zhao Wanzhen , Cai Manbo , Xie Xiaoming
Published: October 2022

Growing evidence indicates a connection between cancer-associated fibroblasts (CAFs) and tumor microenvironment (TME) remodeling and tumor progression. Nevertheless, how patterns of CAFs impact TME and immunotherapy responsiveness in triple-negative breast cancer (TNBC) remains unclear. Here, we systematically investigate the relationship between TNBC progression and patterns of CAFs. By using unsupervised clustering methods in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, we identified two distinct CAF-associated clusters that were related to clinical features, characteristics of TME, and prognosis of patients. Then, we established a CAF-related prognosis index (CPI) by the least absolute shrinkage and selection operator (LASSO)-Cox regression method. CPI showed prognostic accuracy in both training and validation cohorts (METABRIC, GSE96058, and GSE21653). Consequently, we constructed a nomogram with great predictive performance. Moreover, the CPI was verified to be correlated with the responsiveness of immunotherapy in three independent cohorts (GSE91061, GSE165252, and GSE173839). Taken together, the CPI might help us improve our recognition of the TME of TNBC, predict the prognosis of TNBC patients, and offer more immunotherapy strategies in the future.
Identification of cell senescence molecular subtypes in prediction of the prognosis and immunotherapy of hepatitis B virus-related hepatocellular carcinoma
Authors: Yu Xue , Chen Peng , Yi Wei , Ruan Wen , Xiong Xiaoli
Published: October 2022

Hepatitis B virus (HBV)-infected hepatocellular carcinoma (HCC) has a high incidence and fatality rate worldwide, being among the most prevalent cancers. The growing body of data indicating cellular senescence (CS) to be a critical factor in hepatocarcinogenesis. The predictive value of CS in HBV-related HCC and its role in the immune microenvironment are unknown. To determine the cellular senescence profile of HBV-related HCC and its role in shaping the immune microenvironment, this study employed a rigorous evaluation of multiple datasets encompassing 793 HBV-related HCC samples. Two novel distinct CS subtypes were first identified by nonnegative matrix factorization, and we found that the senescence-activated subgroup had the worst prognosis and correlated with cancer progression. C1 and C2 were identified as the senescence-suppressed and senescence-activated subgroups. The immune microenvironment indicated that C2 exhibited a relatively low immune status, higher tumor purity, and lower immune scores and estimated scores, while the C1 subgroup possessed a better prognosis. The CS score signature based on five genes (CENPA, EZH2, G6PD, HDAC1, and PRPF19) was established using univariate Cox regression and the lasso method. ICGC-LIRI and GSE14520 cohorts were used to validate the reliability of the CS scoring system. In addition, we examined the association between the risk score and hallmark pathways through gene set variation analysis and gene set enrichment analysis. The results revealed a high CS score to be associated with the activation of cell senescence-related pathways. The CS score and other clinical features were combined to generate a CS dynamic nomogram with a better predictive capacity for OS at 1, 2, and 3 years than other clinical parameters. Our study demonstrated that cellular senescence patterns play a non-negligible role in shaping the characteristics of the immune microenvironment and profoundly affecting tumor prognosis. The results of this study will help predict patient prognosis more accurately and may assist in development of personalized immunotherapy for HBV-related HCC patients.
Inhibition of MRGPRX2 but not FcεRI or MrgprB2-mediated mast cell degranulation by a small molecule inverse receptor agonist
Authors: Bawazir Maram , Amponnawarat Aetas , Hui Yvonne , Oskeritzian Carole A. , Ali Hydar
Published: October 2022

Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) contributes to hypersensitivity reactions to cationic US-Food and Drug Administration (FDA) approved drugs such as the neuromuscular blocking agent, rocuronium. In addition, activation of MRGPRX2 by the neuropeptide substance P (SP) and the pro-adrenomedullin peptide (PAMP-12) is associated with a variety of cutaneous conditions such as neurogenic inflammation, pain, atopic dermatitis, urticaria, and itch. Thus, small molecules aimed at blocking MRGPRX2 constitute potential options for modulating IgE-independent MC-mediated disorders. Two inverse MRGPRX2 agonists, named C9 and C9-6, have recently been identified, which inhibit basal G protein activation and agonist-induced calcium mobilization in transfected HEK293 cells. Substance P serves as a balanced agonist for MRGPRX2 whereby it activates both G protein-mediated degranulation and β-arrestin-mediated receptor internalization. The purpose of this study was to determine if C9 blocks MRGPRX2’s G protein and β-arrestin-mediated signaling and to determine its specificity. We found that C9, but not its inactive analog C7, inhibited degranulation in RBL-2H3 cells stably expressing MRGPRX2 in response to SP, PAMP-12 and rocuronium with an IC50 value of ~300 nM. C9 also inhibited degranulation as measured by cell surface expression of CD63, CD107a and β-hexosaminidase release in LAD2 cells and human skin-derived MCs in response to SP but not the anaphylatoxin, C3a or FcϵRI-aggregation. Furthermore, C9 inhibited β-arrestin recruitment and MRGPRX2 internalization in response to SP and PAMP-12. We found that a G protein-coupling defective missense MRGPRX2 variant (V282M) displays constitutive activity for β-arrestin recruitment, and that this response was significantly inhibited by C9. Rocuronium, SP and PAMP-12 caused degranulation in mouse peritoneal MCs and these responses were abolished in the absence of MrgprB2 or cells treated with pertussis toxin but C9 had no effect. These findings suggest that C9 could provide an important framework for developing novel therapeutic approaches for the treatment of IgE-independent MC-mediated drug hypersensitivity and cutaneous disorders.
Histamine induced high mobility group box-1 release from vascular endothelial cells through H1 receptor
Authors: Gao Shangze , Liu Keyue , Ku Wenhan , Wang Dengli , Wake Hidenori , Qiao Handong , Teshigawara Kiyoshi , Nishibori Masahiro
Published: October 2022

Background

Systemic allergic reaction is characterized by vasodilation and vascular leakage, which causes a rapid, precipitous and sustained decrease in arterial blood pressure with a concomitant decrease of cardiac output. Histamine is a major mediator released by mast cells in allergic inflammation and response. It causes a cascade of inflammation and strongly increases vascular permeability within minutes through its four G-protein-coupled receptors (GPCRs) on endothelial cells. High mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extracellular space by endothelial cells. HMGB1 has been reported to exert pro-inflammatory effects on endothelial cells and to increase vascular endothelial permeability. However, the relationship between histamine and HMGB1-mediated signaling in vascular endothelial cells and the role of HMGB1 in anaphylactic-induced hypotension have never been studied.

Methods and results

EA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H1 receptor antagonist, but not by H2 or H3/4 receptor antagonists. Moreover, an H1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibody successfully facilitated the recovery from compound 48/80-induced hypotension.

Conclusion

Histamine induces HMGB1 release from vascular endothelial cells solely through H1 receptor stimulation. Anti-HMGB1 therapy may provide a novel treatment for life-threatening systemic anaphylaxis.
Clinical relevance of vitamin B12 level and vitamin B12 metabolic gene variation in pulmonary tuberculosis
Authors: Zhang Tian-Ping , Li Rui , Wang Li-Jun , Tang Fei , Li Hong-Miao
Published: October 2022

The aim of this study was to assess the association of vitamin B12 level and single nucleotide polymorphisms (SNPs) in vitamin B12 metabolic genes with pulmonary tuberculosis (PTB) in Chinese Han population. The plasma vitamin B12 expression level was detected using ELISA. Ten SNPs in six key genes (TCN1, TCN2, CUBN, MMACHC, FUT6, and MUT) of vitamin B12 metabolic pathway were included for genotyping by the SNPscan technique among 454 PTB patients and 467 controls. Our results found that vitamin B12 level was significantly reduced in PTB patients when compared with controls. There was no significant association between TCN1 rs526934, TCN2 rs1801198, CUBN rs7906242, rs10904861, rs1801222, MMACHC rs10789465, FUT6 rs3760776, rs3760775, MUT rs9473555, rs9381784 variants, and PTB susceptibility. TCN2 rs1801198 CC genotype, C allele was significantly associated with hypoproteinemia in PTB patients. In CUBN, rs7906242 GG genotype, G allele, rs10904861 TT genotype, and T allele were significantly related to the decreased frequency of sputum smear-positive, and rs10904861 variant affected the occurrence of drug resistance in PTB patients. In addition, the increased frequency of CUBN rs1801222 AA genotype was significantly associated with leukopenia. The decreased frequency of MUT rs9473555 CC genotype was found in the PTB patients with hypoproteinemia. However, vitamin B12 expression was not associated with the genotype distribution of above SNPs. In conclusion, vitamin B12 level was significantly decreased in PTB patients and genetic variants in vitamin B12 metabolic genes were not contributed to PTB susceptibility. Several SNPs in TCN2, CUBN, and MUT gene might associate with multiple clinical manifestations in PTB.
A durable response to programmed cell death 1 blockade in a multidrug-resistant recurrent ovarian cancer patient with HLA-B44 supertype: A case report
Authors: Luo Xukai , Sun Yating , Li Jiajia , Jiang Qidi , Yuan Lei , Li Ting , Chen Mo , Yao Liangqing
Published: October 2022

Relapsed/refractory ovarian cancer, especially platinum resistance recurrence, remains a major therapeutic challenge. Here, we present the case of a patient with recurrent ovarian clear cell carcinoma (OCCC) who failed to respond to multiline chemotherapy and target therapy but achieved an immune complete response (iCR) with programmed cell death 1 (PD-1) inhibitor treatment. The overall survival (OS) was 59 months, and the recurrence-free survival (RFS) was 34 months after immunotherapy, which was counting. Meantime, molecular testing results revealed that traditional biomarkers for immunotherapy, including PD-L1 expression, microsatellite instability (MSI), and tumor mutational burden (TMB), were negative. HLA-B44 (B*18:01) supertype was confirmed by sequence-based HLA typing. This case raises the possibility that ovarian cancer patients with multidrug resistance may still benefit from PD-1 inhibitor therapy, even if PD-L1 pathology is negative.
UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling
Authors: Sancerni Tiphaine , Renoult Ophélie , Luby Angèle , Caradeuc Cédric , Lenoir Véronique , Croyal Mikael , Ransy Céline , Aguilar Esther , Postic Catherine , Bertho Gildas , Dentin Renaud , Prip-Buus Carina , Pecqueur Claire , Alves-Guerra Marie-Clotilde
Published: October 2022

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells.
Identifying a novel ferroptosis-related prognostic score for predicting prognosis in chronic lymphocytic leukemia
Authors: Pan Bihui , Li Yue , Xu Zhangdi , Miao Yi , Yin Hua , Kong Yilin , Zhang Xinyu , Liang Jinhua , Xia Yi , Wang Li , Li Jianyong , Wu Jiazhu , Xu Wei
Published: October 2022

Background

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Although the treatment landscape for CLL is rapidly evolving, there are still some patients who develop drug resistance or disease refractory. Ferroptosis is a type of lipid peroxidation–induced cell death and has been suggested to have prognostic value in several cancers. Our research aims to build a prognostic model to improve risk stratification in CLL patients and facilitate more accurate assessment for clinical management.

Methods

The differentially expressed ferroptosis-related genes (FRGs) in CLL were filtered through univariate Cox regression analysis based on public databases. Least absolute shrinkage and selection operator (LASSO) Cox algorithms were performed to construct a prognostic risk model. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were performed to estimate the immune infiltration score and immune-related pathways. A total of 36 CLL patients in our center were enrolled in this study as a validation cohort. Moreover, a nomogram model was established to predict the prognosis.

Results

A total of 15 differentially expressed FRGs with prognostic significance were screened out. After minimizing the potential risk of overfitting, we constructed a novel ferroptosis-related prognostic score (FPS) model with nine FRGs (AKR1C3, BECN1, CAV1, CDKN2A, CXCL2, JDP2, SIRT1, SLC1A5, and SP1) and stratified patients into low- and high-risk groups. Kaplan–Meier analysis showed that patients with high FPS had worse overall survival (OS) (P<0.0001) and treatment-free survival (TFS) (P<0.0001). ROC curves evaluated the prognostic prediction ability of the FPS model. Additionally, the immune cell types and immune-related pathways were correlated with the risk scores in CLL patients. In the validation cohort, the results confirmed that the high-risk group was related to worse OS (P<0.0001), progress-free survival (PFS) (P=0.0140), and TFS (P=0.0072). In the multivariate analysis, only FPS (P=0.011) and CLL-IPI (P=0.010) were independent risk indicators for OS. Furthermore, we established a nomogram including FPS and CLL-IPI that could strongly and reliably predict individual prognosis.

Conclusion

A novel FPS model can be used in CLL for prognostic prediction. The model index may also facilitate the development of new clinical ferroptosis-targeted therapies in patients with CLL.
Immunotherapy improves disease prognosis by affecting the tumor microenvironment: A bibliometric study
Authors: Wu Xin , Deng Zhen , Zhao Qiangqiang
Published: October 2022

Background

Immunotherapy has shown great potential for the treatment of multiple cancer and has been proven to be closely related to the tumor microenvironment. This article reveals collaborations and interactions among authors, nations, organizations, and periodicals assesses the knowledge base, and discovers hot tendencies and new topics associated with immunotherapy-tumor microenvironment (TME) research.

Methods

This article utilized bibliometrics and visual methods to provide a comprehensive overview of immunotherapy-TME research. Our team retrieved the WoSCC for research and reviews associated with immunotherapy and the tumor microenvironment. VOSviewer and Citespace were primarily used for literature measurement and knowledge graph analysis.

Result

All English articles and reviews on cancer immunotherapy effectiveness were collected, and 1,419 academic journals with 53,773 authors from 7,008 institutions in 92 countries/regions were found. Publications associated with immunotherapy-TME research were stably increasing. Frontiers of Immunology (n = 722) published the most papers on immunotherapy-TME, and Cancer Research (n = 6761) was the top co-cited journal. The published journals and co-cited journals focused on cancer and immunology fields. The League of European Research Universities (n = 978), Harvard University (n = 528), and the University of Texas system (n = 520) were the most productive institutions. Yang Liu (n = 34) and Topalian (n = 1978) ranked first among the top 10 scholars and co-cited scholars. Simultaneously, immunotherapy-TME researchers were involved in active collaborations. Elements of TME, the foundation of immunotherapy, and the application of immunotherapy in cancers represented the three principal aspects of immunotherapy-TME research. The latest hot spots are drug resistance, prognosis prediction, efficacy prediction, and m6A. Nanomedicine and m6A may be future hot topics. Future research in immunotherapy-TME may be directed at discovering how m6A modification affects tumor development by altering the tumor microenvironment and exploring how to enhance response or reduce drug resistance to immunotherapy by reversing or mediating the physicochemical properties of the TME.

Conclusions

M6A and nanomedicine are also emerging hotspots in time zone diagrams with high centrality, and prognosis prediction using bioinformatics based on the development of prediction technology may be another future research hotspot.
A retrospective study of the correlation between herpes zoster neuralgia and the serum neuron-specific enolase level in the largest dermatological hospital in Zhejiang province, China
Authors: Zhong Changyang , Lin Ding , Liu Yuan , Wu Chunli
Published: October 2022

We studied the changes and clinical significance of the serum neuron-specific enolase (NSE) level in peripheral blood of patients with post-herpetic neuralgia (PHN).

Material and methods

Patients with PHN were divided into a mild PHN group and a severe PHN group according to their scores on a 100-point Likert scale representing the degree of neuralgia. NSE levels in neuralgia patients and healthy volunteers were then compared by t-test. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic efficiency of NSE for PHN. The correlation between NSE level and Likert scale score after treatment was analyzed.

Results

NSE levels in PHN patients were higher than those in the healthy volunteers. Patients in the severe PHN group had higher NSE levels than those in the mild PHN group. NSE level at admission was associated with the Likert scale score recorded on the 14th day of treatment (136.1 ± 32.81 vs. 87.53 ± 16.23 pg/mL) (P < 0.05). The ROC curve of NSE levels for PHN is shown that the area was 0.8713 (95% confidence interval, 0.7861–0.9564; p < 0.0001).

Conclusions

There was a correlation between NSE and PHN, in that the NSE level positively correlated with the short-term prognosis of patients with PHN.
Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice
Authors: Hatamnejad Mohammad Reza , Baradaran Ghavami Shaghayegh , Shirvani Marzieh , Asghari Ahmadabad Mona , Shahrokh Shabnam , Farmani Maryam , Sherkat Ghazal , Asadzadeh Aghdaei Hamid , Zali Mohammad Reza
Published: October 2022

IBD, a chronic inflammatory disease, has been manifested as a growing health problem. No Crohn’s and Colitis councils have officially ratified anti-depressants as a routine regimen for IBD patients. However, some physicians empirically prescribe them to rectify functional bowel consequences such as pain and alleviate psychiatric comorbidities. On the other side, SSRIs’ prescription is accompanied by adverse effects such as sleep disturbances. Prolonged intermittent hypoxia throughout sleep disturbance such as sleep apnea provokes periodic reductions in the partial oxygen pressure gradient in the gut lumen. It promotes gut microbiota to dysbiosis, which induces intestinal inflammation. This phenomenon and evidence representing the higher amount of serotonin associated with Crohn’s disease challenged our previous knowledge. Can SSRIs worsen the IBD course? Evidence answered the question with the claim on anti-inflammatory properties (central and peripheral) of SSRIs and illuminated the other substantial elements (compared to serotonin elevation) responsible for IBD pathogenesis. However, later clinical evidence was not all in favor of the benefits of SSRIs. Hence, in this review, the molecular mechanisms and clinical evidence are scrutinized and integrated to clarify the interfering molecular mechanism justifying both supporting and disproving clinical evidence. Biphasic dose-dependent serotonin behavior accompanying SSRI shifting function when used up for the long-term can be assumed as the parameters leading to IBD patients’ adverse outcomes. Despite more research being needed to elucidate the effect of SSRI consumption in IBD patients, periodic prescriptions of SSRIs at monthly intervals can be recommended.
Tumor microenvironment features decipher the outperformance of neoadjuvant immunochemotherapy over chemotherapy in resectable non-small cell lung cancer
Authors: Cai Wenhan , Jing Miao , Gu Yajun , Bei Ting , Zhao Xiaochen , Chen Shiqing , Wen Jiaxin , Gao Jie , Wu Chongchong , Xue Zhiqiang
Published: October 2022

This study evaluated the efficacy of neoadjuvant immunochemotherapy (Io+Chemo) versus chemotherapy alone (Chemo) in resectable non–small cell lung cancer (NSCLC) in a real-world setting. The association of tumor immune microenvironment (TIME) with pathologic response to different neoadjuvant therapies was also explored.Stage I−III NSCLC patients who received Io+Chemo or Chemo alone followed by surgery were included in the study. Tumor tissues collected during surgery were subjected to TIME evaluation using multiplex immunohistochemistry to measure immune cell subsets, including T cells, B cells, NK cells, and macrophages. Fifty-five patients were included, including 24 treated with neoadjuvant Io+Chemo and 31 with Chemo alone. Io+Chemo induced significantly higher major pathologic response (MPR) (75.0% vs. 38.7%, P = 0.0133) and numerically better pathologic complete response (pCR) (33.3% vs. 12.9%, P = 0.1013) than Chemo. Compared with tumors with Chemo, tumors with Io+Chemo demonstrated a significantly higher ratio of M1 macrophage density in the tumor to that in the stroma (P = 0.0446), more abundant CD8+ cells in the stroma (P = 0.0335), and fewer PD-L1+CD68+ cells in both tumor and stroma. pCR/MPR patients displayed significantly higher density of CD3+, CD3+CD4+, CD20+, CD56 bright cell subsets and more tertiary lymphoid structures and significantly lower density of PD-L1+CD68+ and CD3+CD4+Foxp3+cells in the tumor or stroma. This study favored neoadjuvant Io+Chemo over Chemo and revealed the TIME features underlying the outperformance of Io+Chemo over Chemo.
Case report: A successful re-challenge report of GLS-010 (Zimberelimab), a novel fully humanized mAb to PD-1, in a case of recurrent endometrial cancer
Authors: Chen Yeshan , Huang Ai , Yang Qin , Yu Jing , Li Guiling
Published: October 2022

With the widespread use of immune checkpoint inhibitors (ICI), there is growing concern about reports of immune-related adverse events (irAE). In clinical practice, patients who experience severe toxicities by ICI-based therapies would require utmost caution in resuming ICI therapy because of the potential risk of serious irAEs caused by the reintroduction of immunotherapy. In this study, we report a case of recurrent endometrial cancer patient with PD-L1 positive as well as dMMR suffering from immunotherapy-associated myocarditis after first-line treatment with ICI combined with a multi-targeted anti-angiogenic agent. After symptomatic treatment, the patient was in complete remission from treatment toxicities. Subsequently, through MDT discussions, we selected a new PD-1 agent, zimberelimab, for rechallenge therapy, and the patient achieved a sustained disease remission without any treatment-related toxicities. To date, the manner and timing of the ICI re-challenge has been a subject of iterative deliberation. We believe that our experience could shed some light on ICI rechallenge therapy, and we look forward to more literatures to refine the ICI rechallenge scenarios.