bluuebunny/crossref_metadata_2025 huggingface dataset:
A Common R219K Variant of ATP-Binding Cassette Transporter A1 Gene Alters Atherometabolic Traits in Pregnant Women With Gestational Diabetes Mellitus
Authors: Tang Fangmei , Guan Linbo , Liu Xinghui , Fan Ping , Zhou Mi , Wu Yujie , Liu Rui , Liu Yu , Liu Sixu , Li Dehua , Bai Huai
Published: December 2021

Background

ATP-binding cassette transporter A1 (ABCA1) has important roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport, and is implicated in lipid-related disorders. Genetic variants are involved in the pathogenesis of gestational diabetes mellitus (GDM). The objective of this study was to investigate the association of rs2230806 (R219K), a single nucleotide polymorphism (SNP) in the lipid-related gene, with the risk of GDM and related traits.

Methods

The SNP, rs2230806, was genotyped, and clinical and metabolic parameters were determined in 660 GDM patients and 1,097 control subjects. Genetic associations with related traits were also analyzed.

Results

The genotype distributions were similar in GDM patients and normal controls. However, significant differences in the variables examined in the study subjects were noted across the three genotypes. The genotype at the rs2230806 polymorphism was significantly associated with HDL-cholesterol (HDL-C) levels and atherogenic index (AI) values in GDM patients and total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in control subjects. Subgroup analysis showed that the polymorphism was associated with diastolic blood pressure, in addition to HDL-C levels and AI, in overweight/obese GDM patients, while it was associated with TC levels, AI, pre-pregnancy body mass index (BMI), and BMI at delivery in non-obese GDM patients. In addition, this polymorphism was associated with TC, LDL-C, and apoB levels in overweight/obese control subjects.

Conclusions

The rs2230806 polymorphism in the ABCA1 gene was associated with variations in atherometabolic traits in GDM patients, with characteristics of BMI dependency, but not with GDM. Our findings highlight a link between related phenotypes in women with GDM and genetic factors.
The Application of the Combined Fission Matrix Theory in Fast Reactors
Authors: He Donghao , Zhang Tengfei , Liu Xiaojing
Published: December 2021

The combined fission matrix theory is a recently-developed hybrid neutron transport method. It features high efficiency, fidelity, and resolution whole-core transport calculation. The theory is based on the assumption that the fission matrix element ai,j is dominated by the property of the destination cell i. This assumption can be well explained in thermal reactors, and the combined fission matrix method has been validated in a series of thermal neutron system benchmarks. This work examines the feasibility of the combined fission matrix theory in fast reactors. The European Sodium Fast Reactor is used as the numerical benchmark. Compared to the Monte Carlo method, the combined fission matrix theory reports a 64 pcm keff difference and 8.3% 2D RMS error. The error is much larger than that in thermal reactors, and the correction ratio cannot significantly reduce the material discontinuity error in fast reactors. Overall, the combined fission matrix theory is more suited for thermal reactor transport calculations. Its application in fast reactors needs further developments.
Ultra-Short-Term Wind Power Prediction Based on Bidirectional Gated Recurrent Unit and Transfer Learning
Authors: Chen Wenjin , Qi Weiwen , Li Yu , Zhang Jun , Zhu Feng , Xie Dong , Ru Wei , Luo Gang , Song Meiya , Tang Fei
Published: December 2021

Wind power forecasting (WPF) is imperative to the control and dispatch of the power grid. Firstly, an ultra-short-term prediction method based on multilayer bidirectional gated recurrent unit (Bi-GRU) and fully connected (FC) layer is proposed. The layers of Bi-GRU extract the temporal feature information of wind power and meteorological data, and the FC layer predicts wind power by changing dimensions to match the output vector. Furthermore, a transfer learning (TL) strategy is utilized to establish the prediction model of a target wind farm with fewer data and less training time based on the source wind farm. The proposed method is validated on two wind farms located in China and the results prove its superior prediction performance compared with other approaches.
Persistence of Seed Dispersal in Agroecosystems: Effects of Landscape Modification and Intensive Soil Management Practices in Avian Frugivores, Frugivory and Seed Deposition in Olive Croplands
Authors: Rey Pedro J. , Camacho Francisco M. , Tarifa Rubén , Martínez-Núñez Carlos , Salido Teresa , Pérez Antonio J. , García Daniel
Published: December 2021

Farming impacts animal-mediated seed dispersal through mechanisms operating on at least two spatial scales. First, at the landscape scale, through habitat loss and land conversion to agriculture/livestock grazing, and second, at the farm scale, via a local intensification of agricultural practices. These two scales of farming impact seed dispersal function but have rarely been integrated. In particular, studies evaluating the effect of agriculture on the seed dispersal function of frugivorous birds in Mediterranean ecosystems are lacking. This study evaluates the role of landscape transformation, from fruit-rich woodland habitats to olive grove landscapes, together with local intensive practices of soil management on the persistence of the seed dispersal function for Mediterranean fleshy-fruited plants in olive landscapes of south Spain. We used bird censuses, mist-nets, and seed traps to characterize avian frugivore assemblages, frugivory, and seed deposition in the seminatural woodland habitat (SNWH) patches and olive fields of 40 olives farms spanning 20 localities distributed across the whole range of olive cultivation in Andalusia (southern Spain). We found that despite the remarkable dispersal function of olive grove landscapes, avian frugivore abundance and diversity, frugivory, and seed arrival decreased in olive fields compared to SNWH patches. Likewise, SNWH cover loss and/or olive growing expansion decreased avian frugivory and seed arrival. Interestingly, the habitat effects in the olive farms often depended on the landscape context. In particular, less diverse fruit-eating bird assemblages pooled in SNWH patches as olive grove cover increased or SNWH decreased in the landscape, while remaining relatively invariant in the olive fields. Finally, compared to conventional intensive agriculture, low-intensity management increased frugivory and seed deposition. We conclude that olive fields are less permeable to frugivores than expected due to the agroforest-like nature of these landscapes and that the presence of SNWH patches is crucial for the maintenance of frugivory and seed dispersal in agricultural landscapes. These results evidence that woodland habitat loss by olive expansion and intensive practices seriously threaten the dispersal service in olive-dominated landscapes. Maintenance, restoration, and promotion of woodland patches should be prioritized for the conservation of seed dispersal service and for enhancing the functional connectivity in human-shaped olive landscapes.
Targeted Gene Knockouts by Protoplast Transformation in the Moss Physcomitrella patens
Authors: Zhu Lei
Published: December 2021

Targeted gene knockout is particularly useful for analyzing gene functions in plant growth, signaling, and development. By transforming knockout cassettes consisting of homologous sequences of the target gene into protoplasts, the classical gene targeting method aims to obtain targeted gene replacement, allowing for the characterization of gene functionsin vivo. The mossPhyscomitrella patensis a known model organism for a high frequency of homologous recombination and thus harbors a remarkable rate of gene targeting. Other moss features, including easy to culture, dominant haploidy phase, and sequenced genome, make gene targeting prevalent inPhyscomitrella patens. However, even gene targeting was powerful to generate knockouts, researchers using this method still experienced technical challenges. For example, obtaining a good number of targeted knockouts after protoplast transformation and regeneration disturbed the users. Off-target mutations such as illegitimate random integration mediated by nonhomologous end joining and targeted insertion wherein one junction on-target but the other end off-target is commonly present in the knockouts. Protoplast fusion during transformation and regeneration was also a problem. This review will discuss the advantages and technical challenges of gene targeting. Recently, CRISPR-Cas9 is a revolutionary technology and becoming a hot topic in plant gene editing. In the second part of this review, CRISPR-Cas9 technology will be focused on and compared to gene targeting regarding the practical use inPhyscomitrella patens. This review presents an updated perspective of the gene targeting and CRISPR-Cas9 techniques to plant biologists who may consider studying gene functions in the model organismPhyscomitrella patens.
Association of a Novel Prognosis Model with Tumor Mutation Burden and Tumor-Infiltrating Immune Cells in Thyroid Carcinoma
Authors: Zhang Siqin , Chen Shaoyong , Wang Yuchen , Zhan Yuxiang , Li Jiarui , Nong Xiaolin , Gao Biyun
Published: December 2021

Although immunotherapy has recently demonstrated a substantial promise in treating advanced thyroid carcinoma (THCA), it is not appropriate for all THCA patients. As a result, this study aims to identify biomarkers for predicting immunotherapy efficacy and prognosis in THCA patients based on a constructed prognostic model. The transcriptomic and corresponding clinical data of THCA patients were obtained from the Cancer Genome Atlas (TCGA) database. We identified differentially expressed genes (DEGs) between THCA and normal samples and performed an intersection analysis of DEGs with immune-related genes (IRGs) downloaded from the ImmPort database. Functional enrichment analysis was performed on the chosen immune-related DEGs. Subsequently, Cox and LASSO regression analyses were conducted to obtain three hub immune-related DEGs, including PPBP, SEMA6B, and GCGR. Following that, a prognostic risk model was established and validated based on PPBP, SEMA6B, and GCGR genes to predict immunotherapy efficacy and THCA prognosis. Finally, we investigated the association between the constructed risk model and tumor mutational burden (TMB), abundance of tumor-infiltrating immune cells (TICs) as well as immunotherapeutic targets (PDL-1, PD-1, and CTLA4) in THCA. THCA patients in the high-risk score (RS) group showed higher TMB levels and worse prognosis than the low RS group. Patients in the high-RS group had higher proportions of monocytes, M2 macrophages, and activated dendritic cells, whereas those in the low-RS group exhibited higher numbers of M1 macrophages and dendritic resting cells. Our data implied that the constructed THCA prognostic model was sound and we concluded that the THCA patients having high TMB and low PD-L1 expression levels might respond poorly to immunotherapy. Taken together, we constructed a novel prognostic model for THCA patients to predict their prognosis and immunotherapy efficacy, providing a viable option for the future management of THCA patients in the clinic.
Immunotherapy Resistance in Glioblastoma
Authors: Wang Elaina J. , Chen Jia-Shu , Jain Saket , Morshed Ramin A. , Haddad Alexander F. , Gill Sabraj , Beniwal Angad S. , Aghi Manish K.
Published: December 2021

Glioblastoma is the most common malignant primary brain tumor in adults. Despite treatment consisting of surgical resection followed by radiotherapy and adjuvant chemotherapy, survival remains poor at a rate of 26.5% at 2 years. Recent successes in using immunotherapies to treat a number of solid and hematologic cancers have led to a growing interest in harnessing the immune system to target glioblastoma. Several studies have examined the efficacy of various immunotherapies, including checkpoint inhibitors, vaccines, adoptive transfer of lymphocytes, and oncolytic virotherapy in both pre-clinical and clinical settings. However, these therapies have yielded mixed results at best when applied to glioblastoma. While the initial failures of immunotherapy were thought to reflect the immunoprivileged environment of the brain, more recent studies have revealed immune escape mechanisms created by the tumor itself and adaptive resistance acquired in response to therapy. Several of these resistance mechanisms hijack key signaling pathways within the immune system to create a protumoral microenvironment. In this review, we discuss immunotherapies that have been trialed in glioblastoma, mechanisms of tumor resistance, and strategies to sensitize these tumors to immunotherapies. Insights gained from the studies summarized here may help pave the way for novel therapies to overcome barriers that have thus far limited the success of immunotherapy in glioblastoma.
A Novel Model of Tumor-Infiltrating B Lymphocyte Specific RNA-Binding Protein-Related Genes With Potential Prognostic Value and Therapeutic Targets in Multiple Myeloma
Authors: Zhang JingJing , He Pengcheng , Wang Xiaoning , Wei Suhua , Ma Le , Zhao Jing
Published: December 2021

Background: RNA-binding proteins (RBPs) act as important regulators in the progression of tumors. However, their role in the tumorigenesis and prognostic assessment in multiple myeloma (MM), a B-cell hematological cancer, remains elusive. Thus, the current study was designed to explore a novel prognostic B-cell-specific RBP signature and the underlying molecular mechanisms.

Methods: Data used in the current study were obtained from the Gene Expression Omnibus (GEO) database. Significantly upregulated RBPs in B cells were defined as B cell-specific RBPs. The biological functions of B-cell-specific RBPs were analyzed by the cluster Profiler package. Univariate and multivariate regressions were performed to identify robust prognostic B-cell specific RBP signatures, followed by the construction of the risk classification model. Gene set enrichment analysis (GSEA)-identified pathways were enriched in stratified groups. The microenvironment of the low- and high-risk groups was analyzed by single-sample GSEA (ssGSEA). Moreover, the correlations among the risk score and differentially expressed immune checkpoints or differentially distributed immune cells were calculated. The drug sensitivity of the low- and high-risk groups was assessed via Genomics of Drug Sensitivity in Cancer by the pRRophetic algorithm. In addition, we utilized a GEO dataset involving patients with MM receiving bortezomib therapy to estimate the treatment response between different groups.

Results: A total of 56 B-cell-specific RBPs were identified, which were mainly enriched in ribonucleoprotein complex biogenesis and the ribosome pathway. ADAR, FASTKD1 and SNRPD3 were identified as prognostic B-cell specific RBP signatures in MM. The risk model was constructed based on ADAR, FASTKD1 and SNRPD3. Receiver operating characteristic (ROC) curves revealed the good predictive capacity of the risk model. A nomogram based on the risk score and other independent prognostic factors exhibited excellent performance in predicting the overall survival of MM patients. GSEA showed enrichment of the Notch signaling pathway and mRNA cis-splicing via spliceosomes in the high-risk group. Moreover, we found that the infiltration of diverse immune cell subtypes and the expression of CD274, CD276, CTLA4 and VTCN1 were significantly different between the two groups. In addition, the IC50 values of 11 drugs were higher in the low-risk group. Patients in the low-risk group exhibited a higher complete response rate to bortezomib therapy.

Conclusion: Our study identified novel prognostic B-cell-specific RBP biomarkers in MM and constructed a unique risk model for predicting MM outcomes. Moreover, we explored the immune-related mechanisms of B cell-specific RBPs in regulating MM. Our findings could pave the way for developing novel therapeutic strategies to improve the prognosis of MM patients.
Ferroptosis-Related Long Non-Coding RNA Signature Contributes to the Prediction of Prognosis Outcomes in Head and Neck Squamous Cell Carcinomas
Authors: Jiang Wenru , Song Yingtao , Zhong Zhaowei , Gao Jili , Meng Xiaofei
Published: December 2021

Background: Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor, which makes the prognosis prediction challenging. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death, which could affect cancer development. However, the prognostic value of ferroptosis-related long non-coding RNA (lncRNA) in HNSCC is still limited.

Methods: In the current study, we employed the DESeq2 method to characterize the differentially expressed ferroptosis-related genes (FEGs) between cancer and normal samples. Next, the FEG-related lncRNAs (FElncRNAs) were identified using Spearman’s correlation analysis and multiple permutation hypotheses. Subsequently, LASSO and stepwise multivariate Cox regression analyses were undertaken to recognize the prognosis-related FElncRNA signature (PFLS) and risk scores.

Results: Herein, we first identified 60 dysregulated FEGs and their co-expressed FElncRNAs in HNSCC. Then, we recognized a set of six FElncRNAs PFLS (SLCO4A1-AS1, C1RL-AS1, PCED1B-AS1, HOXB-AS3, MIR9-3HG, and SFTA1P) for predicting patients’ prognostic risks and survival outcomes. We also assessed the efficiency of PFLS in the test set and an external validation cohort. Further parsing of the tumor immune microenvironment showed the PFLS was closely associated with immune cell infiltration abundances. Notably, the low-risk group of the PFLS showed a higher MHC score and cytolytic activity (CYT) score than the high-risk group, implying the low-risk group may have greater tumor surveillance and killing ability. In addition, we observed that the expression levels of two immune checkpoints (ICPs), i.e., programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1), showed significant associations with patients’ risk score, prompting the role of the PFLS in ICP blockade therapy. Finally, we also constructed a drug–PFLS network to reinforce the clinical utilities of the PFLS.

Conclusion: In summary, our study indicated that FElncRNAs played an important role in HNSCC survival prediction. Identification of PFLS will contribute to the development of novel anticancer therapeutic strategies.
A Pilot Study on Early-Onset Schizophrenia Reveals the Implication of Wnt, Cadherin and Cholecystokinin Receptor Signaling in Its Pathophysiology
Authors: Drozd Malgorzata Marta , Capovilla Maria , Previderé Carlo , Grossi Mauro , Askenazy Florence , Bardoni Barbara , Fernandez Arnaud
Published: December 2021

Early-Onset Schizophrenia (EOS) is a very rare mental disorder that is a form of schizophrenia occurring before the age of 18. EOS is a brain disease marked by an early onset of positive and negative symptoms of psychosis that impact development and cognitive functioning. Clinical manifestations commonly include premorbid features of Autism Spectrum Disorder (ASD), attention deficits, Intellectual Disability (ID), neurodevelopmental delay, and behavioral disturbances. After the onset of psychotic symptoms, other neuropsychiatric comorbidities are also common, including obsessive-compulsive disorder, major depressive disorder, expressive and receptive language disorders, auditory processing, and executive functioning deficits. With the purpose to better gain insight into the genetic bases of this disorder, we developed a pilot project performing whole exome sequencing of nine trios affected by EOS, ASD, and mild ID. We carried out gene prioritization by combining multiple bioinformatic tools allowing us to identify the main pathways that could underpin the neurodevelopmental phenotypes of these patients. We identified the presence of variants in genes belonging to the Wnt, cadherin and cholecystokinin receptor signaling pathways.
Maternal Experience Does Not Predict Fear Extinction and Anxiety-Like Behaviour in Primiparous Rats Post-weaning
Authors: Pestana Jodie E. , McCutcheon Tayla B. , Harmon-Jones Sylvia K. , Richardson Rick , Graham Bronwyn M.
Published: December 2021

Reproductive experience leads to long-lasting changes in anxiety-like behaviour and fear extinction, the laboratory model of exposure therapy for anxiety disorders. For example, fear extinction is influenced by estrous cycle in nulliparous (no reproductive experience) female rats, but this effect is abolished in primiparous (one reproductive experience) females. It is unclear whether such changes are driven by pregnancy, maternal experience of caring for offspring during the postpartum period, or a combination of both experiences. The present study sought to determine the influence of maternal experience (i.e., exposure to pups and mother-pup interactions) on fear extinction in primiparous rats. In Experiment 1, we tested whether pup exposure is necessary to mitigate estrous effects on fear extinction in primiparous rats. Age-matched nulliparous rats, primiparous rats, and primiparous rats who experienced pregnancy but not pup exposure, underwent fear conditioning on day 1 (2 months post-parturition), extinction training during proestrus (high sex hormones) or metestrus (low sex hormones) on day 2, and extinction recall on day 3. Replicating past research, nulliparous rats showed impaired extinction recall when they were extinguished during metestrus compared to proestrus. In contrast, primiparous rats with and without pup exposure showed comparable extinction recall irrespective of estrous phase. In Experiment 2, we assessed whether naturally-occurring variation in mother-pup interactions predict future fear extinction performance and anxiety-like behaviour. During the first week of lactation, primiparous rats were measured for maternal behaviours toward pups. Primiparous rats were then tested on the light-dark box and elevated plus maze to measure anxiety-like behaviour and underwent a fear extinction protocol 1 month post-weaning. We found no significant correlations between maternal behaviour and fear extinction outcomes or anxiety-like behaviour. Our findings suggest that pregnancy, not maternal experience, mitigates the impact of estrous cycle on fear extinction. In addition, natural variation in maternal experience does not appear to contribute to variability in future fear extinction outcomes or anxiety-like behaviour in primiparous rats.
Alcohol Use and Abuse Conspires With HIV Infection to Aggravate Intestinal Dysbiosis and Increase Microbial Translocation in People Living With HIV: A Review
Authors: Yan Jiangyu , Ouyang Jing , Isnard Stéphane , Zhou Xin , Harypursat Vijay , Routy Jean-Pierre , Chen Yaokai
Published: December 2021

The intestinal microbiome is an essential so-called human “organ”, vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the “leaky” intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a “partner” with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH.
Acute and Chronic Changes in Gene Expression After CMV DNAemia in Kidney Transplant Recipients
Authors: Ahn Richard , Schaenman Joanna , Qian Zachary , Pickering Harry , Groysberg Victoria , Rossetti Maura , Llamas Megan , Hoffmann Alexander , Gjertson David , Deng Mario , Bunnapradist Suphamai , Reed Elaine F. ,   CMV Systems Immunobiology Group
Published: December 2021

Cytomegalovirus (CMV) viremia continues to cause significant morbidity and mortality in kidney transplant patients with clinical complications including organ rejection and death. Whole blood gene expression dynamics in CMV viremic patients from onset of DNAemia through convalescence has not been well studied to date in humans. To evaluate how CMV infection impacts whole blood leukocyte gene expression over time, we evaluated a matched cohort of 62 kidney transplant recipients with and without CMV DNAemia using blood samples collected at multiple time points during the 12-month period after transplant. While transcriptomic differences were minimal at baseline between DNAemic and non-DNAemic patients, hundreds of genes were differentially expressed at the long-term timepoint, including genes enriching for pathways important for macrophages, interferon, and IL-8 signaling. Amongst patients with CMV DNAemia, the greatest amount of transcriptomic change occurred between baseline and 1-week post-DNAemia, with increase in pathways for interferon signaling and cytotoxic T cell function. Time-course gene set analysis of these differentially expressed genes revealed that most of the enriched pathways had a significant time-trend. While many pathways that were significantly down- or upregulated at 1 week returned to baseline-like levels, we noted that several pathways important in adaptive and innate cell function remained upregulated at the long-term timepoint after resolution of CMV DNAemia. Differential expression analysis and time-course gene set analysis revealed the dynamics of genes and pathways involved in the immune response to CMV DNAemia in kidney transplant patients. Understanding transcriptional changes caused by CMV DNAemia may identify the mechanism behind patient vulnerability to CMV reactivation and increased risk of rejection in transplant recipients and suggest protective strategies to counter the negative immunologic impact of CMV. These findings provide a framework to identify immune correlates for risk assessment and guiding need for extending antiviral prophylaxis.
Characterization of Glycosylation-Specific Systemic and Mucosal IgA Antibody Responses to Escherichia coli Mucinase YghJ (SslE)
Authors: Riaz Saman , Steinsland Hans , Thorsing Mette , Andersen Ann Z. , Boysen Anders , Hanevik Kurt
Published: December 2021

Efforts to develop broadly protective vaccines against pathogenic Escherichia coli are ongoing. A potential antigen candidate for vaccine development is the metalloprotease YghJ, or SslE. YghJ is a conserved mucinase that is immunogenic, heavily glycosylated, and produced by most pathogenic E. coli. To develop efficacious YghJ-based vaccines, there is a need to investigate to what extent potentially protective antibody responses target glycosylated epitopes in YghJ and to describe variations in the quality of YghJ glycosylation in the E. coli population. In this study we estimated the proportion of anti-YghJ IgA antibodies that targeted glycosylated epitopes in serum and intestinal lavage samples from 21 volunteers experimentally infected with wild-type enterotoxigenic E. coli (ETEC) strain TW10722. Glycosylated and non-glycosylated YghJ was expressed, purified, and then gycosylation pattern was verified by BEMAP analysis. Then we used a multiplex bead flow cytometric assay to analyse samples from before and 10 days after TW10722 was ingested. We found that 20 (95%) of the 21 volunteers had IgA antibody responses to homologous, glycosylated YghJ, with a median fold increase in IgA levels of 7.9 (interquartile range [IQR]: 7.1, 11.1) in serum and 3.7 (IQR: 2.1, 10.7) in lavage. The median proportion of anti-YghJ IgA response that specifically targeted glycosylated epitopes was 0.45 (IQR: 0.30, 0.59) in serum and 0.07 (IQR: 0.01, 0.22) in lavage. Our findings suggest that a substantial, but variable, proportion of the IgA antibody response to YghJ in serum during ETEC infection is targeted against glycosylated epitopes, but that gut IgA responses largely target non-glycosylated epitopes. Further research into IgA targeting glycosylated YghJ epitopes is of interest to the vaccine development efforts.
PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer
Authors: Wang Yali , Zheng Kun , Xiong Hua , Huang Yongbiao , Chen Xiuqiong , Zhou Yilu , Qin Wan , Su Jinfang , Chen Rui , Qiu Hong , Yuan Xianglin , Wang Yihua , Zou Yanmei
Published: December 2021

Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, pamiparib attenuated tumor growth; while co-administration of pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8+ T cells, suggesting a potential role of CD8+ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.
C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
Authors: Pozo-Rodrigálvarez Andrea , Li YiXian , Stokowska Anna , Wu Jingyun , Dehm Verena , Sourkova Hana , Steinbusch Harry , Mallard Carina , Hagberg Henrik , Pekny Milos , Pekna Marcela
Published: December 2021

Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis.
High Dose Steroids as First-Line Treatment Increased the Risk of In-Hospital Infections in Patients With Anti-NMDAR Encephalitis
Authors: Wang Jierui , Lin Jingfang , Wang Minjin , Meng Zirui , Zhou Dong , Li Jinmei
Published: December 2021

Objective

To address the effects of high dose steroids on in-hospital infection and neurologic outcome in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis patients.

Methods

We retrospectively reviewed the clinical data of anti-NMDAR encephalitis patients in West China Hospital, the Third Hospital of Mianyang and Mianyang Central Hospital between October 2011 and August 2020. The development of infections, inflammatory factors, neurologic outcome at discharge and risk factors for in-hospital infection were assessed in patients with and without high dose steroid therapy before and after immunotherapy. Least absolute shrinkage and selection operator (LASSO) regression and logistic regression models were established to assess risk factors for in-hospital infection.

Results

A total of 278 patients with anti-NMDAR encephalitis were included in the study. Thirty-four patients received high dose methylprednisolone (IVMP) therapy only, 84 patients received intravenous immunoglobulin (IVIG) therapy, and 160 patients received IVIG and IVMP therapy. Compared with the IVIG group, IVIG + IVMP group had a higher infection rate (64.38% vs 39.29%,P< 0.001), a higher incidence of noninfectious complications (76.25% vs 61.90%,P= 0.018) and a higher modified Rankin Scale (mRS) score at discharge from the hospital (3 vs 2,P< 0.001). Inflammatory indicators, including white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII), were higher (9.93 vs 5.65, 6.94 vs 3.47 and 1.47 vs 0.70, respectively,P< 0.001) in the IVIG + IVMP group than in the IVIG group. Moreover, lymphocyte-to-monocyte ratio (LMR) was lower (2.20 vs 2.54,P= 0.047) in the IVIG + IVMP group. The LASSO model showed that mRS score on admission, seizure, body temperature, uric acid (URIC), cerebrospinal fluid immunoglobulin G (CSF IgG), NLR and LMR were risk factors for in-hospital infection. The prediction model exhibited an area under the curve (AUC) of 0.885.

Conclusions

High dose steroids therapy was significantly associated with higher in-hospital infectious complication rates and a poor short-term prognosis in relatively severe anti-NMDAR encephalitis patients. The established prediction model might be helpful to reduce the risk of in-hospital infection.
Validation of the Clinical Assessment Scale in Autoimmune Encephalitis in Chinese Patients
Authors: Zhang Yingchi , Tu Ewen , Yao Chenxiao , Liu Jia , Lei Qiang , Lu Wei
Published: December 2021

Background and Objectives

The Clinical Assessment Scale in Autoimmune Encephalitis (CASE) is a scale for assessing severity in autoimmune encephalitis. We aimed to validate the CASE score in a Chinese population and evaluate its clinical significance.

Methods

Patients diagnosed with autoimmune encephalitis were recruited between June 2014 and May 2019 from two hospitals. CASE and modified Rankin Scale (mRS) scores were obtained. Data regarding clinical features, treatment, and available information were gathered from the hospital information system.

Results

Of the 176 patients with autoimmune encephalitis, 11 died and 14 had tumors. Ten patients received second-line treatment. The CASE scores of patients receiving second-line treatment were significantly higher (median CASE: 15) than in those receiving first-line treatment (median CASE: 8) (p<0.001). Twenty-two patients had poor functional status (mRS>2). Areas under the curve of CASE on whether functional status was poor at 1 year were 0.89 (p<0.001). Sixty patients were admitted to the intensive care unit (ICU), and the CASE scores were positively correlated with days in the ICU (r=0.58, p<0.001). There was no statistically significant association between the CASE scores and relapse (p=0.39>0.05). Additionally, the CASE scores were positively associated with the mRS scores (r=0.85 p<0.001).

Conclusions

The CASE score is suitable for the comprehensive assessment of Chinese patients with autoimmune encephalitis, which may help clinicians to select the appropriate intervention and estimate the disease severity and prognosis.
Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report
Authors: Leblanc Julie , Hoibian Solene , Boucraut Agathe , Ratone Jean-Philippe , Stoffaes Louis , Dano Domitille , Louvel-Perrot Delphine , Chanez Brice , Chretien Anne-Sophie , Madroszyk Anne , Rochigneux Philippe
Published: December 2021

Immune checkpoint inhibitors (ICI) reinvigorate the immune system to recognize and destroy tumor cells. Because of this biological mechanism, patients might develop autoimmune toxicities, notably in the digestive tract (most frequently, hepatitis or colitis). A 70-year-old man with relapsed mesothelioma was treated with nivolumab in 3rd line. He was hospitalized for watery and foul-smelling diarrhea. He underwent gastrointestinal endoscopy, showing duodenitis and villous atrophy and measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA+), leading to the diagnosis of ICI-induced celiac disease. He was treated with steroids, proton pump inhibitors, and a gluten-free diet. If ICI-induced celiac disease is rare in the literature, increasing reports suggest that celiac disease might represent an underestimated ICI toxicity. This case highlights the necessity of complementary investigation (including tTG-IgA and endoscopic biopsies) in patients with atypical digestive symptoms during immunotherapy.
The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology
Authors: Hugonnet Marjolaine , Singh Pushpita , Haas Quentin , von Gunten Stephan
Published: December 2021

Aberrant glycosylation is a key feature of malignant transformation. Hypersialylation, the enhanced expression of sialic acid-terminated glycoconjugates on the cell surface, has been linked to immune evasion and metastatic spread, eventually by interaction with sialoglycan-binding lectins, including Siglecs and selectins. The biosynthesis of tumor-associated sialoglycans involves sialyltransferases, which are differentially expressed in cancer cells. In this review article, we provide an overview of the twenty human sialyltransferases and their roles in cancer biology and immunity. A better understanding of the individual contribution of select sialyltransferases to the tumor sialome may lead to more personalized strategies for the treatment of cancer.
Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells
Authors: Holland Elizabeth M. , Gonzalez Corina , Levy Elliot , Valera Vladimir A. , Chalfin Heather , Klicka-Skeels Jacquelyn , Yates Bonnie , Kleiner David E. , Hadigan Colleen , Dave Hema , Shalabi Haneen , Hickstein Dennis D. , Su Helen C. , Grimley Michael , Freeman Alexandra F. , Shah Nirali N.
Published: December 2021

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.
Trends of Phase I Clinical Trials of New Drugs in Mainland China Over the Past 10 Years (2011–2020)
Authors: Chen Chen , Lou Ning , Zheng Xin , Wang Shasha , Chen Haizhu , Han Xiaohong
Published: December 2021

Background: In recent years, the number of clinical trials initiated in China has increased rapidly. The aim of this study was to overview the changing landscape of phase I clinical trials in mainland China from 2011 to 2020.

Methods: We analyzed phase I clinical trials registered on 3 websites including the Chinese Clinical Trial Registry, ClinicalTrials.gov, and the China National Medical Products Administration Center for Drug Evaluation platform.

Findings: A total of 2,842 phase I clinical trials were posted from January 1, 2011, to December 31, 2020. The overall number of clinical trials for innovative drugs was 1,497, accounting for half of all the phase I clinical trials (53%). Among these 1,486 innovative drug clinical trials, 924 were newly tested drugs with an average annual growth rate of 59%. Biological drug research increased significantly from 22.6% during 2011–2015 to 33.3% during 2016–2020. These principal investigators (PIs) of these clinical trials were mainly from Beijing (n = 871), followed by Shanghai (n = 496) and Jiangsu (n = 281). As for the therapeutic area of phase I clinical trials, cancer took up the most percentage of all the clinical trials (35%), followed by infectious disease (9%), nervous system disease (9%), etc. Most phase I clinical trials are conducted on healthy volunteers (n = 1,642, 57.8%), some cancer drugs are conducted in patients with cancer (n = 846, 29.8%), and only a few clinical trials were conducted in the elderly (n = 7). Among these clinical trials of the newly tested innovative drugs, the first in human (FIH) clinical trials accounted for 82% (744), and the First in Chinese (FIC) clinical trials only took up 18% (167). Only a small number of drugs could be made the transition to phase II (n = 207, 22%). In addition, despite the number of newly tested drugs during 2011–2015 (n = 163) was much less than that in 2016–2020 (n = 761), the percentage of drugs that could enter into phase II clinical trials in 2011–2015 (34%) was higher than that in 2016–2020 (20%).

Conclusion: In the past 10 years, the development of phase I clinical trials has achieved great progress in mainland China due to the novel design and drug innovation policy. Nevertheless, future efforts are needed to make for improving the phase transition success rate of innovative drugs.
Evaluating Phage Tail Fiber Receptor-Binding Proteins Using a Luminescent Flow-Through 96-Well Plate Assay
Authors: Farquharson Emma L. , Lightbown Ashlyn , Pulkkinen Elsi , Russell Téa , Werner Brenda , Nugen Sam R.
Published: December 2021

Phages have demonstrated significant potential as therapeutics in bacterial disease control and as diagnostics due to their targeted bacterial host range. Host range has typically been defined by plaque assays; an important technique for therapeutic development that relies on the ability of a phage to form a plaque upon a lawn of monoculture bacteria. Plaque assays cannot be used to evaluate a phage’s ability to recognize and adsorb to a bacterial strain of interest if the infection process is thwarted post-adsorption or is temporally delayed, and it cannot highlight which phages have the strongest adsorption characteristics. Other techniques, such as classic adsorption assays, are required to define a phage’s “adsorptive host range.” The issue shared amongst all adsorption assays, however, is that they rely on the use of a complete bacteriophage and thus inherently describe when all adsorption-specific machinery is working together to facilitate bacterial surface adsorption. These techniques cannot be used to examine individual interactions between a singular set of a phage’s adsorptive machinery (like long tail fibers, short tail fibers, tail spikes, etc.) and that protein’s targeted bacterial surface receptor. To address this gap in knowledge we have developed a high-throughput, filtration-based, bacterial binding assay that can evaluate the adsorptive capability of an individual set of a phage’s adsorption machinery. In this manuscript, we used a fusion protein comprised of an N-terminal bioluminescent tag translationally fused to T4’s long tail fiber binding tip (gp37) to evaluate and quantify gp37’s relative adsorptive strength against the Escherichia coli reference collection (ECOR) panel of 72 Escherichia coli isolates. Gp37 could adsorb to 61 of the 72 ECOR strains (85%) but coliphage T4 only formed plaques on 8 of the 72 strains (11%). Overlaying these two datasets, we were able to identify ECOR strains incompatible with T4 due to failed adsorption, and strains T4 can adsorb to but is thwarted in replication at a step post-adsorption. While this manuscript only demonstrates our assay’s ability to characterize adsorptive capabilities of phage tail fibers, our assay could feasibly be modified to evaluate other adsorption-specific phage proteins.
Silver Nanoparticles Functionalized With Antimicrobial Polypeptides: Benefits and Possible Pitfalls of a Novel Anti-infective Tool
Authors: Zharkova Maria S. , Golubeva Olga Yu. , Orlov Dmitriy S. , Vladimirova Elizaveta V. , Dmitriev Alexander V. , Tossi Alessandro , Shamova Olga V.
Published: December 2021

Silver nanoparticles (AgNPs) and antimicrobial peptides or proteins (AMPs/APs) are both considered as promising platforms for the development of novel therapeutic agents effective against the growing number of drug-resistant pathogens. The observed synergy of their antibacterial activity suggested the prospect of introducing antimicrobial peptides or small antimicrobial proteins into the gelatinized coating of AgNPs. Conjugates with protegrin-1, indolicidin, protamine, histones, and lysozyme were comparatively tested for their antibacterial properties and compared with unconjugated nanoparticles and antimicrobial polypeptides alone. Their toxic effects were similarly tested against both normal eukaryotic cells (human erythrocytes, peripheral blood mononuclear cells, neutrophils, and dermal fibroblasts) and tumor cells (human erythromyeloid leukemia K562 and human histiocytic lymphoma U937 cell lines). The AMPs/APs retained their ability to enhance the antibacterial activity of AgNPs against both Gram-positive and Gram-negative bacteria, including drug-resistant strains, when conjugated to the AgNP surface. The small, membranolytic protegrin-1 was the most efficient, suggesting that a short, rigid structure is not a limiting factor despite the constraints imposed by binding to the nanoparticle. Some of the conjugated AMPs/APs clearly affected the ability of nanoparticle to permeabilize the outer membrane of Escherichia coli, but none of the conjugated AgNPs acquired the capacity to permeabilize its cytoplasmic membrane, regardless of the membranolytic potency of the bound polypeptide. Low hemolytic activity was also found for all AgNP-AMP/AP conjugates, regardless of the hemolytic activity of the free polypeptides, making conjugation a promising strategy not only to enhance their antimicrobial potential but also to effectively reduce the toxicity of membranolytic AMPs. The observation that metabolic processes and O2 consumption in bacteria were efficiently inhibited by all forms of AgNPs is the most likely explanation for their rapid and bactericidal action. AMP-dependent properties in the activity pattern of various conjugates toward eukaryotic cells suggest that immunomodulatory, wound-healing, and other effects of the polypeptides are at least partially transferred to the nanoparticles, so that functionalization of AgNPs may have effects beyond just modulation of direct antibacterial activity. In addition, some conjugated nanoparticles are selectively toxic to tumor cells. However, caution is required as not all modulatory effects are necessarily beneficial to normal host cells.