bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: Overlapping syndrome mimicking infectious meningoencephalitis in a patient with coexistent MOG, NMDAR, mGluR5 antibody positivity
Authors: Fu Jie , Peng Lilei , Yang Yang , Xie Yang , Li Zuoxiao , Rong Benbing
Published: August 2022

A 38-year-old Chinese Han man presented with fever, headache and difficulty in language expression. The initial cerebrospinal fluid (CSF) analysis revealed lymphocytic-predominant pleocytosis with a normal glucose level, and magnetic resonance imaging (MRI) showed extensive cortical edema in left cerebral hemisphere. He received the antiviral treatment. However, one week later, he developed psychomotor agitation and seizures. Lumbar puncture was performed again and further testing for autoantibodies was conducted in both the CSF and serum. His CSF was positive for anti-myelin oligodendrocyte glycoprotein (MOG), anti-N-methyl-D-aspartate receptor (NMDAR) and anti-metabotropic glutamate receptor 5 (mGluR5) antibodies. He was diagnosed with overlapping syndrome of MOG antibody-related cerebral cortical encephalitis and anti-NMDAR, anti-mGluR5 autoimmune encephalitis. He received intravenous methylprednisolone and immunoglobulin, followed by oral prednisone and mycophenolate mofetil. His psychomotor agitation and seizures were relieved, and he gradually recovered his language expression ability. We reported for the first time a case that was positive for coexistent MOG, NMDAR, mGluR5 antibodies, which was initially misdiagnosed as infectious meningoencephalitis. This case widens the clinical spectrum of the overlapping syndrome recently reported.
Efficacy and safety of atezolizumab plus bevacizumab combined with hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma
Authors: Xin Yujing , Cao Fei , Yang Hongcai , Zhang Xinyuan , Chen Yi , Cao Xiaojing , Zhou Xiang , Li Xiao , Zhou Jinxue
Published: August 2022

Background

Atezolizumab plus bevacizumab has been proved to have promising antitumor activity and tolerable safety in patients with unresectable hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) also demonstrated high response rates and favorable survival for patients with advanced HCC. This study aimed to explore the preliminary clinical efficacy and safety of atezolizumab plus bevacizumab combined with HAIC for patients with treatment-naive advanced HCC.

Methods

Between October 2020 and September 2021, patients with advanced HCC who initially received atezolizumab plus bevacizumab combined with HAIC of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) from three hospitals in China were reviewed for eligibility. The efficacy was evaluated by tumor response rate and survival, and the safety was evaluated by the frequency of key adverse events (AEs).

Results

In total, 52 eligible patients with advanced HCC who received triple therapy were included in this study. The objective response rates (ORRs) based on mRECIST and RECIST1.1 criteria were 67.3% and 44.2%, respectively. The median progression-free survival (PFS) of patients was 10.6 months (95% CI, 8.37–13.8), and the overall survival (OS) was not reached. Extrahepatic metastasis was an independent risk factor associated with PFS. All AEs were controlled and no treatment-related deaths occurred.

Conclusion

Atezolizumab plus bevacizumab combined with HAIC-FOLFOX had a significant therapeutic effect and manageable AEs in patients with advanced HCC, which may be a potential treatment option for advanced HCC.
A genomic instability-related lncRNA model for predicting prognosis and immune checkpoint inhibitor efficacy in breast cancer
Authors: Jiao Ying , Li Shiyu , Wang Xuan , Yi Ming , Wei Hongqu , Rong Shanjie , Zheng Kun , Zhang Li
Published: August 2022

Breast cancer has overtaken lung cancer as the most frequently diagnosed cancer type and is the leading cause of death for women worldwide. It has been demonstrated in published studies that long non-coding RNAs (lncRNAs) involved in genomic stability are closely associated with the progression of breast cancer, and remarkably, genomic stability has been shown to predict the response to immune checkpoint inhibitors (ICIs) in cancer therapy, especially colorectal cancer. Therefore, it is of interest to explore somatic mutator-derived lncRNAs in predicting the prognosis and ICI efficacy in breast cancer patients. In this study, the lncRNA expression data and somatic mutation data of breast cancer patients from The Cancer Genome Atlas (TCGA) were downloaded and analyzed thoroughly. Univariate and multivariate Cox proportional hazards analyses were used to generate the genomic instability-related lncRNAs in a training set, which was subsequently used to analyze a testing set and combination of the two sets. The qRT-PCR was conducted in both normal mammary and breast cancer cell lines. Furthermore, the Kaplan–Meier and receiver operating characteristic (ROC) curves were applied to validate the predictive effect in the three sets. Finally, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the association between genomic instability-related lncRNAs and immune checkpoints. As a result, a six-genomic instability-related lncRNA signature (U62317.4, MAPT-AS1, AC115837.2, EGOT, SEMA3B-AS1, and HOTAIR) was identified as the independent prognostic risk model for breast cancer patients. Compared with the normal mammary cells, the qRT-PCR showed that HOTAIR was upregulated while MAPT-AS1, EGOT, and SEMA3B-AS1 were downregulated in breast cancer cells. The areas under the ROC curves at 3 and 5 years were 0.711 and 0.723, respectively. Moreover, the patients classified in the high-risk group by the prognostic model had abundant negative immune checkpoint molecules. In summary, this study suggested that the prognostic model comprising six genomic instability-related lncRNAs may provide survival prediction. It is necessary to identify patients who are suitable for ICIs to avoid severe immune-related adverse effects, especially autoimmune diseases. This model may predict the ICI efficacy, facilitating the identification of patients who may benefit from ICIs.
Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors
Authors: Chen Qian , Shang Xiaoling , Liu Ni , Ma Xinchun , Han Wenfei , Wang Xiuwen , Liu Yanguo
Published: August 2022

Background

Although immune checkpoint inhibitors (ICIs) generally show poor therapeutic efficacy in patients with epidermal growth factor receptor (EGFR) mutations, certain research indicate that a small proportion of these patients do respond to ICIs. The present study sought to identify the features of patients with EGFR mutations who might benefit from ICIs from multiple studies and discussed the optimal treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations.

Methods

The profiles of 114 advanced NSCLC patients with EGFR mutations who received ICIs treatment were retrospectively reviewed. EGFR subtypes, programmed cell death ligand 1 (PD-L1) expression, and clinical characteristics regarding their impact on the efficacy of ICIs were investigated.

Results

Patients with major EGFR mutations (L858R or 19Del) had a shorter progression-free survival (PFS) and a lower objective response rate (ORR) as compared to patients with rare (20ins or G719X) and other EGFR mutations. Although not statistically significant, median overall survival (OS) tended to be longer in patients with negative (<1%) PD-L1 expression than with positive (≥1%) PD-L1 expression (15.61 vs. 7.40 months, p = 0.138). Median PFS and OS were significantly shorter in heavily treated patients (prior lines of therapy ≥3 lines vs. <3 lines: mPFS, 1.80 vs. 2.50 months, p = 0.003; mOS, 6.70 vs. 14.00 months, p = 0.031). ORR was also lower in patients who had received ≥3 prior lines of therapy compared to in those <3 prior lines of therapy (0.00% vs. 21.67%, p = 0.002).

Conclusion

Patients with major EGFR mutations showed poorer responses to ICIs than those with rare EGFR mutations. EGFR-mutated patients with lower PD-L1 expression showed a trend towards a longer OS after receiving ICIs. ICIs should be administered as early as possible to previously treated EGFR-mutated NSCLC patients. ICI-based combined therapies may be a direction for treatment of these patient subtypes in the future.
Protection of transplants against antibody-mediated injuries: from xenotransplantation to allogeneic transplantation, mechanisms and therapeutic insights
Authors: Kervella Delphine , Le Bas-Bernardet Stéphanie , Bruneau Sarah , Blancho Gilles
Published: August 2022

Long-term allograft survival in allotransplantation, especially in kidney and heart transplantation, is mainly limited by the occurrence of antibody-mediated rejection due to anti-Human Leukocyte Antigen antibodies. These types of rejection are difficult to handle and chronic endothelial damages are often irreversible. In the settings of ABO-incompatible transplantation and xenotransplantation, the presence of antibodies targeting graft antigens is not always associated with rejection. This resistance to antibodies toxicity seems to associate changes in endothelial cells phenotype and modification of the immune response. We describe here these mechanisms with a special focus on endothelial cells resistance to antibodies. Endothelial protection against anti-HLA antibodies has been describedin vitroand in animal models, but do not seem to be a common feature in immunized allograft recipients. Complement regulation and anti-apoptotic molecules expression appear to be common features in all these settings. Lastly, pharmacological interventions that may promote endothelial cell protection against donor specific antibodies will be described.
Inhibitor of DNA binding proteins revealed as orchestrators of steady state, stress and malignant hematopoiesis
Authors: Singh Shweta , Sarkar Tanmoy , Jakubison Brad , Gadomski Stephen , Spradlin Andrew , Gudmundsson Kristbjorn O. , Keller Jonathan R.
Published: August 2022

Adult mammalian hematopoiesis is a dynamic cellular process that provides a continuous supply of myeloid, lymphoid, erythroid/megakaryocyte cells for host survival. This process is sustained by regulating hematopoietic stem cells (HSCs) quiescence, proliferation and activation under homeostasis and stress, and regulating the proliferation and differentiation of downstream multipotent progenitor (MPP) and more committed progenitor cells. Inhibitor of DNA binding (ID) proteins are small helix-loop-helix (HLH) proteins that lack a basic (b) DNA binding domain present in other family members, and function as dominant-negative regulators of other bHLH proteins (E proteins) by inhibiting their transcriptional activity. ID proteins are required for normal T cell, B cell, NK and innate lymphoid cells, dendritic cell, and myeloid cell differentiation and development. However, recent evidence suggests that ID proteins are important regulators of normal and leukemic hematopoietic stem and progenitor cells (HSPCs). This chapter will review our current understanding of the function of ID proteins in HSPC development and highlight future areas of scientific investigation.
Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension
Authors: Rodriguez-Irizarry Valerie J. , Schneider Alina C. , Ahle Daniel , Smith Justin M. , Suarez-Martinez Edu B. , Salazar Ethan A. , McDaniel Mims Brianyell , Rasha Fahmida , Moussa Hanna , Moustaïd-Moussa Naima , Pruitt Kevin , Fonseca Marcelo , Henriquez Mauricio , Clauss Matthias A. , Grisham Matthew B. , Almodovar Sharilyn
Published: August 2022

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.
Genomic crossroads between non-Hodgkin’s lymphoma and common variable immunodeficiency
Authors: Guevara-Hoyer Kissy , Fuentes-Antrás Jesús , de la Fuente-Muñoz Eduardo , Fernández-Arquero Miguel , Solano Fernando , Pérez-Segura Pedro , Neves Esmeralda , Ocaña Alberto , Pérez de Diego Rebeca , Sánchez-Ramón Silvia
Published: August 2022

Common variable immunodeficiency (CVID) represents the largest group of primary immunodeficiencies that may manifest with infections, inflammation, autoimmunity, and cancer, mainly B-cell non-Hodgkin’s lymphoma (NHL). Indeed, NHL may result from chronic or recurrent infections and has, therefore, been recognized as a clinical phenotype of CVID, although rare. The more one delves into the mechanisms involved in CVID and cancer, the stronger the idea that both pathologies can be a reflection of the same primer events observed from different angles. The potential effects of germline variants on specific somatic modifications in malignancies suggest that it might be possible to anticipate critical events during tumor development. In the same way, a somatic alteration in NHL could be conditioning a similar response at the transcriptional level in the shared signaling pathways with genetic germline alterations in CVID. We aimed to explore the genomic substrate shared between these entities to better characterize the CVID phenotype immunodeficiency in NHL. By means of an in-silico approach, we interrogated the large, publicly available datasets contained in cBioPortal for the presence of genes associated with genetic pathogenic variants in a panel of 50 genes recurrently altered in CVID and previously described as causative or disease-modifying. We found that 323 (25%) of the 1,309 NHL samples available for analysis harbored variants of the CVID spectrum, with the most recurrent alteration presented in NHL occurring in PIK3CD (6%) and STAT3 (4%). Pathway analysis of common gene alterations showed enrichment in inflammatory, immune surveillance, and defective DNA repair mechanisms similar to those affected in CVID, with PIK3R1 appearing as a central node in the protein interaction network. The co-occurrence of gene alterations was a frequent phenomenon. This study represents an attempt to identify common genomic grounds between CVID and NHL. Further prospective studies are required to better know the role of genetic variants associated with CVID and their reflection on the somatic pathogenic variants responsible for cancer, as well as to characterize the CVID-like phenotype in NHL, with the potential to influence early CVID detection and therapeutic management.
TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner
Authors: Äijö Tarmo , Theofilatos Dimitris , Cheng Meng , Smith Matthew D. , Xiong Yue , Baldwin Albert S. , Tsagaratou Ageliki
Published: August 2022

TET proteins mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other oxidative derivatives. We have previously demonstrated a dynamic enrichment of 5hmC during T and invariant natural killer T cell lineage specification. Here, we investigate shared signatures in gene expression of Tet2/3 DKO CD4 single positive (SP) and iNKT cells in the thymus. We discover that TET proteins exert a fundamental role in regulating the expression of the lineage specifying factor Th-POK, which is encoded by Zbtb7b. We demonstrate that TET proteins mediate DNA demethylation - surrounding a proximal enhancer, critical for the intensity of Th-POK expression. In addition, TET proteins drive the DNA demethylation of site A at the Zbtb7b locus to facilitate GATA3 binding. GATA3 induces Th-POK expression in CD4 SP cells. Finally, by introducing a novel mouse model that lacks TET3 and expresses full length, catalytically inactive TET2, we establish a causal link between TET2 catalytic activity and lineage specification of both conventional and unconventional T cells.
TIM-4 in macrophages contributes to nasal polyp formation through the TGF-β1–mediated epithelial to mesenchymal transition in nasal epithelial cells
Authors: Qin Danxue , Liu Peiqiang , Zhou Huiqin , Jin Jing , Gong Wanyang , Liu Kunyu , Chen Siyuan , Huang Jingyu , Fan Wenjun , Tao Zezhang , Xu Yu
Published: August 2022

Chronic rhinosinusitis with nasal polyps (CRSwNP) is caused by prolonged inflammation of the paranasal sinus mucosa. The epithelial to mesenchymal transition (EMT) is involved in the occurrence and development of CRSwNP. The T-cell immunoglobulin domain and the mucin domain 4 (TIM-4) is closely related to chronic inflammation, but its mechanism in CRSwNP is poorly understood. In our study, we found that TIM-4 was increased in the sinonasal mucosa of CRSwNP patients and, especially, in macrophages. TIM-4 was positively correlated with α-SMA but negatively correlated with E-cadherin in CRS. Moreover, we confirmed that TIM-4 was positively correlated with the clinical parameters of the Lund-Mackay and Lund-Kennedy scores. In the NP mouse model, administration of TIM-4 neutralizing antibody significantly reduced the polypoid lesions and inhibited the EMT process. TIM-4 activation by stimulating with tissue extracts of CRSwNP led to a significant increase of TGF-β1 expression in macrophages in vitro. Furthermore, coculture of macrophages and human nasal epithelial cells (hNECs) results suggested that the overexpression of TIM-4 in macrophages made a contribution to the EMT process in hNECs. Mechanistically, TIM-4 upregulated TGF-β1 expression in macrophages via the ROS/p38 MAPK/Egr-1 pathway. In conclusion, TIM-4 contributes to the EMT process and aggravates the development of CRSwNP by facilitating the production of TGF-β1 in macrophages. Inhibition of TIM-4 expression suppresses nasal polyp formation, which might provide a new therapeutic approach for CRSwNP.
Heat shock proteins and viral infection
Authors: Zhang Xizhen , Yu Wei
Published: August 2022

Heat shock proteins (HSPs) are a kind of proteins which mostly found in bacterial, plant and animal cells, in which they are involved in the monitoring and regulation of cellular life activities. HSPs protect other proteins under environmental and cellular stress by regulating protein folding and supporting the correctly folded structure of proteins as chaperones. During viral infection, some HSPs can have an antiviral effect by inhibiting viral proliferation through interaction and activating immune pathways to protect the host cell. However, although the biological function of HSPs is to maintain the homeostasis of cells, some HSPs will also be hijacked by viruses to help their invasion, replication, and maturation, thereby increasing the chances of viral survival in unfavorable conditions inside the host cell. In this review, we summarize the roles of the heat shock protein family in various stages of viral infection and the potential uses of these proteins in antiviral therapy.
Case report: Revealing a special and rare autoimmune GFAP astrocytopathy in the spinal cord succeeding Neurobrucellosis infection
Authors: He Qiang , Liu Junxian , Zhu Zehua , Tang Yongxiang , Long Lili , Hu Kai
Published: August 2022

Brucellosis, a zoonosis, can cause an inflammatory response in most organs and continues to be a public health problem in some endemic areas, whereas neurobrucellosis is a morbid form of brucellosis that affects the central nervous system (CNS) with poor prognosis. Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an autoimmune disease, and there have been no reports of a Brucella infection, leading to GFAP astrocytopathy. We report the case of a patient with a positive and high level of GFAP antibodies in the cerebrospinal fluid (CSF), following a Brucella infection. Although this patient did not show any responsible lesions in the diffusion sequence of the magnetic resonant imaging (MRI) scan, we found an evidence of thoracolumbar (T12) involvement on fluorodeoxyglucose (FDG) positron emission tomography (PET). The symptoms of spinal cord involvement were only partly relieved after initial treatment [doxycycline (0.1 g Bid) and rifampicin (0.6 g Qd) for 6 weeks]; however, they markedly improved after the subsequent immunosuppressive therapy [intravenous methylprednisolone (1,000 mg for 3 days)], followed by a 50% reduction from the preceding dose after 3 days, and subsequently, oral prednisone tablets (60 mg/day) was started, which was then gradually tapered [reduced to 10 mg/day every 1–2 weeks)]. The positive response to immunosuppressive therapy and treatment outcome strongly indicated the presence of an autoimmune neurological disease probably triggered by some infectious factors. Therefore, our findings reveal that a Brucella infection is one of the causes of autoimmune GFAP astrocytopathy, and when this infection is difficult to be identified by regular MRI, FDG PET can be used as a supplementary method for diagnosis and treatment.
Integration of transcriptomics, proteomics, and metabolomics data to reveal HER2-associated metabolic heterogeneity in gastric cancer with response to immunotherapy and neoadjuvant chemotherapy
Authors: Yuan Qihang , Deng Dawei , Pan Chen , Ren Jie , Wei Tianfu , Wu Zeming , Zhang Biao , Li Shuang , Yin Peiyuan , Shang Dong
Published: August 2022

Background

Currently available prognostic tools and focused therapeutic methods result in unsatisfactory treatment of gastric cancer (GC). A deeper understanding of human epidermal growth factor receptor 2 (HER2)-coexpressed metabolic pathways may offer novel insights into tumour-intrinsic precision medicine.

Methods

The integrated multi-omics strategies (including transcriptomics, proteomics and metabolomics) were applied to develop a novel metabolic classifier for gastric cancer. We integrated TCGA-STAD cohort (375 GC samples and 56753 genes) and TCPA-STAD cohort (392 GC samples and 218 proteins), and rated them as transcriptomics and proteomics data, resepectively. 224 matched blood samples of GC patients and healthy individuals were collected to carry out untargeted metabolomics analysis.

Results

In this study, pan-cancer analysis highlighted the crucial role of ERBB2 in the immune microenvironment and metabolic remodelling. In addition, the metabolic landscape of GC indicated that alanine, aspartate and glutamate (AAG) metabolism was significantly associated with the prevalence and progression of GC. Weighted metabolite correlation network analysis revealed that glycolysis/gluconeogenesis (GG) and AAG metabolism served as HER2-coexpressed metabolic pathways. Consensus clustering was used to stratify patients with GC into four subtypes with different metabolic characteristics (i.e. quiescent, GG, AAG and mixed subtypes). The GG subtype was characterised by a lower level of ERBB2 expression, a higher proportion of the inflammatory phenotype and the worst prognosis. However, contradictory features were found in the mixed subtype with the best prognosis. The GG and mixed subtypes were found to be highly sensitive to chemotherapy, whereas the quiescent and AAG subtypes were more likely to benefit from immunotherapy.

Conclusions

Transcriptomic and proteomic analyses highlighted the close association of HER-2 level with the immune status and metabolic features of patients with GC. Metabolomics analysis highlighted the co-expressed relationship between alanine, aspartate and glutamate and glycolysis/gluconeogenesis metabolisms and HER2 level in GC. The novel integrated multi-omics strategy used in this study may facilitate the development of a more tailored approach to GC therapy.
Modes of action and diagnostic value of miRNAs in sepsis
Authors: Antonakos Nikolaos , Gilbert Charly , Théroude Charlotte , Schrijver Irene T. , Roger Thierry
Published: August 2022

Sepsis is a clinical syndrome defined as a dysregulated host response to infection resulting in life-threatening organ dysfunction. Sepsis is a major public health concern associated with one in five deaths worldwide. Sepsis is characterized by unbalanced inflammation and profound and sustained immunosuppression, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based therapies for sepsis. Yet, the picture is not so straightforward because of the versatile and dynamic features of miRNAs. Clearly, more research is needed to clarify the expression and role of miRNAs in sepsis, and to promote the use of miRNAs for sepsis management.
Case report: A colorectal cancer patient with microsatellite instability-high and MSH2 germline mutation failed to respond to anti-PD-1 immunotherapy
Authors: Zhang Qun , Hu Jing , Zhang Yaping , Li Li , Wang Ting , Qian Xiaoping
Published: August 2022

Lynch syndrome (LS) is characterized by germline mutations in the DNA mismatch repair (MMR) genes. In colorectal cancer (CRC), germline mutations of DNA MMR genes commonly lead to microsatellite instability-high (MSI-H) subtype formation. Recent studies have demonstrated that CRC patients with MSI-H or mismatch repair-deficient (dMMR) status can benefit from anti-PD1 immunotherapy. However, almost 50% of CRC patients with MSI-H status do not respond to it. It is reported that heterogeneity of tumor and abnormal activation of cancer-related signaling pathways contribute to resistance to anti-PD1 therapy. To improve the clinical efficacy of such patients, the underlying mechanisms of resistance to anti-PD1 treatment must be explored. In this case, we describe an LS-associated CRC patient with MSI-H who suffered resistance to anti-PD1 therapy. Here, we attempted to elucidate the potential reasons, and thus appropriate strategies may be derived to overcome this clinical problem.
Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential
Authors: XL Lei , GY Zhao , R Guo , N Cui
Published: August 2022

Sepsis is a common critical illness in the Intensive care unit(ICU) and its management and treatment has always been a major challenge in critical care medicine. The dysregulated host response to infection, causing systemic multi-organ and multi-system damage is the main pathogenesis. Notably, intense stress during sepsis can lead to metabolic disturbances of ions, lipids and energy in the organism. Ferroptosis is an iron-dependent, non-apoptotic cell death distinguished by a disruption of iron metabolism and iron-dependent accumulation of lipid peroxides. Mounting researches have established that ferroptosis has an essential part in anti-inflammatory and sepsis, and drugs targeting ferroptosis-related molecules, such as ferroptosis inhibitors, are gradually proving their effectiveness in sepsis. This paper summarizes and reviews the pathogenesis of ferroptosis, its regulatory network, and its vital involvement in the initiation of sepsis and related organ damage, and finally discusses the possible target drugs provided by the above mechanisms, describes the dilemmas as well as the outlook, in the hope of finding more links between ferroptosis and sepsis and providing new perspectives for the future treatment of sepsis.
Of mice and men: Laboratory murine models for recapitulating the immunosuppression of human sepsis
Authors: Wang Ning , Lu Yongling , Zheng Jiang , Liu Xin
Published: August 2022

Prolonged immunosuppression is increasingly recognized as the major cause of late phase and long-term mortality in sepsis. Numerous murine models with different paradigms, such as lipopolysaccharide injection, bacterial inoculation, and barrier disruption, have been used to explore the pathogenesis of immunosuppression in sepsis or to test the efficacy of potential therapeutic agents. Nonetheless, the reproducibility and translational value of such models are often questioned, owing to a highly heterogeneric, complex, and dynamic nature of immunopathology in human sepsis, which cannot be consistently and stably recapitulated in mice. Despite of the inherent discrepancies that exist between mice and humans, we can increase the feasibility of murine models by minimizing inconsistency and increasing their clinical relevance. In this mini review, we summarize the current knowledge of murine models that are most commonly used to investigate sepsis-induced immunopathology, highlighting their strengths and limitations in mimicking the dysregulated immune response encountered in human sepsis. We also propose potential directions for refining murine sepsis models, such as reducing experimental inconsistencies, increasing the clinical relevance, and enhancing immunological similarities between mice and humans; such modifications may optimize the value of murine models in meeting research and translational demands when applied in studies of sepsis-induced immunosuppression.
Induced expression of CCL19 promotes the anti-tumor ability of CAR-T cells by increasing their infiltration ability
Authors: Hu Jian-fei , Wang Zu-wei , Liao Cheng-yu , Chen Zhi-wen , Kang Feng-ping , Lin Cai-feng , Lin Tian-sheng , Huang Long , Tian Yi-feng , Chen Shi
Published: August 2022

Background

Chimeric antigen receptor-engineered T cell (CAR-T) therapy has shown promising potential for anti-cancer treatment. However, for pancreatic ductal adenocarcinoma (PDAC), the lack of infiltrative ability of these CAR-T cells leads to sub-optimal treatment outcome.

Methods

Chemokine (C-C motif) ligand 19 (CCL19), the expression of which is regulated by the nuclear factor of activated T cell pathway, was transfected into targeting mesothelin CAR-T cells (mesoCAR-N19) using NFAT regulating element. It was expressed in activated CAR-T cells by OKT3 or mesothelin+ tumor cells but not in inactive cells. The migratory ability of these CAR-T cells was then measured. Subsequently, functional identification of these CAR-T cells was performed in vivo. In addition, the tumor lytic activity and proliferation of the CAR-T cells were measured in vitro. The degree of CAR-T cell infiltration and distribution into the PDAC tumors was examined using the immunohistochemical staining of hCD3 and the detection of CAR gene copy number by quantitative PCR. Finally, the functional assessment of chemokine (C-C motif) receptor 7 knock-out was performed in the CAR-T cells.

Results

Through in vitro Transwell assays, it was demonstrated that mesoCAR-N19 can be specifically expressed in CAR-T cells activated by tumor cells compared with conventional mesothelin CAR-T (mesoCAR) cells. We also observed that upregulating the expression of CCL19 can increase the recruitment of additional T cells. In vivo studies subsequently revealed that this highly specific recruitment of T cell infiltration is associated with enhanced tumor-suppressive activities downstream.

Conclusion

Induced expression of CCL19 can promote the anti-tumor ability of CAR-T cells by increasing their infiltrative ability. This study potentially uncovered novel method of activating CAR-T cells to enhance their infiltrative capacities, which offers a novel direction for PDAC treatment.
Inhibition of IL1R1 or CASP4 attenuates spinal cord injury through ameliorating NLRP3 inflammasome-induced pyroptosis
Authors: Wang Chenfeng , Ma Hongdao , Zhang Bangke , Hua Tong , Wang Haibin , Wang Liang , Han Lin , Li Qisheng , Wu Weiqing , Sun Yulin , Yang Haisong , Lu Xuhua
Published: August 2022

Spinal cord injury (SCI) is a devastating trauma characterized by serious neuroinflammation and permanent neurological dysfunction. However, the molecular mechanism of SCI remains unclear, and few effective medical therapies are available at present. In this study, multiple bioinformatics methods were used to screen out novel targets for SCI, and the mechanism of these candidates during the progression of neuroinflammation as well as the therapeutic effects were both verified in a rat model of traumatic SCI. As a result, CASP4, IGSF6 and IL1R1 were identified as the potential diagnostic and therapeutic targets for SCI by computational analysis, which were enriched in NF-κB and IL6-JAK-STATA3 signaling pathways. In the injured spinal cord, these three signatures were up-regulated and closely correlated with NLRP3 inflammasome formation and gasdermin D (GSDMD) -induced pyroptosis. Intrathecal injection of inhibitors of IL1R1 or CASP4 improved the functional recovery of SCI rats and decreased the expression of these targets and inflammasome component proteins, such as NLRP3 and GSDMD. This treatment also inhibited the pp65 activation into the nucleus and apoptosis progression. In conclusion, our findings of the three targets shed new light on the pathogenesis of SCI, and the use of immunosuppressive agents targeting these proteins exerted anti-inflammatory effects against spinal cord inflammation by inhibiting NF-kB and NLRP3 inflammasome activation, thus blocking GSDMD -induced pyroptosis and immune activation.
A survey of genome-wide association studies, polygenic scores and UK Biobank highlights resources for autoimmune disease genetics
Authors: Saurabh Rochi , Fouodo Césaire J. K. , König Inke R. , Busch Hauke , Wohlers Inken
Published: August 2022

Autoimmune diseases share a general mechanism of auto-antigens harming tissues. Still. they are phenotypically diverse, with genetic as well as environmental factors contributing to their etiology at varying degrees. Associated genomic loci and variants have been identified in numerous genome-wide association studies (GWAS), whose results are increasingly used for polygenic scores (PGS) that are used to predict disease risk. At the same time, a technological shift from genotyping arrays to next generation sequencing (NGS) is ongoing. NGS allows the identification of virtually all - including rare - genetic variants, which in combination with methodological developments promises to improve the prediction of disease risk and elucidate molecular mechanisms underlying disease. Here we review current, publicly available autoimmune disease GWAS and PGS data based on information from the GWAS and PGS catalog, respectively. We summarize autoimmune diseases investigated, respective studies conducted and their results. Further, we review genetic data and autoimmune disease patients in the UK Biobank (UKB), the largest resource for genetic and phenotypic data available for academic research. We find that only comparably prevalent autoimmune diseases are covered by the UKB and at the same time assessed by both GWAS and PGS catalogs. These are systemic (systemic lupus erythematosus) as well as organ-specific, affecting the gastrointestinal tract (inflammatory bowel disease as well as specifically Crohn’s disease and ulcerative colitis), joints (juvenile ideopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis), glands (Sjögren syndrome), the nervous system (multiple sclerosis), and the skin (vitiligo).
Full-Scale Simulation of the Fluid–Particle Interaction Under Magnetic Field Based on IIM–IBM–LBM Coupling Method
Authors: Peng Wei , Hu Yang , Li Decai , He Qiang
Published: August 2022

In this article, a full-scale computational model for fluid–particle interaction under a magnetic field is developed. In this model, the fluid field is solved by the lattice Boltzmann method, and the hydrodynamic force acting on the particle is computed by the immersed boundary method . The numerical solutions of the magnetic field in the fluid–solid domain are achieved by the immersed interface method with a finite difference scheme, in which the normal and tangential jump conditions of the magnetic field intensity are applied to modify the standard finite difference scheme. The magnetic stress tensor along the fluid–particle interface can be calculated accurately. Unlike the widely used point–dipole model, the magnetic force acting on the particle is determined by the stress integration method. Numerical simulation of several numerical tests are carried out to validate the proposed model. The numerical results demonstrate the validity of the present model. Moreover, the magnetoviscous effect is studied by simulating the motion of elliptical particles under the uniform magnetic field in shear flow.
Assessing the Lightweight Potential of Additively Manufactured Metals by Density-Specific Woehler and Shiozawa Diagrams
Authors: Merghany Mohamed , Teschke Mirko , Stern Felix , Tenkamp Jochen , Walther Frank
Published: August 2022

Additive manufacturing (AM) using the powder bed fusion (PBF) process is building up the components layer by layer, which enables the fabrication of complex 3D structures with unprecedented degrees of freedom. Due to the high cooling rates of the AM process, fine microstructures are generated. This leads to an improvement in quasistatic properties such as tensile strength, whereas the fatigue strength is comparable to that of conventionally manufactured metal or even reduced. This is due to the presence of process-induced defects formulated during the manufacturing process in combination with the increased notch stress sensitivity of high-strength metals. In this work, the fatigue damage assessment using different approaches like those of Murakami and Shiozawa for three AM alloys (AlSi10Mg, 316L, and TNM-B1) containing defects is studied for better understanding of capability and mechanisms. Moreover, the effect of the lightweight potential is investigated, and how the specific material density can be considered when the fatigue damage tolerance is characterized.
Promotion of Nitrogen Fixation of Diverse Heterotrophs by Solid-Phase Humin
Authors: Dey Sujan , Kasai Takuya , Katayama Arata
Published: August 2022

Although biological nitrogen fixation (BNF) proceeds under mild conditions compared to the energy-intensive Haber–Bosch process, the slow kinetics of BNF necessitate the promotion of BNF activity in its practical application. The BNF promotion using purified nitrogenases and using genetically modified microorganisms has been studied, but these enzymes are unstable and expensive; moreover, designing genetically modified microorganisms is also a difficult task. Alternatively, the BNF promotion in non-modified (wild-type) microorganisms (enriched consortia) with humin has been shown, which is a humic substance insoluble at any pH and functions as an extracellular electron mediator. However, the taxonomic distribution of the diazotrophs promoted by humin, the levels of BNF promotion, and the underlying mechanism in BNF promotion with humin remain unknown. In this study, we show that taxonomically diverse heterotrophic diazotrophs, harboringnifHclusters I, II, and III, promoted their BNF by accepting extracellular electrons from humin, based on the characterization of the individual responses of isolated diazotrophs to humin. The reduced humin increased the acetylene reduction activity of the diazotrophs by 194–916% compared to the level achieved by the organic carbon source, causing adenosine triphosphate (ATP) synthesis in the diazotroph cells without increase in the CO2production and direct electron donation to the MoFe protein of the nitrogenase in the cells without relying on the biological electron transfer system. These would result in BNF promotion in the wild-type diazotroph cells beyond their biochemical capacity. This significant promotion of BNF with humin would serve as a potential basis for sustainable technology for greener nitrogen fixation.
A novel structural maintenance of chromosomes (SMC)-related protein family specific to Archaea
Authors: Yoshinaga Mari , Nakayama Takuro , Inagaki Yuji
Published: August 2022

The ATPases belonging to the structural maintenance of chromosomes (SMC) superfamily are involved in the maintenance of chromosome organization and dynamics, as well as DNA repair. The major proteins in this superfamily recognized to date are either conserved among the three domains of Life (i.e., SMC and Rad50) or specific to Bacteria (i.e., RecF, RecN, and MukB). In Archaea, no protein related to SMC (SMC-related protein) with a broad taxonomic distribution has been reported. Nevertheless, two SMC-related proteins, namely coalescin and Sph, have been identified in crenarchaea Sulfolobus spp. and the euryarchaeon Halobacterium salinarum, respectively, hinting that the diversity of SMC-related proteins has been overlooked in Archaea. In this study, we report a novel SMC-related protein that is distributed among broad archaeal lineages and termed “Archaea-specific SMC-related proteins” or “ASRPs.” We further demonstrate that the ASRP family encloses both coalescin and Sph but the two proteins represent only a tip of the diversity of this family.
Application of a novel lytic phage vB_EcoM_SQ17 for the biocontrol of Enterohemorrhagic Escherichia coli O157:H7 and Enterotoxigenic E. coli in food matrices
Authors: Zhou Yan , Wan Qiyang , Bao Hongduo , Guo Yonghao , Zhu Shujiao , Zhang Hui , Pang Maoda , Wang Ran
Published: August 2022

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 and Enterotoxigenic E. coli (ETEC) are important foodborne pathogens, causing serious food poisoning outbreaks worldwide. Bacteriophages, as novel antibacterial agents, have been increasingly exploited to control foodborne pathogens. In this study, a novel broad-host range lytic phage vB_EcoM_SQ17 (SQ17), was isolated, characterized, and evaluated for its potential to control bacterial counts in vitro and in three different food matrices (milk, raw beef, and fresh lettuce). Phage SQ17 was capable of infecting EHEC O157:H7, ETEC, and other E. coli strains. Morphology, one-step growth, and stability assay showed that phage SQ17 belongs to the Caudovirales order, Myoviridae family, and Mosigvirus genus. It has a short latent period of 10 min, a burst size of 71 PFU/infected cell, high stability between pH 4 to 12 as well as thermostability between 30°C and 60°C for 60 min. Genome sequencing analysis revealed that the genome of SQ17 does not contain any genes associated with antibiotic resistance, toxins, lysogeny, or virulence factors, indicating the potential safe application of phage SQ17 in the food industry. In Luria-Bertani (LB) medium, phage SQ17 significantly decreased the viable counts of EHEC O157:H7 by more than 2.40 log CFU/ml (p < 0.05) after 6 h of incubation at 37°C. Phage SQ17 showed great potential to be applied for biocontrol of EHEC O157:H7 in milk and raw beef. In fresh lettuce, treatment with SQ17 also resulted in significant reduction of viable cell counts of EHEC O157:H7 and ETEC at both 4°C and 25°C. Our results demonstrate that SQ17 is a good candidate for application as an EHEC O157:H7 and ETEC biocontrol agent in the processing stages of food production and food preservation.
Application of metagenomic next-generation sequencing in the detection of pathogens in bronchoalveolar lavage fluid of infants with severe pneumonia after congenital heart surgery
Authors: Zheng Yi-Rong , Lin Shi-Hao , Chen Yu-Kun , Cao Hua , Chen Qiang
Published: August 2022

Background

Metagenomic next-generation sequencing (mNGS) has become a valuable diagnostic tool in clinical etiology detection due to its rapidity, accuracy, and high throughput. However, the role of this technology in the diagnosis and treatment of infants with severe pneumonia after congenital heart surgery is still unclear.

Methods

We conducted a retrospective cohort study of infants with severe pneumonia after congenital heart surgery. Samples were collected from infants in the hospital’s cardiac intensive care unit between January 2010 and January 2022. The conventional microbiological test (CMT) group consisted of patients who underwent routine microbiological examination, and the infants’ bronchoalveolar lavage fluid was examined. The mNGS group consisted of patients who underwent mNGS and routine microbiological examinations.

Results

The overall positive rate of mNGS was significantly higher than that of CMT (88.4 vs. 62.5%, P = 0.009). After receipt of the microbiological results, 30/43 (70%) patients in the mNGS group had a change in antibiotic use compared with 14/40 (35%) in the CMT group (P = 0.002). Subsequently, after adjusting the treatment plan according to the microbiological test results, the number of people with improved pulmonary infection in the mNGS group was significantly higher than that in the CMT group (63 vs. 28%, P < 0.05). In addition, the duration of invasive ventilation, length of CICU stay and total hospital length of stay in the mNGS group were significantly lower than those in the CMT group (P < 0.05).

Conclusion

mNGS is a valuable tool to determine the etiology of infants with severe pneumonia after congenital heart disease surgery. It can significantly improve the sensitivity of pathogen detection, which can help determine appropriate antimicrobial drugs, improve the diagnostic accuracy of the disease, and improve outcomes.
Accumulation patterns of intracellular salts in a new halophilic amoeboflagellate, Euplaesiobystra salpumilio sp. nov., (Heterolobosea; Discoba) under hypersaline conditions
Authors: Lee Hyeon Been , Jeong Dong Hyuk , Park Jong Soo
Published: August 2022

Halophilic microbial eukaryotes are present in many eukaryotic lineages and major groups; however, our knowledge of their diversity is still limited. Furthermore, almost nothing is known about the intracellular accumulation of salts in most halophilic eukaryotes. Here, we isolate a novel halophilic microbial eukaryote from hypersaline water of 134 practical salinity units (PSU) in a solar saltern. This species is an amoeboflagellate (capable of the amoeba-flagellate-cyst transformation) in the heterolobosean group and belongs to the genus Euplaesiobystra based on morphological data and 18S rDNA sequences. However, the isolate is distinct from any of the described Euplaesiobystra species. Especially, it is the smallest Euplaesiobystra to date, has a distinct cytostome, and grows optimally at 75–100 PSU. Furthermore, the phylogenetic tree of the 18S rDNA sequences demonstrates that the isolate forms a strongly supported group, sister to Euplaesiobystra hypersalinica. Thus, we propose that the isolate, Euplaesiobystra salpumilio, is a novel species. E. salpumilio displays a significantly increased influx of the intracellular Na+ and K+ at 50, 100, and 150 PSU, compared to freshwater species. However, the intracellular retention of the Na+ and K+ at 150 PSU does not significantly differ from 100 PSU, suggesting that E. salpumilio can extrude the Na+ and K+ from cells under high-salinity conditions. Interestingly, actively growing E. salpumilio at 100 and 150 PSU may require more intracellular accumulation of Na+ than the no-growth but-viable state at 50 PSU. It seems that our isolate displays two salt metabolisms depending on the tested salinities. E. salpumilio shows a salt-in strategy for Na+ at lower salinity of 100 PSU, while it displays a salt-out strategy for Na+ at higher salinity of 150 PSU. Our results suggest that the novel halophilic E. salpumilio fundamentally uses a salt-out strategy at higher salinities, and the accumulation patterns of intracellular salts in this species are different from those in other halophilic microbial eukaryotes.