bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of BK polyomavirus-associated nephropathy using plasma graft-derived cell-free DNA: Development of a novel algorithm from programmed monitoring
Authors: Wen Jingyu , Sun Rongcun , Yang Hongji , Ran Qing , Hou Yifu
Published: October 2022

Graft-derived cell-free DNA (GcfDNA) is a promising non-invasive biomarker for detecting allograft injury. In this study, we aimed to evaluate the efficacy of programmed monitoring of GcfDNA for identifying BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant recipients. We recruited 158 kidney transplant recipients between November 2020 and December 2021. Plasma GcfDNA was collected on the tenth day, first month, third month, and sixth month for programmed monitoring and one day before biopsy. ΔGcfDNA (cp/mL) was obtained by subtracting the baseline GcfDNA (cp/mL) from GcfDNA (cp/mL) of the latest programmed monitoring before biopsy. The receiver operating characteristic curve showed the diagnostic performance of GcfDNA (cp/mL) at biopsy time and an optimal area under the curve (AUC) of 0.68 in distinguishing pathologically proven BKPyVAN from pathologically unconfirmed BKPyVAN. In contrast, ΔGcfDNA (cp/mL) had a sensitivity and specificity of 80% and 84.6%, respectively, and an AUC of 0.83. When distinguishing clinically diagnosed BKPyVAN from clinical excluded BKPyVAN, the AUC of GcfDNA (cp/mL) was 0.59 at biopsy time, and ΔGcfDNA (cp/mL) had a sensitivity and specificity of 81.0% and 76.5%, respectively, and an AUC of 0.81. Plasma ΔGcfDNA (cp/mL) was not significantly different between TCMR [0.15 (0.08, 0.24) cp/mL] and pathologically proven BKPyVAN[0.34 (0.20, 0.49) cp/mL]. In conclusion, we recommend programmed monitoring of plasma GcfDNA levels after a kidney transplant. Based on our findings from the programmed monitoring, we have developed a novel algorithm that shows promising results in identifying and predicting BKPyVAN.
Immunogenic cell death as driver of autoimmunity in granulomatosis with polyangiitis
Authors: Brieske Christoph , Lamprecht Peter , Kerstein-Staehle Anja
Published: October 2022

Cell death and dysregulated clearance of dead cells play essential roles in the induction of chronic inflammatory processes and autoimmune diseases. Granulomatosis with polyangiitis (GPA), a neutrophil-driven autoimmune disorder, is characterized by necrotizing inflammation predominantly of the respiratory tract and an anti-neutrophil cytoplasmic autoantibody (ANCA)-associated systemic necrotizing vasculitis. Defective regulation of neutrophil homeostasis and cell death mechanisms have been demonstrated in GPA. Disturbed efferocytosis (i.e., phagocytosis of apoptotic neutrophils by macrophages) as well as cell death-related release of damage-associated molecular patterns (DAMP) such as high mobility group box 1 (HMGB1) contribute to chronic non-resolving inflammation in GPA. DAMP have been shown to induce innate as well as adaptive cellular responses thereby creating a prerequisite for the development of pathogenic autoimmunity. In this review, we discuss factors contributing to as well as the impact of regulated cell death (RCD) accompanied by DAMP-release as early drivers of the granulomatous tissue inflammation and autoimmune responses in GPA.
Gastric alarmin release: A warning signal in the development of gastric mucosal diseases
Authors: Wu Enqin , Zhu Jiaxing , Ma Zhiyuan , Tuo Biguang , Terai Shuji , Mizuno Kenichi , Li Taolang , Liu Xuemei
Published: October 2022

Alarmins exist outside cells and are early warning signals to the immune system; as such, alarmin receptors are widely distributed on various immune cells. Alarmins, proinflammatory molecular patterns associated with tissue damage, are usually released into the extracellular space, where they induce immune responses and participate in the damage and repair processes of mucosal diseases.In the stomach, gastric alarmin release has been shown to be involved in gastric mucosal inflammation, antibacterial defense, adaptive immunity, and wound healing; moreover, this release causes damage and results in the development of gastric mucosal diseases, including various types of gastritis, ulcers, and gastric cancer. Therefore, it is necessary to understand the role of alarmins in gastric mucosal diseases. This review focuses on the contribution of alarmins, including IL33, HMGB1, defensins and cathelicidins, to the gastric mucosal barrier and their role in gastric mucosal diseases. Here, we offer a new perspective on the prevention and treatment of gastric mucosal diseases.
Prospective approaches to enhancing CAR T cell therapy for glioblastoma
Authors: Choi Sun Il , Yin Jinlong
Published: October 2022

Glioblastoma (GBM) is the most common malignant brain tumor. The poor clinical outcome and overall ineffectiveness of current standard treatments, including surgery, chemotherapy, and radiation, highlight the urgent need for alternative tumor-specific therapies for GBM. Chimeric antigen receptor (CAR) T cell therapy is a revolutionary therapeutic strategy for hematological malignancies, but the optimal potency of CAR T cell therapy for solid tumors, especially GBM, has not been achieved. Although CAR T cell therapeutic strategies for GBM have been assessed in clinical trials, the current antitumor activity of CAR T cells remains insufficient. In this review, we present our perspective on genetically modifying CAR constructs, overcoming T cell dysfunctions, and developing additional treatments that can improve CAR T cell effectiveness, such as functionality, persistence, and infiltration into tumor sites. Effectively improved CAR T cells may offer patients with GBM new treatment opportunities, and this review is intended to provide a comprehensive overview for researchers to develop potent CAR T cells using genetic engineering or combinatorial preparations.
Complement C1s as a diagnostic marker and therapeutic target: Progress and propective
Authors: Ye Jun , Yang Peng , Yang Yili , Xia Sheng
Published: October 2022

The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.
Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut–brain communications
Authors: Ge Li , Liu Shuman , Li Sha , Yang Jing , Hu Guangran , Xu Changqing , Song Wengang
Published: October 2022

Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn’s disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain–gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.
Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity
Authors: Greene Elizabeth , MacIver Nancie J.
Published: October 2022

Disorders of systemic metabolism can influence immunity. Individuals with obesity are known to have increased inflammation, increased risk to select autoimmune diseases, impaired response to several infections, and impaired vaccine response. For example, over the last decade, it has become clear that individuals with obesity have increased risk of morbidity and mortality from influenza infection. Unsurprisingly, this finding is also observed in the current COVID-19 pandemic: individuals with obesity, particularly severe obesity, have increased risk of poor outcomes from SARS-CoV-2 infection, including increased rates of hospitalization, ICU admission, mechanical ventilation, and death. Several studies have now demonstrated a critical role for T cells in the context of obesity-associated immune dysfunction in response to viral infection, and one mechanism for this may be altered T cell metabolism. Indeed, recent studies have shown that activated T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, both in vitro and in vivo following viral infection. For that reason, treatments that target abnormal immune cell metabolism in obesity may improve outcomes to viral infection. To that end, several recent studies have shown that use of the metabolic drug, metformin, can reverse abnormal T cell metabolism and restore T cell immunity, as well as survival, in response to viral infection. These findings will be discussed in detail here.
Deficiency of C-reactive protein or human C-reactive protein transgenic treatment aggravates influenza A infection in mice
Authors: Zhang Zhuohan , Gao Yongjun , Li Li , Luo Junhao , Gao Rongbao
Published: October 2022

C-reactive protein (CRP) has been shown to be a potential candidate target in the immunotherapy of severe influenza A infection. However, it is unclear on the pathogenesis associated with CRP in influenza infections. Here, we used influenza A H1N1 CA04 to infect human CRP transgenic mice (KI), CRP knockout mice (KO), and wild-type mice (WT), respectively, and compared the viral pathogenicity and associated immune response in those mice. The results showed that CA04 infection resulted in 100%, 80%, and 60% death in KO, KI, and WT mice, respectively. Compared to WT mice, CA04 infection resulted in higher TCID50 in lungs on day 3 after infection but lowered HI antibody titers in sera of survivors on day 21 after infection in KI mice. ELISA assay showed that IFN-γconcentration was significantly increased in sera of WT, KI, or KO mice on day 7 after infection, and IL-17 was remarkably increased in sera of WT mice but decreased in sera of KI mice while no significant change in sera of KO mice on day 3 or 7 after infection. Quantitative RT-PCR showed that the relative expression levels of immune checkpoint CTLA-4, LAIR-1, GITR, BTLA, TIM-3, or PD-1 mRNA in the lung presented decreased levels on day 3 or 7 after infection in KI or KO mice. The correlation analysis showed that mRNA expression levels of the 6 molecules positively correlated with viral TICD50 in WT mice but negatively correlated with viral TCID50 in KI or KO mice. However, only LAIR-1 presented a significant correlation in each lung tissue of WT, KI, or KO mice with CA07 infection statistically. IHC results showed that LAIR-1 positive cells could be found in WT, KO, or KI mice lung tissues with CA04 infection, and the positive cells were mainly distributed in an inflammatory dense area. Our results suggested that deficiency of CRP or human CRPtransgenic treatment aggravates influenza A virus infection in mice. CRP is a double sword in immune regulation of influenza infection in which IL-17 and immune checkpoint may be involved.
GRK2 inhibitors, paroxetine and CCG258747, attenuate IgE-mediated anaphylaxis but activate mast cells via MRGPRX2 and MRGPRB2
Authors: Thapaliya Monica , Amponnawarat Aetas , Tesmer John J. G. , Ali Hydar
Published: October 2022

G protein-coupled receptor (GPCR) kinase 2 (GRK2), which phosphorylates agonist-occupied GPCRs to promote their desensitization, has been investigated as an attractive therapeutic target for cardiovascular and metabolic diseases. Several GRK2-targeted inhibition strategies have been reported including the use of direct pharmacological inhibitors such as paroxetine (a widely prescribed antidepressant) and its analogs such as compound CCG258747. Cross-linking of high affinity IgE receptor (FcϵRI) on mast cells (MCs) and the resulting degranulation causes anaphylaxis and allergic asthma. Using gene silencing strategy, we recently showed that GRK2 contributes to FcεRI signaling and MC degranulation. The purpose of this study was to determine if the GRK2 inhibitors paroxetine and CCG258747 modulate FcεRI-mediated MC responsesin vitroandin vivo. Utilizing rat basophilic leukemia (RBL-2H3) cells and primary mouse lung MCs (LMCs), we found that paroxetine and CCG258747 inhibit FcϵRI-mediated calcium mobilization and degranulation. Furthermore, intravenous administration of paroxetine and CCG258747 in mice resulted in substantial reduction of IgE-mediated passive cutaneous anaphylaxis. Unlike LMCs, human cutaneous MCs abundantly express a novel GPCR known as MRGPRX2 (mouse; MRGPRB2). We found that in contrast to their inhibitory effects on FcεRI-mediated MC responses, both paroxetine and CCG258747 induce calcium mobilization and degranulation in RBL-2H3 cells stably expressing MRGPRX2 but not in untransfected cells. Furthermore, paroxetine and CCG258747 induced degranulation in peritoneal MCs from Wild-type (WT) micein vitroand caused increased cutaneous vascular permeabilityin vivo, but these responses were substantially reduced inMrgprb2−/−mice. Additionally, upon intradermal injection, paroxetine also induced neutrophil recruitment in WT but notMrgprb2−/−mice. These findings suggest that in addition to their potential therapeutic utility against cardiovascular and metabolic disorders, paroxetine-based GRK2-inhibitors may serve to modulate IgE-mediated anaphylaxis and to enhance cutaneous host defense by harnessing MC’s immunomodulatory property through the activation of MRGPRX2/MRGPRB2.
Efficacy evaluation of multi-immunotherapy in ovarian cancer: From bench to bed
Authors: Hu Xiaoyi , Bian Ce , Zhao Xia , Yi Tao
Published: October 2022

Ovarian cancer, one of the most common gynecological malignancies, is characterized by high mortality and poor prognosis. Cytoreductive surgery and chemotherapy remain the mainstay of ovarian cancer treatment, and most women experience recurrence after standard care therapies. There is compelling evidence that ovarian cancer is an immunogenic tumor. For example, the accumulation of tumor-infiltrating lymphocytes is associated with increased survival, while increases in immunosuppressive regulatory T cells are correlated with poor clinical outcomes. Therefore, immunotherapies targeting components of the tumor microenvironment have been gradually integrated into the existing treatment options, including immune checkpoint blockade, adoptive cell therapy, and cancer vaccines. Immunotherapies have changed guidelines for maintenance treatment and established a new paradigm in ovarian cancer treatment. Despite single immunotherapies targeting DNA repair mechanisms, immune checkpoints, and angiogenesis bringing inspiring efficacy, only a subset of patients can benefit much from it. Thus, the multi-immunotherapy investigation remains an active area for ovarian cancer treatment. The current review provides an overview of various clinically oriented forms of multi-immunotherapy and explores potentially effective combinational therapies for ovarian cancer.
T cell kinetics reveal expansion of distinct lung T cell subsets in acute versus in resolved influenza virus infection
Authors: Eriksson Malin , Nylén Susanne , Grönvik Kjell-Olov
Published: October 2022

Influenza virus infection is restricted to airway-associated tissues and elicits both cellular and humoral responses ultimately resulting in generation of memory cells able to initiate a rapid immune response against re-infections. Resident memory T cells confer protection at the site of infection where lung-resident memory T cells are important for protecting the host against homologous and heterologous influenza virus infections. Mapping kinetics of local and systemic T cell memory formation is needed to better understand the role different T cells have in viral control and protection. After infecting BALB/c mice with influenza virus strain A/Puerto Rico/8/1934 H1N1 the main proportion of activated T cells and B cells expressing the early activation marker CD69 was detected in lungs and lung-draining mediastinal lymph nodes. Increased frequencies of activated cells were also observed in the peripheral lymphoid organs spleen, inguinal lymph nodes and mesenteric lymph nodes. Likewise, antigen-specific T cells were most abundant in lungs and mediastinal lymph nodes but present in all organs studied. CD8+CD103-CD49a+lung-resident T cells expanded simultaneously with timing of viral clearance whereas CD8+CD103+CD49a+lung-resident T cells was the most abundant subset after resolution of infection and antigen-specific, lung-resident T cells were detected up to seven months after infection. In conclusion, the results in this detailed kinetic study demonstrate that influenza virus infection elicits adaptive immune responses mainly in respiratory tract-associated tissues and that distinct subsets of lung-resident T cells expand at different time points during infection. These findings contribute to the understanding of the adaptive immune response locally and systemically following influenza virus infection and call for further studies on the roles of the lung-resident T cell subsets.
Case Report: Chronic hepatitis E in a hematopoietic stem cell transplant recipient: The first report of hepatitis E virus genotype 4 causing chronic infection in a non-solid organ recipient
Authors: Chen Zihao , Wei Junfeng , Jiang Li , Ying Dong , Tian Weikun , Zhang Mengyang , Wen Guiping , Wang Siling , Liu Chang , Wang Yingbin , Wu Ting , Tang Zimin , Zheng Zizheng , Yan Li , Xia Ningshao
Published: October 2022

Hepatitis E virus (HEV) is one of the most important public health issues around the world, and chronic HEV infection has been reported in immunosuppressed individuals. This study reported a male case, with very severe aplastic anemia (AA), who developed chronic hepatitis E after hematopoietic stem cell transplantation (HSCT). Abnormal alanine aminotransferase (ALT) appeared after HSCT and persisted for twenty-nine months. The case was seropositive for anti-HEV IgG and IgM after HSCT. Twenty-two months after HSCT, HEV RNA and antigen (Ag) testing were positive and persisted for five and seven months, respectively. Positive stains of HEV Ag were present in a liver biopsy sample. HEV Ag was present in bone marrow. The individual rapidly developed liver cirrhosis and was rescued by a regimen of oral ribavirin. These factors suggested there is a risk of HEV infection in HSCT recipients.
Sustaining surveillance as an intervention during the COVID-19 pandemic in Cabo Verde and implications for malaria elimination
Authors: DePina Adilson , Barros Helga , Tiffany Amanda , Stresman Gillian
Published: October 2022

Cabo Verde reported the first case of COVID-19 on March 19, 2020. Containment measures were quickly implemented and over 80,000 COVID-19 tests were performed in 2020 with 11,840 confirmed infections (2% of the population) and 154 deaths. In a setting where the last locally acquired malaria case was reported in January 2018, any interruptions to malaria care-seeking have the potential for infections to go untreated and transmission re-establishing. This work aims to determine whether there was any change in the number of people seeking care or being tested for malaria and, using an interrupted time series analysis, identify if any change was associated with implemented COVID-19 measures. Routinely collected surveillance data for outpatient visits, testing for malaria and COVID-19 were aggregated by month for each health facility (outpatient and malaria) or by municipality (COVID-19) from 2017 through 2020. The timeline of COVID-19 measures was generated based on when and where they were implemented. Results show that there was a marked shift in care-seeking in Cabo Verde. Overall, the mean number of observed outpatient visits decreased from 2,057 visits per month during 2017-2019 to 1,088 in 2020, an estimated 28% reduction. However, malaria testing rates per 1,000 outpatient visits after the pandemic began increased by 8% compared to expected trends. Results suggest that the pandemic impacted care-seeking but led to a non-significant increase in testing for malaria per 1,000 outpatient visits. With the cessation of international travel, the risk of imported infections seeding new transmission declined suggesting the risk of undetected transmission was low. It is important for countries to understand their specific malaria risks and vulnerabilities in order to ensure that any progress towards the interruption of malaria transmission can be sustained.
Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency
Authors: van Schouwenburg Pauline , Unger Susanne , Payne Kathryn J. , Kaiser Fabian M. P. , Pico-Knijnenburg Ingrid , Pfeiffer Jens , Hausmann Oliver , Friedmann David , Erbel Michelle , Seidl Maximilian , van Zessen David , Stubbs Andrew P. , van der Burg Mirjam , Warnatz Klaus
Published: October 2022

Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation.
Uveitis increases the risk of stroke among patients with ankylosing spondylitis: A nationwide population-based longitudinal study
Authors: Tsung Ta-hsin , Huang Ke-Hao , Chien Wu-Chien , Chen Yi-Hao , Yen I-Chuan , Chung Chi-Hsiang , Chen Jiann-Torng , Chen Ching-Long
Published: October 2022

Ankylosing spondylitis (AS) is known to increase the risk of stroke. Among patients with AS, uveitis is the most common extra-articular manifestation. However, no previous investigations have discussed the association between uveitis and the risk for developing stroke in patients with AS. This retrospective cohort study aimed to explore the relationship between uveitis and the incidence of stroke in patients with AS by obtaining medical records from January 1, 2000, to December 31, 2015, from the National Health Insurance Research Database, according to the International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes. The primary outcome was the incidence of stroke. Pearson’s chi-square test and Fisher’s exact test were used to analyze variables. Kaplan–Meier survival curves and univariate and multivariate Cox proportional hazard regression models with and without Fine and Gray’s competing risk model were used to analyze data. Total 828 AS patients with uveitis and 3,312 AS patients without uveitis were identified. During the follow-up period, 137 patients in the uveitis group and 344 in the non-uveitis group developed stroke. Uveitis is a significant risk factor for stroke development in patients with AS (adjusted hazard ratio = 1.846, p < 0.001). Age, diabetes mellitus, hyperlipidemia, hypertension, congestive heart failure, chronic obstructive pulmonary disease, asthma, coronary artery disease, and atrial fibrillation were associated with a higher risk of stroke. After subgroup analysis, both anterior uveitis and posterior segment involvement were found to increase the risk of stroke in patients with AS. Uveitis is associated with an increased risk in both ischemic and hemorrhagic strokes in patients with AS. Therefore, when uveitis is identified, clinicians should pay more attention to the cerebrovascular risk in patients with AS, especially in those with underlying comorbidities.
H7N9 bearing a mutation in the nucleoprotein leads to increased pathology in chickens
Authors: Layton Daniel S. , Butler Jeffrey , Stewart Cameron , Stevens Vicky , Payne Jean , Rootes Christina , Deffrasnes Celine , Walker Som , Shan Songhua , Gough Tamara J. , Cowled Christopher , Bruce Kerri , Wang Jianning , Kedzierska Katherine , Wong Frank Y. K. , Bean Andrew G. D. , Bingham John , Williams David T.
Published: October 2022

The zoonotic H7N9 avian influenza (AI) virus first emerged in 2013 as a low pathogenic (LPAI) strain, and has repeatedly caused human infection resulting in severe respiratory illness and a mortality of ~39% (>600 deaths) across five epidemic waves. This virus has circulated in poultry with little to no discernible clinical signs, making detection and control difficult. Contrary to published data, our group has observed a subset of specific pathogen free chickens infected with the H7N9 virus succumb to disease, showing clinical signs consistent with highly pathogenic AI (HPAI). Viral genome sequencing revealed two key mutations had occurred following infection in the haemagglutinin (HA 226 L>Q) and nucleoprotein (NP 373 A>T) proteins. We further investigated the impact of the NP mutation and demonstrated that only chickens bearing a single nucleotide polymorphism (SNP) in their IFITM1 gene were susceptible to the H7N9 virus. Susceptible chickens demonstrated a distinct loss of CD8+ T cells from the periphery as well as a dysregulation of IFNγ that was not observed for resistant chickens, suggesting a role for the NP mutation in altered T cell activation. Alternatively, it is possible that this mutation led to altered polymerase activity, as the mutation occurs in the NP 360-373 loop which has been previously show to be important in RNA binding. These data have broad ramifications for our understanding of the pathobiology of AI in chickens and humans and provide an excellent model for investigating the role of antiviral genes in a natural host species.
Origin, activation, and targeted therapy of glioma-associated macrophages
Authors: Xu Can , Xiao Menglin , Li Xiang , Xin Lei , Song Jia , Zhan Qi , Wang Changsheng , Zhang Qisong , Yuan Xiaoye , Tan Yanli , Fang Chuan
Published: October 2022

The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.
Strategies to overcome DC dysregulation in the tumor microenvironment
Authors: Mestrallet Guillaume , Sone Kazuki , Bhardwaj Nina
Published: October 2022

Dendritic cells (DCs) play a key role to modulate anti-cancer immunity in the tumor microenvironment (TME). They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. In this regard, the TME plays a major role in adversely affecting DC function. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. We further focus on how cancer cells modulate DCs to escape from the host’s immune-surveillance. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies.
Immune infiltration landscape on prognosis and therapeutic response and relevant epigenetic and transcriptomic mechanisms in lung adenocarcinoma
Authors: Zhang Liangming , Jiang Biwang , Lan Zhuxiang , Yang Chaomian , Yao Yien , Lin Jie , Wei Qiu
Published: October 2022

Objective

Lung adenocarcinoma (LUAD) is the most prevalent lung cancer subtype, but its immune infiltration features are not comprehensively understood. To address the issue, the present study was initiated to describe the immune infiltrations across LUAD from cellular compositional, functional, and mechanism perspectives.

Methods

We adopted five LUAD datasets (GSE32863, GSE43458, GSE75037, TCGA-LUAD, and GSE72094). Differentially expressed genes between LUAD and controls were selected for co-expression network analysis. Risky immune cell types were determined for classifying LUAD patients as diverse subtypes, followed by a comparison of antitumor immunity and therapeutic response between subtypes. Then, LUAD- and subtype-related key module genes affected by DNA methylation were determined for quantifying a scoring scheme. EXO1 was chosen for functional analysis via in vitro assays.

Results

Two immune cell infiltration-based subtypes (C1 and C2) were established across LUAD, with poorer prognostic outcomes and lower infiltration of immune cell types in C1. Additionally, C1 presented higher responses to immune checkpoint blockade and targeted agents (JNK inhibitor VIII, BI-D1870, RO-3306, etc.). The scoring system (comprising GAPDH, EXO1, FYN, CFTR, and KLF4) possessed higher accuracy in estimating patients’ prognostic outcomes. EXO1 upregulation contributed to the growth, migration, and invasion of LUAD cells. In addition, EXO1 facilitated PD-L1 and sPD-L1 expression in LUAD cells.

Conclusion

Altogether, our findings offer a comprehensive understanding of the immune infiltration landscape on prognosis and therapeutic response of LUAD as well as unveil potential epigenetic and transcriptomic mechanisms, which might assist personalized treatment.
Pulsed radiotherapy to mitigate high tumor burden and generate immune memory
Authors: Sezen Duygu , Barsoumian Hampartsoum B. , He Kewen , Hu Yun , Wang Qi , Abana Chike O. , Puebla-Osorio Nahum , Hsu Ethan Y. , Wasley Mark , Masrorpour Fatemeh , Wang Jing , Cortez Maria Angelica , Welsh James W.
Published: October 2022

Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used with immune-check-point inhibitors in metastatic disease, especially when immunotherapy fails due to tumor immune evasion. We hypothesized that using high-dose stereotactic radiation in cycles (pulses) would increase T-cell priming and repertoire with each pulse and build immune memory in an incremental manner. To prove this hypothesis, we studied the combination of anti-CTLA-4 and Pulsed radiation therapy in our 344SQ non-small cell lung adenocarcinoma murine model. Primary and secondary tumors were bilaterally implanted in 129Sv/Ev mice. In the Pulsed XRT group, both primary and secondary tumors received 12Gyx2 radiation one week apart, and blood was collected seven days afterwards for TCR repertoire analysis. As for the delayed-Pulse group, primary tumors received 12Gyx2, and after a window of two weeks, the secondary tumors received 12Gyx2. Blood was collected seven days after the second cycle of radiation. The immunotherapy backbone for both groups was anti-CTLA-4 antibody to help with priming. Treatment with Pulsed XRT + anti-CTLA-4 led to significantly improved survival and resulted in a delayed tumor growth, where we observed enhanced antitumor efficacy at primary tumor sites beyond XRT + anti-CTLA-4 treatment group. More importantly, Pulsed XRT treatment led to increased CD4+ effector memory compared to single-cycle XRT. Pulsed XRT demonstrated superior efficacy to XRT in driving antitumor effects that were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. These results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and sustained antitumor response.
Lipid metabolism in type 1 diabetes mellitus: Pathogenetic and therapeutic implications
Authors: Zhang Jing , Xiao Yang , Hu Jingyi , Liu Shanshan , Zhou Zhiguang , Xie Lingxiang
Published: October 2022

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease with insulin deficiency due to pancreatic β cell destruction. Multiple independent cohort studies revealed specific lipid spectrum alterations prior to islet autoimmunity in T1DM. Except for serving as building blocks for membrane biogenesis, accumulative evidence suggests lipids and their derivatives can also modulate different biological processes in the progression of T1DM, such as inflammation responses, immune attacks, and β cell vulnerability. However, the types of lipids are huge and majority of them have been largely unexplored in T1DM. In this review, based on the lipid classification system, we summarize the clinical evidence on dyslipidemia related to T1DM and elucidate the potential mechanisms by which they participate in regulating inflammation responses, modulating lymphocyte function and influencing β cell susceptibility to apoptosis and dysfunction. This review systematically recapitulates the role and mechanisms of various lipids in T1DM, providing new therapeutic approaches for T1DM from a nutritional perspective.
Target tumor microenvironment by innate T cells
Authors: Li Yan-Ruide , Wilson Matthew , Yang Lili
Published: October 2022

The immunosuppressive tumor microenvironment (TME) remains one of the most prevailing barriers obstructing the implementation of effective immunotherapy against solid-state cancers. Eminently composed of immunosuppressive tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) among others, the TME attenuates the effects of immune checkpoint blockade and adoptive cell therapies, mandating a novel therapy capable of TME remediation. In this review we explore the potential of three innate-like T cell subsets, invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδT) cells, that display an intrinsic anti-TAM/MDSC capacity. Exhibiting both innate and adaptive properties, innate-like T cell types express a subset-specific TCR with distinct recombination, morphology, and target cell recognition, further supplemented by a variety of NK activating receptors. Both NK activating receptor and TCR activation result in effector cell cytotoxicity against targeted immunosuppressive cells for TME remediation. In addition, innate-like T cells showcase moderate levels of tumor cell killing, providing dual antitumor and anti-TAM/MDSC function. This latent antitumor capacity can be further bolstered by chimeric antigen receptor (CAR) engineering for recognition of tumor specific antigens to enhance antitumor targeting. In contrast with established CAR-T cell therapies, adoption of these innate-like cell types provides an enhanced safety profile without the risk of graft versus host disease (GvHD), due to their non-recognition of mismatched major histocompatibility complex (MHC) molecules, for use as widely accessible, allogeneic “off-the-shelf” cancer immunotherapy.
Lake Erie field trials to advance autonomous monitoring of cyanobacterial harmful algal blooms
Authors: Den Uyl Paul A. , Thompson Luke R. , Errera Reagan M. , Birch James M. , Preston Christina M. , Ussler William , Yancey Colleen E. , Chaganti Subba Rao , Ruberg Steven A. , Doucette Gregory J. , Dick Gregory J. , Scholin Christopher A. , Goodwin Kelly D.
Published: October 2022

Biomolecular analyses are used to investigate the dynamics of cyanobacterial harmful algal blooms (cyanoHABs), with samples collected during monitoring often analyzed by qPCR and sometimes amplicon and metagenomic sequencing. However, cyanoHAB research and monitoring programs face operational constraints due to the reliance on human resources for sample collections. To address this impediment, a third-generation Environmental Sample Processor (3G ESP) integrated with a long-range autonomous underwater vehicle (LRAUV) was tested during seasonal blooms of Microcystis in western Lake Erie (WLE) in 2018 and 2019. The LRAUV-3G ESP successfully performed flexible, autonomous sampling across a wide range of cyanoHAB conditions, and results indicated equivalency between autonomous and manual methods. No significant differences were found between LRAUV-3G ESP and manual sample collection and handling methods in the 12 parameters tested. Analyzed parameters included concentrations of total cyanobacteria and microcystin toxin gene via qPCR; relative abundances of bacterial amplicon sequence variants (ASVs) from 16S rRNA gene amplicon sequencing; and community diversity measures from both 16S amplicon and metagenomic sequencing. The LRAUV-3G ESP provided additional sampling capacity and revealed differences between field seasons for bacterial taxa and concentrations of total cyanobacteria and microcystin toxin gene. Metagenomic analysis of multiple microcystin toxin genes corroborated the use of the mcyE gene as a proxy for the genomic potential of WLE cyanoHABs to produce microcystin. Overall, this study provides support for the use of autonomous ‘omics capability in WLE to help expand the spatial and temporal coverage of cyanoHAB monitoring operations.
Effects of three feed attractants on the growth performance and meat quality of the largemouth bass (Micropterus salmoides)
Authors: Yue Yuhua , Chen Mingshi , Bao Xiaoxue , Yu Yingying , Shi Wei , Kumkhong Suksan , Liu Yuhong , Yang Ying , Yu Hui
Published: October 2022

The trial was conducted to investigate the effects of limonene, allicin and betaine supplementation in low fish meal (FM) diet on growth performance, antioxidant capacity, meat quality and intestinal health in largemouth bass (M. salmoides). The biting-balls test and feeding trial were successively conducted. For the one, the results of the biting-ball test showed that with the increase of the concentration of the three attractants, the attracting effect firstly increased, then decreased, and the effect reached maximum at 0.2% concentration. (P < 0.05). Further, a 9-week feeding trial was conducted using five diets, including a basal diet with 30% and 40% fish meal without attractant, 30% fish meal supplemented with 0.2% limonene, 0.2% allicin or 0.2% betaine (the diets were named FM30, FM40, FM30 + L, FM30 + A, FM30 + B, respectively). The results demonstrated that adding limonene, allicin and betaine at concentration of 0.2% to the low fish meal feed could improve final body weight, weight gain rate, and specific growth rate of M. salmoides but only in 4 weeks (P > 0.05). Besides, dietary supplementation with attractants could significantly reduce the content of MDA in serum and liver, and increase the activity of GSH in liver (P < 0.05). Compared with FM30 group, the supplementation with limonene, allicin or betaine diet had higher pH, redness (a*), yellowness (b*) (P > 0.05), and lower refrigeration loss, cooking loss values (P < 0.05). Furthermore, supplementation with attractants groups had higher values for villus height, lamina propria, crypt depth, submucous layer, and serous layer (P < 0.05). Taken together, these results indicated that limonene, allicin and betaine had a time effect on the growth performance, and could improve antioxidant capacity, meat quality and intestinal health of M. salmoide.
Sulfur-containing benzofurans and α-pyrones from the mangrove-derived fungus Talaromyces sp. WHUF0341
Authors: Zhang Ruohan , Zhang Jinxin , Huo Ruiyun , Xue Yaxin , Hong Kui , Liu Ling
Published: October 2022

Two new sulfur-containing benzofurans, talarobenzofurans A and B (1 and 2), one new benzofuran talarobenzofuran C (3) and two new α-pyrones talaropyrones A and B (5 and 6), along with five known compounds eurothiocin A (4), nodulisporipyrone A (7), peniazaphilin B (8), ramulosin (9) and 6-hydroxyramulosin (10) were isolated and identified from the culture extract of the mangrove-derived fungus Talaromyces sp. WHUF0341 guided by OSMAC (one strain-many compounds) strategy. Their structures were established by extensive spectroscopic data analysis, the modified Mosher’s method and electronic circular dichroism (ECD) calculations. Structurally, compounds 1 and 2 possesed the unique thioester moiety derived from benzofuran and 2-hydroxy-3-mercaptopropionic acid, which was rarely-observed in natural products. The α-glucosidase inhibitory and antibacterial activities of the isolated compounds were evaluated. Compounds 3 and 4 exhibited inhibitory effects against α-glucosidase activity with IC50 values of 48.9 ± 2.16 and 8.8 ± 1.08 µM, respectively. The inhibitory type of 3 on α-glucosidase was determined as non-competitive-type inhibition with Ki value of 242.3 μM by using Lineweaver-Burk double reciprocal and Dixon single reciprocal plots. Meanwhile, the binding model of 3 and 4 with α-glucosidase was determined by molecular docking assay. The biosynthetic pathways of compounds 1−4 were also proposed. This study suggested that benzofurans 3 and 4 could be potential lead compounds for the hypoglycemic drugs.
Application of multi-regression machine learning algorithms to solve ocean water mass mixing in the Atlantic Ocean
Authors: Romera-Castillo Cristina , Heras Jónathan , Álvarez Marta , Álvarez-Salgado X. Antón , Mata Gadea , Sáenz-de-Cabezón Eduardo
Published: October 2022

The distribution of any non-conservative variable in the deep open ocean results from the circulation and mixing of water masses (WMs) of contrasting origin and from the initial preformed composition, modified during ongoing simultaneous biological and/or geochemical processes. Estimating the contribution of the WMs composing a sample is useful to trace the distribution of each water mass and to quantitatively separate the physical (mixing) and biogeochemical components of the variability of any, non- conservative variable (e.g., dissolved organic carbon, prokaryote biomass) in the ocean. Other than potential temperature and salinity, additional semi-conservative and non-conservative variables have been used to solve the mixing of more than three water masses using Optimum Multi-Parameter (OMP) approaches. Successful application of an OMP analysis requires knowledge of the characteristics of the water masses in their source regions as well as their circulation and mixing patterns. Here, we propose the application of multi-regression machine learning models to solve ocean water mass mixing. The models tested were trained using the solutions from OMP analyses previously applied to samples from cruises in the Atlantic Ocean. Extremely Randomized Trees algorithm yielded the highest score (R2 = 0.9931; mse = 0.000227). Our model allows solving the mixing of water masses in the Atlantic Ocean using potential temperature, salinity, latitude, longitude and depth. Therefore, basic hydrographic data collected during typical research cruises or autonomous systems can be used as input variables and provide results in real time. The model can be fed with new solutions from compatible OMP analyses as well as with new water masses not previously considered in it. Our tool will provide knowledge on water mass composition and distribution to a broader community of marine scientists not specialized in OMP analysis and/or in the oceanography of the studied area. This will allow a quantitative analysis of the effect of water mass mixing on the variables or processes under study.