bluuebunny/crossref_metadata_2025 huggingface dataset:
Programmable Attenuation of Antigenic Sensitivity for a Nanobody-Based EGFR Chimeric Antigen Receptor Through Hinge Domain Truncation
Authors: McComb Scott , Nguyen Tina , Shepherd Alex , Henry Kevin A. , Bloemberg Darin , Marcil Anne , Maclean Susanne , Zafer Ahmed , Gilbert Rénald , Gadoury Christine , Pon Robert A. , Sulea Traian , Zhu Qin , Weeratna Risini D.
Published: July 2022

Epidermal growth factor family receptor (EGFR) is commonly overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR)-T therapy, but as EGFR is also expressed at lower levels in healthy tissues a therapeutic strategy must balance antigenic responsiveness against the risk of on-target off-tumor toxicity. Herein, we identify several camelid single-domain antibodies (also known as nanobodies) that are effective EGFR targeting moieties for CARs (EGFR-sdCARs) with very strong reactivity to EGFR-high and EGFR-low target cells. As a strategy to attenuate their potent antigenic sensitivity, we performed progressive truncation of the human CD8 hinge commonly used as a spacer domain in many CAR constructs. Single amino acid hinge-domain truncation progressively decreased both EGFR-sdCAR-Jurkat cell binding to EGFR-expressing targets and expression of the CD69 activation marker. Attenuated signaling in hinge-truncated EGFR-sdCAR constructs increased selectivity for antigen-dense EGFR-overexpressing cells over an EGFR-low tumor cell line or healthy donor derived EGFR-positive fibroblasts. We also provide evidence that epitope location is critical for determining hinge-domain requirement for CARs, as hinge truncation similarly decreased antigenic sensitivity of a membrane-proximal epitope targeting HER2-CAR but not a membrane-distal EGFRvIII-specific CAR. Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors in vitro and in vivo. Overall, these results indicate that hinge length tuning provides a programmable strategy for throttling antigenic sensitivity in CARs targeting membrane-proximal epitopes, and could be employed for CAR-optimization and improved tumor selectivity.
Structure-Guided Engineering of a Complement Component C3-Binding Nanobody Improves Specificity and Adds Cofactor Activity
Authors: Pedersen Henrik , Jensen Rasmus Kjeldsen , Hansen Annette Gudmann , Petersen Steen Vang , Thiel Steffen , Laursen Nick Stub , Andersen Gregers Rom
Published: July 2022

The complement system is a part of the innate immune system, where it labels intruding pathogens as well as dying host cells for clearance. If complement regulation is compromised, the system may contribute to pathogenesis. The proteolytic fragment C3b of complement component C3, is the pivot point of the complement system and provides a scaffold for the assembly of the alternative pathway C3 convertase that greatly amplifies the initial complement activation. This makes C3b an attractive therapeutic target. We previously described a nanobody, hC3Nb1 binding to C3 and its degradation products. Here we show, that extending the N-terminus of hC3Nb1 by a Glu-Trp-Glu motif renders the resulting EWE-hC3Nb1 (EWE) nanobody specific for C3 degradation products. By fusing EWE to N-terminal CCP domains from complement Factor H (FH), we generated the fusion proteins EWEnH and EWEµH. In contrast to EWE, these fusion proteins supported Factor I (FI)-mediated cleavage of human and rat C3b. The EWE, EWEµH, and EWEnH proteins bound C3b and iC3b with low nanomolar dissociation constants and exerted strong inhibition of alternative pathway-mediated deposition of complement. Interestingly, EWEnH remained soluble above 20 mg/mL. Combined with the observed reactivity with both human and rat C3b as well as the ability to support FI-mediated cleavage of C3b, this features EWEnH as a promising candidate forin vivostudies in rodent models of complement driven pathogenesis.
Efficacy and Safety of Curcumin and Curcuma longa Extract in the Treatment of Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trial
Authors: Zeng Liuting , Yang Tiejun , Yang Kailin , Yu Ganpeng , Li Jun , Xiang Wang , Chen Hua
Published: July 2022

Background

Modern pharmacological research found that the chemical components of Curcuma longa L. are mainly curcumin and turmeric volatile oil. Several recent randomized controlled trials (RCT) have shown that curcumin improves symptoms and inflammation in patients with arthritis.

Methods

Pubmed, Cochran Library, CNKI, and other databases were searched to collect the randomized controlled trials (RCTs). Then, the risk of bias of RCTs were assessed and data of RCTs were extracted. Finally, RevMan 5.3 was utilized for meta-analysis.

Results

Twenty-nine (29) RCTs involving 2396 participants and 5 types of arthritis were included. The arthritis included Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA), Osteoarthritis (OA), Juvenile idiopathic arthritis (JIA) and gout/hyperuricemia. Curcumin and Curcuma longa Extract were administered in doses ranging from 120 mg to 1500 mg for a duration of 4-36 weeks. In general, Curcumin and Curcuma longa Extract showed safety in all studies and improved the severity of inflammation and pain levels in these arthritis patients. However, more RCTs are needed in the future to elucidate the effect of Curcumin and Curcuma longa Extract supplementation in patients with arthritis, including RA, OA, AS and JIA.

Conclusion

Curcumin and Curcuma longa Extract may improve symptoms and inflammation levels in people with arthritis. However, due to the low quality and small quantity of RCTs, the conclusions need to be interpreted carefully.
Cytotoxic T Lymphocyte Antigen 4 Haploinsufficiency Presenting As Refractory Celiac-Like Disease: Case Report
Authors: Collen Lauren V. , Salgado Carlos Andres , Bao Bin , Janssen Erin , Weir Dascha , Goldsmith Jeffrey , Leichtner Alan , Sabery Khavari Nasim , Gernez Yael , Snapper Scott B.
Published: July 2022

Primary immunodeficiency may present with treatment-refractory enteropathy. We present two patients with celiac/celiac-like disease diagnosed in early childhood and refractory to the gluten-free diet. One patient had features of multi-system autoimmunity, whereas the other had celiac-like disease as an isolated clinical finding. Both patients underwent genetic testing given disease refractoriness and were ultimately diagnosed with cytotoxic T lymphocyte antigen 4 (CTLA4) haploinsufficiency. They are both now in complete clinical and endoscopic remission on abatacept. CTLA4 haploinsufficiency has incomplete penetrance and significant phenotypic heterogeneity but should be considered in the differential diagnosis of refractory celiac/celiac-like disease, as treatment implications are significant.
Nano-silica particles synergistically IgE-mediated mast cell activation exacerbating allergic inflammation in mice
Authors: Yang Yong-Shi , Cao Meng-Da , Wang An , Liu Qing-Mei , Zhu Dan-Xuan , Zou Ying , Ma Ling-Ling , Luo Min , Shao Yang , Xu Dian-Dou , Wei Ji-Fu , Sun Jin-Lyu
Published: July 2022

Background

Allergic respiratory diseases have increased dramatically due to air pollution over the past few decades. However, studies are limited on the effects of inorganic components and particulate matter with different particle sizes in smog on allergic diseases, and the possible molecular mechanism of inducing allergies has not been thoroughly studied.

Methods

Four common mineral elements with different particle sizes in smog particles were selected, including Al2O3, TiO2, Fe2O3, and SiO2. We studied the relationship and molecular mechanism of smog particle composition, particle size, and allergic reactions using mast cells, immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis (PCA) model, and an ovalbumin (OVA)-induced asthmatic mouse model in vitro and in vivo, combined with transmission electron microscopy, scanning transmission X-ray microscopy analysis, and transcriptome sequencing.

Results

Only 20 nm SiO2 particles significantly increased β-hexosaminidase release, based on dinitrophenol (DNP)-human serum albumin (HSA) stimulation, from IgE-sensitized mast cells, while other particles did not. Meanwhile, the PCA model showed that Evan’s blue extravasation in mice was increased after treatment with nano-SiO2 particles. Nano-SiO2 particles exposure in the asthmatic mouse model caused an enhancement of allergic airway inflammation as manifested by OVA-specific serum IgE, airway hyperresponsiveness, lung inflammation injury, mucous cell metaplasia, cytokine expression, mast cell activation, and histamine secretion, which were significantly increased. Nano-SiO2 particles exposure did not affect the expression of FcϵRI or the ability of mast cells to bind IgE but synergistically activated mast cells by enhancing the mitogen-activated protein kinase (MAPK) signaling pathway, especially the phosphorylation levels of the extracellular signal-regulated kinase (ERK)1/2. The ERK inhibitors showed a significant inhibitory effect in reducing β-hexosaminidase release.

Conclusion

Our results indicated that nano-SiO2 particles stimulation might synergistically activate IgE-sensitized mast cells by enhancing the MAPK signaling pathway and that nano-SiO2 particles exposure could exacerbate allergic inflammation. Our experimental results provide useful information for preventing and treating allergic diseases.
TRAPS mutations in Tnfrsf1a decrease the responsiveness to TNFα via reduced cell surface expression of TNFR1
Authors: Akagi Takahiko , Hiramatsu-Asano Sumie , Ikeda Kenta , Hirano Hiroyasu , Tsuji Shoko , Yahagi Ayano , Iseki Masanori , Matsuyama Makoto , Mak Tak W. , Nakano Kazuhisa , Ishihara Katsuhiko , Morita Yoshitaka , Mukai Tomoyuki
Published: July 2022

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory periodic fever syndrome associated with heterozygous mutations in TNFRSF1A, which encodes TNF receptor type I (TNFR1). Although possible proinflammatory mechanisms have been proposed, most previous studies were performed using in vitro overexpression models, which could lead to undesirable inflammatory responses due to artificial overexpression. It is crucial to reproduce heterozygous mutations at physiological expression levels; however, such studies remain limited. In this study, we generated TRAPS mutant mice and analyzed their phenotypes. Three Tnfrsf1a mutant strains were generated by introducing T79M, G87V, or T90I mutation. T79M is a known mutation responsible for TRAPS, whereas G87V is a TRAPS mutation that we have reported, and T90I is a variant of unknown significance. Using these murine models, we investigated whether TRAPS mutations could affect the inflammatory responses in vivo and in vitro. We found that none of the mutant mice exhibited detectable inflammatory phenotypes under standard housing conditions for 1 year. Interestingly, TRAPS mutant (T79M and G87V) mice had reduced mortality rates after the administration of lipopolysaccharide (LPS) and D-galactosamine, which induce TNFα-dependent lethal hepatitis. Moreover, TRAPS mutations strongly suppressed the development of TNFα-mediated arthritis when crossed with human TNFα transgenic mice. In in vitro primary bone marrow-derived macrophage cultures, the T79M and G87V mutations attenuated the inflammatory responses to TNFα compared with the wild-type, whereas these mutations did not alter the responsiveness of these cells to LPS. The T90I mutant macrophages behaved similarly to wild type in response to LPS and TNFα. The TNFR1 levels were increased in whole-cell lysates of TRAPS mutant macrophages, whereas the cell surface expression of TNFR1 was significantly decreased in TRAPS mutant macrophages. Taken together, TRAPS mutations did not augment the inflammatory responses to TNFα and LPS; instead, they suppressed the response to TNFα via decreased cell surface expression of TNFR1. The stimulation of lymphotoxin-α, adenosine triphosphate, and norepinephrine in primary macrophages or various stimuli in murine splenocytes did not induce detectable inflammatory responses. In conclusion, TRAPS mutations suppressed responsiveness to TNFα, and TRAPS-associated inflammation is likely induced by unconfirmed disease-specific proinflammatory factors.
A Signature Based on Costimulatory Molecules for the Assessment of Prognosis and Immune Characteristics in Patients With Stomach Adenocarcinoma
Authors: Chen Bangjie , Yao Yong , Mao Deshen , Li Conghan , Wang Xingyu , Sheng Shuyan , Zhang Lizhi , Wang Xinyi , Chen Sanwei , Xu Wentao , Deng Jianyi , Sun Chenyu , Zhou Qin , Lowe Scott , Bentley Rachel , Shao Wei , Li Haiwen
Published: July 2022

Although costimulatory molecules have been shown to boost antitumor immune responses, their significance in stomach adenocarcinoma (STAD) remains unknown. The purpose of this study was to examine the gene expression patterns of costimulatory molecule genes in patients with STAD and develop a predictive signature to aid in therapy selection and outcome prediction. We used 60 costimulatory family genes from prior research to conduct the first complete costimulatory molecular analysis in patients with STAD. In the two study groups, consensus clustering analysis based on these 60 genes indicated unique distribution patterns and prognostic differences. Using the least absolute shrinkage and selection operator and Cox regression analysis, we identified nine costimulatory molecular gene pairs (CMGPs) with prognostic value. With these nine CMGPs, we were able to develop a costimulatory molecule-related prognostic signature that performed well in an external dataset. For the patients with STAD, the signature was proven to be a risk factor independent of the clinical characteristics, indicating that this signature may be employed in conjunction with clinical considerations. A further connection between the signature and immunotherapy response was discovered. The patients with high mutation rates, an abundance of infiltrating immune cells, and an immunosuppressive milieu were classified as high-risk patients. It is possible that these high-risk patients have a better prognosis for immunotherapy since they have higher cytolytic activity scores and immunophenoscores of CTLA4 and PD-L1/PD-L2 blockers. Therefore, our signature may help clinicians in assessing patient prognosis and developing treatment plans.
Critical Roles of G3BP1 in Red-Spotted Grouper Nervous Necrosis Virus-Induced Stress Granule Formation and Viral Replication in Orange-Spotted Grouper (Epinephelus coioides)
Authors: Sun Mengshi , Wu Siting , Kang Shaozhu , Liao Jiaming , Zhang Luhao , Xu Zhuqing , Chen Hong , Xu Linting , Zhang Xin , Qin Qiwei , Wei Jingguang
Published: July 2022

Viral infection causes changes in the internal environment of host cells, and a series of stress responses are generated to respond to these changes and help the cell survive. Stress granule (SG) formation is a type of cellular stress response that inhibits viral replication. However, the relationship between red-spotted grouper nervous necrosis virus (RGNNV) infection and SGs, and the roles of the SG marker protein RAS GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) in viral infection remain unclear. In this study, RGNNV infection induced grouper spleen (GS) cells to produce SGs. The SGs particles co-located with the classic SG marker protein eIF3η, and some SGs depolymerized under treatment with the translation inhibitor, cycloheximide (CHX). In addition, when the four kinases of the eukaryotic translation initiation factor 2α (eIF2α)-dependent pathway were inhibited, knockdown of HRI and GCN2 with small interfering RNAs and inhibition of PKR with 2-aminopurine had little effect on the formation of SGs, but the PERK inhibitor significantly inhibited the formation of SGs and decreased the phosphorylation of eIF2α. G3BP1 of Epinephelus coioides (named as EcG3BP1) encodes 495 amino acids with a predicted molecular weight of 54.12 kDa and 65.9% homology with humans. Overexpression of EcG3BP1 inhibited the replication of RGNNV in vitro by up-regulating the interferon and inflammatory response, whereas knockdown of EcG3BP1 promoted the replication of RGNNV. These results provide a better understanding of the relationship between SGs and viral infection in fish.
Discoidin domain receptor 1 is a potential target correlated with tumor invasion and immune infiltration in gastric cancer
Authors: Wang Songna , Fu Yuan , Kuerban Kudelaidi , Liu Jiayang , Huang Xuan , Pan Danjie , Chen Huaning , Zhu Yizhun , Ye Li
Published: July 2022

Discoidin domain receptor 1 (DDR1) has been demonstrated to be able to promote tumor invasion and metastasis and being closely related to tumor immune infiltration. However, DDR1 has rarely been studied in gastric cancer. Here, we primarily evaluated DDR1 expression in gastric cancer and its cell lines using multiple databases. Subsequently, the cancer prognosis was investigated in relation to DDR1 expression. After analysis, we discovered that DDR1 was highly expressed and significantly connected with poor prognosis in gastric cancer. To comprehensively understand the molecular mechanism of DDR1, we explored genes and proteins interacting with DDR1 in gastric cancer using databases. Additionally, we found that the expression level of DDR1 was inversely correlated with immune infiltration and significantly relative to various immune cell markers. Overall, DDR1 was implicated in invasion, metastasis, and immune infiltration of gastric cancer. Inhibition of DDR1 may have the potential to alleviate the strong invasiveness and metastasis of advanced gastric cancer. Meanwhile, immune exclusion by DDR1 may also provide a new strategy for improving the efficacy of immune checkpoints inhibitors (ICIs), such as programmed cell death protein 1 (PD-1) antibody.
Early and Long-Term HIV-1 Immunogenicity Induced in Macaques by the Combined Administration of DNA, NYVAC and Env Protein-Based Vaccine Candidates: The AUP512 Study
Authors: Perdiguero Beatriz , Asbach Benedikt , Gómez Carmen E. , Köstler Josef , Barnett Susan W. , Koutsoukos Marguerite , Weiss Deborah E. , Cristillo Anthony D. , Foulds Kathryn E. , Roederer Mario , Montefiori David C. , Yates Nicole L. , Ferrari Guido , Shen Xiaoying , Sawant Sheetal , Tomaras Georgia D. , Sato Alicia , Fulp William J. , Gottardo Raphael , Ding Song , Heeney Jonathan L. , Pantaleo Giuseppe , Esteban Mariano , Wagner Ralf
Published: July 2022

To control HIV infection there is a need for vaccines to induce broad, potent and long-term B and T cell immune responses. With the objective to accelerate and maintain the induction of substantial levels of HIV-1 Env-specific antibodies and, at the same time, to enhance balanced CD4 and CD8 T cell responses, we evaluated the effect of concurrent administration of MF59-adjuvanted Env protein together with DNA or NYVAC vectors at priming to establish if early administration of Env leads to early induction of antibody responses. The primary goal was to assess the immunogenicity endpoint at week 26. Secondary endpoints were (i) to determine the quality of responses with regard to RV144 correlates of protection and (ii) to explore a potential impact of two late boosts. In this study, five different prime/boost vaccination regimens were tested in rhesus macaques. Animals received priming immunizations with either NYVAC or DNA alone or in combination with Env protein, followed by NYVAC + protein or DNA + protein boosts. All regimens induced broad, polyfunctional and well-balanced CD4 and CD8 T cell responses, with DNA-primed regimens eliciting higher response rates and magnitudes than NYVAC-primed regimens. Very high plasma binding IgG titers including V1/V2 specific antibodies, modest antibody-dependent cellular cytotoxicity (ADCC) and moderate neutralization activity were observed. Of note, early administration of the MF59-adjuvanted Env protein in parallel with DNA priming leads to more rapid elicitation of humoral responses, without negatively affecting the cellular responses, while responses were rapidly boosted after repeated immunizations, indicating the induction of a robust memory response. In conclusion, our findings support the use of the Env protein component during priming in the context of an heterologous immunization regimen with a DNA and/or NYVAC vector as an optimized immunization protocol against HIV infection.
IFN-I inducible miR-3614-5p targets ADAR1 isoforms and fine tunes innate immune activation
Authors: Vuillier Françoise , Li Zhi , Black Iain , Cruciani Melania , Rubino Erminia , Michel Frédérique , Pellegrini Sandra
Published: July 2022

Regulation of innate immune responses is essential for maintenance of immune homeostasis and development of an appropriate immunity against microbial infection. We show here that miR-3614-5p, product of the TRIM25 host gene, is induced by type I interferon (IFN-I) in several human non-immune and immune cell types, in particular in primary myeloid cells. Studies in HeLa cells showed that miR-3614-5p represses both p110 and p150 ADAR1 and reduces constitutive and IFN-induced A-to-I RNA editing. In line with this, activation of innate sensors and expression of IFN-β and the pro-inflammatory IL-6 are promoted. MiR-3614-5p directly targets ADAR1 transcripts by binding to one specific site in the 3’UTR. Moreover, we could show that endogenous miR-3614-5p is associated with Ago2 and targets ADAR1 in IFN-stimulated cells. Overall, we propose that, by reducing ADAR1, IFN-I-induced miR-3614-5p contributes to lowering the activation threshold of innate sensors. Our findings provide new insights into the role of miR-3614-5p, placing it as a potential fine tuner of dsRNA metabolism, cell homeostasis and innate immunity.
Efficient cellular and humoral immune response and production of virus-neutralizing antibodies by the Hepatitis B Virus S/preS116-42 antigen
Authors: Pantazica Ana-Maria , Dobrica Mihaela-Olivia , Lazar Catalin , Scurtu Cristina , Tucureanu Catalin , Caras Iuliana , Ionescu Irina , Costache Adriana , Onu Adrian , Clarke Jihong Liu , Stavaru Crina , Branza-Nichita Norica
Published: July 2022

Despite the availability of improved antiviral therapies, infection with Hepatitis B virus (HBV) remains a3 significant health issue, as a curable treatment is yet to be discovered. Current HBV vaccines relaying on the efficient expression of the small (S) envelope protein in yeast and the implementation of mass vaccination programs have clearly contributed to containment of the disease. However, the lack of an efficient immune response in up to 10% of vaccinated adults, the controversies regarding the seroprotection persistence in vaccine responders and the emergence of vaccine escape virus mutations urge for the development of better HBV immunogens. Due to the critical role played by the preS1 domain of the large (L) envelope protein in HBV infection and its ability to trigger virus neutralizing antibodies, including this protein in novel vaccine formulations has been considered a promising strategy to overcome the limitations of S only-based vaccines. In this work we aimed to combine relevant L and S epitopes in chimeric antigens, by inserting preS1 sequences within the external antigenic loop of S, followed by production in mammalian cells and detailed analysis of their antigenic and immunogenic properties. Of the newly designed antigens, the S/preS116–42 protein assembled in subviral particles (SVP) showed the highest expression and secretion levels, therefore, it was selected for further studies in vivo. Analysis of the immune response induced in mice vaccinated with S/preS116–42- and S-SVPs, respectively, demonstrated enhanced immunogenicity of the former and its ability to activate both humoral and cellular immune responses. This combined activation resulted in production of neutralizing antibodies against both wild-type and vaccine-escape HBV variants. Our results validate the design of chimeric HBV antigens and promote the novel S/preS1 protein as a potential vaccine candidate for administration in poor-responders to current HBV vaccines.
Analysis of the OX40/OX40L immunoregulatory axis combined with alternative immune checkpoint molecules in pancreatic ductal adenocarcinoma
Authors: Chen Xianlong , Ma Heng , Mo Shengwei , Zhang Yue , Lu Zhaohui , Yu Shuangni , Chen Jie
Published: July 2022

Immune checkpoint modulation has been a vital therapeutic option in many malignancies, and targeting of novel immune checkpoints, including OX40/OX40L costimulatory signaling, is being assessed in clinical trials. However, little is known about the role of OX40 and OX40L in pancreatic ductal adenocarcinoma (PDAC). Thus, we investigated the clinical significance of OX-40 and OX40L and their associations with alternative immune checkpoints, immune infiltrates, clinicopathological features, and clinical outcomes. We performed multiplexed immunofluorescence staining for OX40, OX40L, CD8, and CD68 using tissue microarrays from 255 patients. Immunohistochemistry data for PD-L1, B7-H3, B7-H4, CD3, and Foxp3 were analyzed. And the RNA sequencing data of OX40/OX40L in The Cancer Genome Atlas and International Cancer Genome Consortium databases were also evaluated. The positive rates for OX40 on tumor cells (TCs) and immune cells (ICs) were 8.6% and 10.2%, respectively, and the positive rates for OX40L on TCs, ICs, and macrophages were 20%, 40.4%, and 12.9%, respectively. OX40 was associated with favorable clinicopathological features. OX40+ on ICs, OX40L+ on TCs, or OX40L+ on macrophages, rather than the total gene and protein levels of OX40/OX40L, were associated with improved survival. OX40+ on ICs and OX40L+ on macrophages were independent factors of clinical outcomes. Moreover, we could more accurately stratify patients through the combination of OX40 on ICs and OX40L on TCs, and patients with OX40+ ICs and OX40L+CK+ showed the best outcome. And we demonstrated that patients with OX40-ICs and low CD8+ T cells infiltration had unfavorable survival. Intriguingly, OX40+ ICs or OX40L+ macrophages demonstrated superior survival in patients with PD-L1 negativity than in those with PD-L1 positivity. Furthermore, OX40+ ICs were correlated with negative B7-H4 on TCs, high densities of CD3 T cells, and high densities of Foxp3 T cells; OX40+ TCs and OX40L+ TCs were associated with low densities of Foxp3 T cells. We identified OX40 and OX40L as promising predictors for prognosis in PDAC.
Research progress on the proteins involved in African swine fever virus infection and replication
Authors: Duan Xianghan , Ru Yi , Yang Wenping , Ren Jingjing , Hao Rongzeng , Qin Xiaodong , Li Dan , Zheng Haixue
Published: July 2022

African swine fever (ASF) is an acute, hemorrhagic and highly contagious infectious disease caused by African swine fever virus (ASFV), which infects domestic pigs or wild boars. It is characterized by short course of disease, high fever and hemorrhagic lesions, with mortality of up to 100% from acute infection. Up to now, the lack of commercial vaccines and effective drugs has seriously threatened the healthy economic development of the global pig industry. ASFV is a double-stranded DNA virus and genome varies between about 170-194 kb, which encodes 150-200 viral proteins, including 68 structural proteins and more than 100 non-structural proteins. In recent years, although the research on structure and function of ASFV-encoded proteins has been deepened, the structure and infection process of ASFV are still not clear. This review summarizes the main process of ASFV infection, replication and functions of related viral proteins to provide scientific basis and theoretical basis for ASFV research and vaccine development.
Comparative Analysis of Mutation Status and Immune Landscape for Squamous Cell Carcinomas at Different Anatomical sites
Authors: Ti Wenqi , Wei Tianhui , Wang Jianbo , Cheng Yufeng
Published: July 2022

Objective

It has been controversial whether tumor mutation burden (TMB) affects the prognosis and the efficacy of immunotherapy in different tumor types. We provided a comprehensive analysis of mutation status and immune landscape of squamous cell carcinomas (SCCs) from four sites in order to investigate the relationship of TMB with prognosis and immune cell infiltration in different SCCs.

Methods

The transcriptome profiles and somatic mutation data of SCCs downloaded from the Cancer Genome Atlas (the Cancer Genome Atlas) database were analyzed and visualized. Then, TMB was calculated to analyze its correlations with prognosis and clinical features. Differentially expressed genes (DEGs) between the high and low TMB groups were screened for functional enrichment analysis. CIBERSORT algorithm was used to compare differences of immune cell infiltration between two groups in different SCCs. In addition, immune DEGs associated with prognosis were identified and risk prediction model was constructed via Cox regression analysis.

Results

Missense mutation was the most dominant mutation type in SCCs. The difference was that the top10 mutated genes varied widely among different SCCs. High TMB group had better prognosis in lung squamous cell carcinoma (LUSC) and cervical squamous cell carcinoma (CESC), while the result was reverse in head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). In addition, patients with older age, smoking history, earlier pathological stage and no lymphatic invasion had higher TMB. The identified DEGs were mainly enriched in the regulation of immune system, muscular system and the activity of epidermal cells. The proportions of CD8+T cells, CD4+ memory T cells, follicular helper T cells, macrophages were distinct between two groups. The prognosis-related hub genes (CHGB, INHBA, LCN1 and VEGFC) screened were associated with poor prognosis.

Conclusion

This study reveals the mutation status and immune cell infiltration of SCCs at different anatomical sites. TMB is closely related to the prognosis of SCCs, and its effects on prognosis are diverse in different SCCs, which might result from the situation of immune cell infiltration. These findings contribute to the exploration of biomarkers for predicting the efficacy of immunotherapy in SCCs and providing innovative insights for accurate application of immunotherapy.
Targeting the antigen processing and presentation pathway to overcome resistance to immune checkpoint therapy
Authors: D’Amico Silvia , Tempora Patrizia , Melaiu Ombretta , Lucarini Valeria , Cifaldi Loredana , Locatelli Franco , Fruci Doriana
Published: July 2022

Despite the significant clinical advances with the use of immune checkpoint inhibitors (ICIs) in a wide range of cancer patients, response rates to the therapy are variable and do not always result in long-term tumor regression. The development of ICI-resistant disease is one of the pressing issue in clinical oncology, and the identification of new targets and combination therapies is a crucial point to improve response rates and duration. Antigen processing and presentation (APP) pathway is a key element for an efficient response to ICI therapy. Indeed, malignancies that do not express tumor antigens are typically poor infiltrated by T cells and unresponsive to ICIs. Therefore, improving tumor immunogenicity potentially increases the success rate of ICI therapy. In this review, we provide an overview of the key elements of the APP machinery that can be exploited to enhance tumor immunogenicity and increase the efficacy of ICI-based immunotherapy.
RNA N1-methyladenosine regulator-mediated methylation modification patterns and heterogeneous signatures in glioma
Authors: Mao Meng , Chu Qinjun , Lou Yongli , Lv Peipei , Wang Lin-jian
Published: July 2022

N1-methyladenosine (m1A) is ubiquitous in eukaryotic RNA and regulates mRNA translation. However, little is known about its regulatory role in glioma. Here, we identified 4 m1A modification-related patterns based on m1A regulators in the TCGA (The Cancer Genome Atlas) and CGGA (Chinese Glioma Genome Atlas) cohorts. The differences in survival prognosis between different clusters were striking. In addition, stemness, genomic heterogeneity, tumor microenvironment (TME), and immune cell infiltration were also significantly different between the poor and best prognostic clusters. To reveal the underlying mechanism, differentially expressed genes (DEGs) between the poor and best prognostic clusters were identified, and then were integrated for weighted correlation network analysis (WGCNA). After Univariate Cox-LASSO-Multivariate Cox analyses, DEGs PLEK2 and ABCC3 were screened as the risk-hub genes and were selected to construct an m1A-related signature. Moreover, ABCC3 exacerbated glioma proliferation and was associated with temozolomide (TMZ) resistance. Overall, our study provided new insights into the function and potential therapeutic role of m1A in glioma.
Contribution of circulatory cells to asthma exacerbations and lung tissue-resident CD4 T cell memory
Authors: Sethi Gurupreet S. , Gracias Donald , Croft Michael
Published: July 2022

Tissue-resident memory CD4 T cells (Trm) are thought to be a major contributor to asthma relapse, but the role of circulatory T cells in asthma exacerbations or to maintaining the population of lung Trm cells is not fully understood. Here, we used a house dust mite allergen-based murine model of asthma relapse, and monitored the development of lung effector/Trm phenotype CD44hiCD62LloCD69+ CD4 T cells. To determine the contribution of circulatory cells, mice were treated with FTY720, to block lymphocyte egress from lymph nodes. Inhibiting the primary migration of circulatory cells to the lungs mitigated the accumulation and expansion of allergen-driven Trm phenotype cells, but subsequent allergen challenges still resulted in strong lung inflammation and Trm cell accumulation. This was blocked if FTY720 was also given at the time of allergen re-exposure, showing that new circulatory cells contributed to this lung memory/effector T cell pool at times well after the initial sensitization. However, once lung-localized Trm cells developed at high frequency, circulatory cells were not required to maintain this population following allergen re-encounter, even though circulatory cells still were major contributors to the overall asthmatic lung inflammatory response. Our results suggest that strategies that target the response of circulatory memory T cells and Trm cells together might be required to strongly inhibit T cell reactivity to airborne allergens and to limit exacerbations of asthma and their reoccurrence, but the contribution of circulatory T cells might vary in long-term asthmatics possessing a large stable Trm cell population in the lungs.
Hexavalent Chromium Exposure Induces Intestinal Barrier Damage via Activation of the NF-κB Signaling Pathway and NLRP3 Inflammasome in Ducks
Authors: Xing Chenghong , Yang Fan , Lin Yiqun , Shan Jiyi , Yi Xin , Ali Farah , Zhu Yibo , Wang Chang , Zhang Caiying , Zhuang Yu , Cao Huabin , Hu Guoliang
Published: July 2022

Hexavalent chromium [Cr(VI)] is a dangerous heavy metal which can impair the gastrointestinal system in various species; however, the processes behind Cr(VI)-induced intestinal barrier damage are unknown. Forty-eight healthy 1-day-old ducks were stochastically assigned to four groups and fed a basal ration containing various Cr(VI) dosages for 49 days. Results of the study suggested that Cr(VI) exposure could significantly increase the content of Cr(VI) in the jejunum, increase the level of diamine oxidase (DAO) in serum, affect the production performance, cause histological abnormalities (shortening of the intestinal villi, deepening of the crypt depth, reduction and fragmentation of microvilli) and significantly reduced the mRNA levels of intestinal barrier-related genes (ZO-1, occludin, claudin-1, and MUC2) and protein levels of ZO-1, occludin, cand laudin-1, resulting in intestinal barrier damage. Furthermore, Cr(VI) intake could increase the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) but decrease the activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione reductase (GR), as well as up-regulate the mRNA levels of TLR4, MyD88, NF-κB, TNFα, IL-6, NLRP3, caspase-1, ASC, IL-1β, and IL-18 and protein levels of TLR4, MyD88, NF-κB, NLRP3, caspase-1, ASC, IL-1β, and IL-18 in the jejunum. In conclusion, Cr(VI) could cause intestinal oxidative damage and inflammation in duck jejunum by activating the NF-κB signaling pathway and the NLRP3 inflammasome.
Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology
Authors: Malko Darya , Elmzzahi Tarek , Beyer Marc
Published: July 2022

Treg cells have been initially described as gatekeepers for the control of autoimmunity, as they can actively suppress the activity of other immune cells. However, their role goes beyond this as Treg cells further control immune responses during infections and tumor development. Furthermore, Treg cells can acquire additional properties for e.g., the control of tissue homeostasis. This is instructed by a specific differentiation program and the acquisition of effector properties unique to Treg cells in non-lymphoid tissues. These tissue Treg cells can further adapt to their tissue environment and acquire distinct functional properties through specific transcription factors activated by a combination of tissue derived factors, including tissue-specific antigens and cytokines. In this review, we will focus on recent findings extending our current understanding of the role and differentiation of these tissue Treg cells. As such we will highlight the importance of tissue Treg cells for tissue maintenance, regeneration, and repair in adipose tissue, muscle, CNS, liver, kidney, reproductive organs, and the lung.
Analysis of luciferase dsRNA production during baculovirus infection of Hi5 cells: RNA hairpins expressed by very late promoters do not trigger gene silencing
Authors: Kolliopoulou Anna , Kontogiannatos Dimitrios , Mazurek Aleksander Józef , Prifti Izabela , Christopoulou Vasiliki-Maria , Labropoulou Vassiliki , Swevers Luc
Published: July 2022

The baculovirus expression vector system (BEVS) has become an important platform for the expression of recombinant proteins and is especially useful for the production of large protein complexes such as virus-like particles (VLPs). An important application for VLPs is their use as vehicles for targeted delivery of drugs or toxins which requires the development of methods for efficient loading with the intended cargo. Our research intends to employ the BEVS for the production of VLPs for the delivery of insecticidal dsRNA molecules to targeted insect pests (as “dsRNA-VLPs”). A convenient strategy would be the co-expression of long dsRNAs with viral capsid proteins and their simultaneous encapsulation during VLP assembly but the capacity of the BEVS for the production of long dsRNA has not been assessed so far. In this study, the efficiency of production of long RNA hairpins targeting the luciferase gene (“dsLuc”) by the polyhedrin promoter during baculovirus infection was evaluated. However, RNAi reporter assays could not detect significant amounts of dsLuc in Hi5 cells infected with recombinant baculovirus, even in the presence of co-expressed dsRNA-binding protein B2-GFP or the employment of the MS2-MCP system. Nevertheless, dot blot analyses using anti-dsRNA antibody revealed that baculovirus-mediated expression of B2-GFP resulted in significant increases in dsRNA levels in infected cells that may correspond to hybridized complementary viral transcripts. Using B2-GFP as a genetically encoded sensor, dsRNA foci were detected in the nuclei that partially co-localized with DAPI staining, consistent with their localization at the virogenic stroma. Co-localization experiments with the baculovirus proteins vp39, Ac93, ODV-E25 and gp64 indicated limited overlap between B2-GFP and the ring zone compartment where assembly of nucleocapsids and virions occurs. Stability experiments showed that exogenous dsRNA is resistant to degradation in extracts of non-infected and infected Hi5 cells and it is proposed that strong unwinding activity at the virogenic stroma in the infected nuclei may neutralize the annealing of complementary RNA strands and block the production of long dsRNAs. Because the strong stability of exogenous dsRNA, transfection can be explored as an alternative method for delivery of cargo for dsRNA-VLPs during their assembly in baculovirus-infected Hi5 cells.
Variation of Carbon–Nitrogen Contents and Allelopathic Disruption of Renieramycin M–Producing Sponge Xestospongia sp. in the Gulf of Thailand
Authors: Darumas Udomsak , Salem Gad Elsayed Mohamed , Suwanborirux Khanit , Viyakarn Voranop , Chavanich Suchana
Published: July 2022

Allelopathy is commonly found in marine sponges. However, information on allelopathic activities of sponge extracts is limited. In this study, variations of nutritional values of Xestospongia sp. were investigated. Xestospongia did not unequally distribute its nutritional values for predatory defense. Carbon–nitrogen contents and renieramycin M concentrations were not significantly different among the areas of Xestospongia sp. (edge, inner, and outer). However, carbon–nitrogen contents and renieramycin M concentrations of Xestospongia sp. coexisting with different organisms were not significantly different. In the laboratory, bleaching and necrosis of coral nubbins were not observed in every treatment, and renieramycin M did not show any allelopathic effect on its coexisting organisms (Porites lutea and Palythoa caesia). However, renieramycin M inhibited settlement of acorn barnacle (Semibalanus balanoides) but did not inhibit the settlement of pelecypods. When testing for antimicrobial effect, renieramycin M did not inhibit the growth of aerobic bacteria in any treatments. This study provides evidence that renieramycin M found in Xestospongia was uniform; however, it can possess strong inhibitory activities against some marine organisms.
Effect of Aquaculture-Related Diets on the Long-Term Performance and Condition of the Rock Crab, Cancer irroratus
Authors: Drolet David , Riley Cyrena , Robert Sonia , Estrada Rafael , Gianasi Bruno L. , McKindsey Christopher W.
Published: July 2022

Shellfish and salmonid aquaculture operations in Eastern Canada attract several mobile epibenthic species as a result of added structural complexity and increased food availability (bivalve fall-off and waste salmonid feed). It is not clear whether the aggregation of predators and scavengers below coastal farms contributes positively or negatively to their population dynamics, due to concerns about the quality of food items found under farms. We conducted an 18-month laboratory study to investigate the effect of diets composed of 1) mixed items, 2) mussels (Mytilus edulis), and 3) salmonid feed on the performance and condition of the rock crab,Cancer irroratus. Diet had no impact on crab survival but several negative consequences were observed in crabs fed the salmonid feed diet when compared to the mixed diet: reduced 1) moulting rates during the second growing season, 2) inter-molt growth, 3) gonad and hepatopancreas indices, 4) hemolymph dissolved compounds, 5) hepatopancreatic glycogen, and 6) shell hardness. Crabs fed the mussel diet had similar performance and condition when compared to the mixed diet. Fatty acid composition of muscle, gonad, and hepatopancreas tissues revealed that a salmonid feed diet decreased n3/n6 ratio when compared to a mixed or a mussel diet; those differences were mostly due to increases in the proportions of terrestrial (18:1n9 and 18:2n6) and decreases in proportions of marine essential (20:5n3 and 22:6n3) fatty acids. Together, these results point to a minimal impact of a mussel-only diet on crabs, whereas the salmonid feed diet resulted in negative impacts on condition. Our experimental results explored the consequences of a ‘worst-case scenario’ in which crabs were forced to feed on a single item for a long period of time; the realized impact in field settings will depend on other factors such as consumption of alternate food items underneath a farm, proportion of time spent in farms, and level of overlap between crab habitat and aquaculture facilities.
Effects of the glacial meltwater supply on carbonate chemistry in Bowdoin Fjord, Northwestern Greenland
Authors: Horikawa Takahito , Nomura Daiki , Kanna Naoya , Fukamachi Yasushi , Sugiyama Shin
Published: July 2022

To understand the effects of the glacial meltwater supply on carbonate chemistry and the air–sea CO2 flux within the fjord, water samples were collected in Bowdoin Fjord in northwestern Greenland for dissolved inorganic carbon (DIC) concentration, total alkalinity (TA), oxygen isotopic ratio (δ18O), and chlorophyll a concentration analyses in the summers of 2016 and 2017. The partial pressure of CO2 (pCO2) in surface water, calculated from DIC and TA, was less than 200 µatm, and was significantly lower than that in the atmosphere (399 ± 3 µatm). Therefore, surface water of the fjord acts as sink for CO2 in the atmosphere (–4.9 ± 0.7 mmol m–2 d–1). To evaluate the effects of freshwater and land-derived substances by glacial meltwater on pCO2 in the fjord, we calculated the changes of pCO2 in salinity and carbonate chemistry that would result from the inflow of glacial meltwater into the fjord. The calculated pCO2 was high near the calving front, where the contribution of glacier meltwater was significant. Examination of the relationship between salinity-normalized DIC and TA, which was considered DIC and TA input from the land, suggested that the land-derived high pCO2 freshwater affected mainly by the remineralization of the organic matter by bacterial activity was supplied to the Bowdoin Fjord.
#OceanOptimism: Balancing the Narrative About the Future of the Ocean
Authors: Borja Angel , Elliott Michael , Basurko Oihane C. , Fernández Muerza Alex , Micheli Fiorenza , Zimmermann Fabian , Knowlton Nancy
Published: July 2022

The ocean is facing multiple pressures from human activities, including the effects of climate change. Science has a prominent role in identifying problems and communicating these to society. However, scientists are also increasingly taking an active role in developing solutions, including strategies for adapting to and mitigating climate change, increasing food security, and reducing pollution. Transmitting these solutions to society changes our narrative about the ocean and motivates actions. The United Nations triple initiatives for this decade—the Sustainable Development Goals, the Decade on Ocean Science for Sustainable Development, and the Decade of Ecosystem Restoration—provide the momentum for this change in narrative and focus. Here, we reflect on the search for solutions and the need for better ways of communicating science in a positive way. We synthesize insights from a summer school held during the COVID-19 pandemic and present some examples of successes and failures and the lessons learned from these.