bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone Morphogenetic Protein-2 Induces Non-Canonical Inflammatory and Oxidative Pathways in Human Retinal Endothelial Cells
Authors: Al-Shabrawey Mohamed , Hussein Khaled , Wang Fang , Wan Ming , Elmasry Khaled , Elsherbiny Nehal , Saleh Heba , Yu Paul B. , Tawfik Amany , Ibrahim Ahmed S.
Published: January 2021

The mechanisms of diabetic retinopathy (DR), are not yet fully understood. We previously demonstrated an upregulation of retinal bone morphogenetic protein-2 (BMP2) in experimental diabetes and in retinas of diabetic human subjects. The purpose of current study was to investigate the role of non-canonical inflammatory pathway in BMP2-induced retinal endothelial cell (REC) barrier dysfunction. For this purpose, we used RT-PCR and western blotting to evaluate the levels of BMP2 signaling components (BMP2, BMP4, BMP receptors), VEGF, phosphorylated p38 MAPK and NFκB, and oxidative stress markers in cultured human retinal endothelial cells (HRECs) subjected to BMP2 (50ng/ml) for up to 24 h. Also, effect of high glucose (HG, 30mM D-glucose) on the expression of BMP2 and its downstream genes was examined in HRECs. H2-DCF is a fluorogenic dye that measures the levels of cellular reactive oxygen species (ROS) was used to measure the pro-oxidative effect of BMP2. Moreover, we evaluated the effect of inhibiting p38 and VEGF signaling on BMP2-induced HRECs barrier dysfunction by measuring the trans-endothelial cell electrical resistance (TER) using electric cell-substrate impedance sensing (ECIS). We also tested the effect of HG on the integrity of HRECs barrier in the presence or absence of inhibitors of BMP2 signaling. Our data reveals that BMP2 and high glucose upregulates BMP components of the BMP signaling pathway (SMAD effectors, BMP receptors, and TGFβ ligand itself) and induces phosphorylation of p38 MAPK and NFκB with nuclear translocation of NFκB. Inhibition of p38 or NFκB attenuated BMP2-induced VEGF expression and barrier dysfunction in HRECs. Also, inhibition of VEGFR2 attenuated BMP2-induced barrier dysfunction. Moreover, BMP2 induces generation of ROS and endothelial nitric oxide synthase (eNOS) expression and activity in HRECs. Finally, HG upregulated BMP2 and its downstream genes (SMAD, BMP4, ALKs, and TGF-β) in HRECs and BMP2 inhibitors attenuated HG-induced HRECs barrier dysfunction. Our results suggest that in addition to the regular canonical SMAD signaling BMP2 induces non-canonical inflammatory pathway in HRECs via activation of p38/NFκB pathway that causes the upregulation of VEGF and the disruption of HRECs. Inhibition of BMP2 signaling is a potential therapeutic intervention to preserve endothelial cell barrier function in DR.
Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner
Authors: Buchele Vera , Konein Patrick , Vogler Tina , Kunert Timo , Enderle Karin , Khan Hanif , Büttner-Herold Maike , Lehmann Christian H. K. , Amon Lukas , Wirtz Stefan , Dudziak Diana , Neurath Markus F. , Neufert Clemens , Hildner Kai
Published: January 2021

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1−/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1−/− but not in colitis-protected Rag1−/−Irf4−/− mice. Colitis mitigation in Rag1−/−Irf4−/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1−/−Irf4−/− T cell receiving mice.
Differential Responsiveness of the Platelet Biomarkers, Systemic CD40 Ligand, CD62P, and Platelet-Derived Growth Factor-BB, to Virally-Suppressive Antiretroviral Therapy
Authors: Steel Helen C. , Venter W. D. Francois , Theron Annette J. , Anderson Ronald , Feldman Charles , Arulappan Natasha , Rossouw Theresa M.
Published: January 2021

Systemic biomarkers of inflammation, including cytokines and chemokines, are potentially useful in the management of both HIV infection and non-AIDS-defining disorders. However, relatively little is known about the utility of measurement of circulating biomarkers of platelet activation as a strategy to monitor the efficacy of combination antiretroviral therapy (cART), as well as the persistence of systemic inflammation following virally-suppressive therapy in HIV-infected persons. These issues have been addressed in the current study to which a cohort consisting of 199 HIV-infected participants was recruited, 100 of whom were cART-naïve and the remainder cART-treated and virally-suppressed. Fifteen healthy control participants were included for comparison. The study focused on the effects of cART on the responsiveness of three biomarkers of platelet activation, specifically soluble CD40 ligand (sCD40L), sCD62P (P-selectin), and platelet-derived growth factor-BB (PDGF-BB), measured using multiplex suspension bead array technology. Most prominently sCD40L in particular, as well as sCD62P, were significantly elevated in the cART-naïve group relative to both the cART-treated and healthy control groups. However, levels of PDGF-BB were of comparable magnitude in both the cART-naïve and –treated groups, and significantly higher than those of the control group. Although remaining somewhat higher in the virally-suppressed group relative to healthy control participants, these findings identify sCD40L, in particular, as a potential biomarker of successful cART, while PDGF-BB may be indicative of persistent low-level antigenemia.
Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?
Authors: Koneczny Inga , Yilmaz Vuslat , Lazaridis Konstantinos , Tzartos John , Lenz Tobias L. , Tzartos Socrates , Tüzün Erdem , Leypoldt Frank
Published: January 2021

IgG4 autoimmune diseases (IgG4-AID) are an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. It has only recently been appreciated, that members of this group share relevant immunobiological and therapeutic aspects even though different antigens, tissues and organs are affected: glomerulonephritis (kidney), pemphigus vulgaris (skin), thrombotic thrombocytopenic purpura (hematologic system) muscle-specific kinase (MuSK) in myasthenia gravis (peripheral nervous system) and autoimmune encephalitis (central nervous system) to give some examples. In all these diseases, patients’ IgG4 subclass autoantibodies block protein-protein interactions instead of causing complement mediated tissue injury, patients respond favorably to rituximab and share a genetic predisposition: at least five HLA class II genes have been reported in individual studies to be associated with several different IgG4-AID. This suggests a role for the HLA class II region and specifically the DRβ1 chain for aberrant priming of autoreactive T-cells toward a chronic immune response skewed toward the production of IgG4 subclass autoantibodies. The aim of this review is to provide an update on findings arguing for a common pathogenic mechanism in IgG4-AID in general and to provide hypotheses about the role of distinct HLA haplotypes, T-cells and cytokines in IgG4-AID.
Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses
Authors: Kerstetter Lucas J. , Buckley Stephen , Bliss Carly M. , Coughlan Lynda
Published: January 2021

It is evident that the emergence of infectious diseases, which have the potential for spillover from animal reservoirs, pose an ongoing threat to global health. Zoonotic transmission events have increased in frequency in recent decades due to changes in human behavior, including increased international travel, the wildlife trade, deforestation, and the intensification of farming practices to meet demand for meat consumption. Influenza A viruses (IAV) possess a number of features which make them a pandemic threat and a major concern for human health. Their segmented genome and error-prone process of replication can lead to the emergence of novel reassortant viruses, for which the human population are immunologically naïve. In addition, the ability for IAVs to infect aquatic birds and domestic animals, as well as humans, increases the likelihood for reassortment and the subsequent emergence of novel viruses. Sporadic spillover events in the past few decades have resulted in human infections with highly pathogenic avian influenza (HPAI) viruses, with high mortality. The application of conventional vaccine platforms used for the prevention of seasonal influenza viruses, such as inactivated influenza vaccines (IIVs) or live-attenuated influenza vaccines (LAIVs), in the development of vaccines for HPAI viruses is fraught with challenges. These issues are associated with manufacturing under enhanced biosafety containment, and difficulties in propagating HPAI viruses in embryonated eggs, due to their propensity for lethality in eggs. Overcoming manufacturing hurdles through the use of safer backbones, such as low pathogenicity avian influenza viruses (LPAI), can also be a challenge if incompatible with master strain viruses. Non-replicating adenoviral (Ad) vectors offer a number of advantages for the development of vaccines against HPAI viruses. Their genome is stable and permits the insertion of HPAI virus antigens (Ag), which are expressedin vivofollowing vaccination. Therefore, their manufacture does not require enhanced biosafety facilities or procedures and is egg-independent. Importantly, Ad vaccines have an exemplary safety and immunogenicity profile in numerous human clinical trials, and can be thermostabilized for stockpiling and pandemic preparedness. This review will discuss the status of Ad-based vaccines designed to protect against avian influenza viruses with pandemic potential.
COVID-19: Imbalanced Immune Responses and Potential Immunotherapies
Authors: Xie Bing , Zhang Jiancheng , Li Yuwen , Yuan Shiying , Shang You
Published: January 2021

The ongoing pandemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading and has resulted in grievous morbidity and mortality worldwide. Despite the high infectiousness of SARS-CoV-2, the majority of infected individuals are asymptomatic or have mild symptoms and could eventually recover as a result of their balanced immune function. On the contrary, immuno-compromised patients are prone to progress into severe or critical types underpinned by the entanglement of an overexuberant proinflammatory response and injured immune function. Therefore, well-coordinated innate and adaptive immune systems are pivotal to viral eradication and tissue repair. An in-depth understanding of the immunological processes underlying COVID-19 could facilitate rapidly identifying and choosing optimal immunotherapy for patients with severe SARS-CoV-2 infection. In this review, based on current immunological evidence, we describe potential immune mechanisms and discuss promising immunotherapies for COVID-19, including IL-6R blockades, convalescent plasma, intravenous gamma globulin, thymosin alpha1, corticosteroids, and type-I interferon, and recent advances in the development of COVID-19 vaccines.
Age-Related Immunoreactivity Profiles to Diverse Mycobacterial Antigens in BCG-Vaccinated Chinese Population
Authors: Yang Qing-yuan , Zhang Yu-tong , Xiao Jia-ni , Liang Yu-shuo , Ji Ping , Wang Shu-jun , Wang Ying , Chen Yingying
Published: January 2021

Long-term immunoreactivity to mycobacterial antigens in Bovis Calmette-Guérin (BCG)-vaccinated population is not well investigated. Herein, 361 volunteer healthy donors (HDs) with neonatal BCG vaccination from Shanghai region (China) were enrolled. They were subdivided into ESAT-6/CFP10- (E6C10-) and ESAT-6/CFP10+ (E6C10+) groups based on gamma-interferon release assays (IGRAs). Three mycobacterial antigens, including Rv0934, Rv3006, and Rv3841, were subjected to the determination of immunoreactivity by ELISPOT assay. The immunoreactivities to three mycobacterial antigens were firstly compared among TB patients (N=39), E6C10+ HDs (N=78, 21.61% of HDs) and E6C10- HDs (N=283, 78.39% of HDs). It was revealed that Rv3006 was dominant upon M.tb infection, while Rv3841 was likely to be more responsive upon latent TB infection. In E6C10- population, the immunoreactivity to Rv3841 maintained along with aging, whereas those to Rv3006 and Rv0934 attenuated in E6C10- HDs older than 45 years old. Our study implies the shift of dominant antigens at different infection statuses, providing the clues for the selection of mycobacterial antigens in vaccine development and precision revaccination in the future.
Identification of New Soluble Factors Correlated With the Development of Graft Failure After Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Weber Gerrit , Strocchio Luisa , Del Bufalo Francesca , Algeri Mattia , Pagliara Daria , Arnone Claudia Manuela , De Angelis Biagio , Quintarelli Concetta , Locatelli Franco , Merli Pietro , Caruana Ignazio
Published: January 2021

Graft failure is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). The mechanisms involved in this phenomenon are still not completely understood; data available suggest that recipient T lymphocytes surviving the conditioning regimen are the main mediators of immune-mediated graft failure. So far, no predictive marker or early detection method is available. In order to identify a non-invasive and efficient strategy to diagnose this complication, as well as to find possible targets to prevent/treat it, we performed a detailed analysis of serum of eight patients experiencing graft failure after T-cell depleted HLA-haploidentical HSCT. In this study, we confirm data describing graft failure to be a complex phenomenon involving different components of the immune system, mainly driven by the IFNγ pathway. We observed a significant modulation of IL7, IL8, IL18, IL27, CCL2, CCL5 (Rantes), CCL7, CCL20 (MIP3a), CCL24 (Eotaxin2), and CXCL11 in patients experiencing graft failure, as compared to matched patients not developing this complication. For some of these factors, the difference was already present at the time of infusion of the graft, thus allowing early risk stratification. Moreover, these cytokines/chemokines could represent possible targets, providing the rationale for exploring new therapeutic/preventive strategies.
Immunological Hallmarks for Clinical Response to BCG in Bladder Cancer
Authors: Lim Chun Jye , Nguyen Phuong Hoang Diem , Wasser Martin , Kumar Pavanish , Lee Yun Hua , Nasir Nurul Jannah Mohamed , Chua Camillus , Lai Liyun , Hazirah Sharifah Nur , Loh Josh Jie Hua , Khor Li Yan , Yeong Joe , Lim Tony Kiat Hon , Low Alvin Wei Xiang , Albani Salvatore , Chong Tsung Wen , Chew Valerie
Published: January 2021

Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumor activity. We observed the temporal changes of peripheral immune subsets including NKT cells, central memory CD4+ T cells, CD8+ T cells and regulatory T cells (Treg) during the course of BCG. Gene expression analysis revealed enriched immune pathways involving in T cell activation and chemotaxis, as well as a more diversified T cell receptor repertoire in post-BCG tissues. Moreover, tissue multiplexed-immunofluorescence (mIF) showed baseline densities of non-Treg and CD8+PD-1+ T cells were predictive of response and better recurrence-free survival after BCG. Remarkably, post-BCG tissues from responders were found to be infiltrated with more active CD8+PD-1- T cells and non-Treg CD4+FOXP3- T cells; but increased exhausted CD8+PD-1+ T cells were found in non-responders. Taken together, we identified predictive biomarkers for response and uncovered the post-treatment expansion of exhausted PD-1+CD8+ T cells as key to BCG resistance, which could potentially be restored by combining with anti-PD-1 immunotherapy.
Persistent Systemic Inflammation in Patients With Severe Burn Injury Is Accompanied by Influx of Immature Neutrophils and Shifts in T Cell Subsets and Cytokine Profiles
Authors: Mulder Patrick P. G. , Vlig Marcel , Boekema Bouke K. H. L. , Stoop Matthea M. , Pijpe Anouk , van Zuijlen Paul P. M. , de Jong Evelien , van Cranenbroek Bram , Joosten Irma , Koenen Hans J. P. M. , Ulrich Magda M. W.
Published: January 2021

Severe burn injury causes local and systemic immune responses that can persist up to months, and can lead to systemic inflammatory response syndrome, organ damage and long-term sequalae such as hypertrophic scarring. To prevent these pathological conditions, a better understanding of the underlying mechanisms is essential. In this longitudinal study, we analyzed the temporal peripheral blood immune profile of 20 burn wound patients admitted to the intensive care by flow cytometry and secretome profiling, and compared this to data from 20 healthy subjects. The patient cohort showed signs of systemic inflammation and persistently high levels of pro-inflammatory soluble mediators, such as IL-6, IL-8, MCP-1, MIP-1β, and MIP-3α, were measured. Using both unsupervised and supervised flow cytometry techniques, we observed a continuous release of neutrophils and monocytes into the blood for at least 39 days. Increased numbers of immature neutrophils were present in peripheral blood in the first three weeks after injury (0.1–2.8 × 106/ml after burn vs. 5 × 103/ml in healthy controls). Total lymphocyte numbers did not increase, but numbers of effector T cells as well as regulatory T cells were increased from the second week onward. Within the CD4+ T cell population, elevated numbers of CCR4+CCR6- and CCR4+CCR6+ cells were found. Altogether, these data reveal that severe burn injury induced a persistent innate inflammatory response, including a release of immature neutrophils, and shifts in the T cell composition toward an overall more pro-inflammatory phenotype, thereby continuing systemic inflammation and increasing the risk of secondary complications.
High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19
Authors: Ma Aiping , Zhang Liang , Ye Xiaokai , Chen Jing , Yu Jie , Zhuang Liangjin , Weng Chaohang , Petersen Frank , Wang Zhanxiang , Yu Xinhua
Published: January 2021

Objectives

The coordinated immune response of the host is the key of the successful combat of the body against SARS-CoV-2 infection and is decisive for the development and progression of COVID-19. In this study, we aimed to investigate whether the immunological phenotype of patients are associated with duration of illness in patients with severe COVID-19.

Method

In this single-center study, 69 patients with severe or critical COVID-19 were recruited retrospectively. Immunological parameters including counts of white blood cells, neutrophils, lymphocytes, the neutrophil-to-lymphocyte ratio, and levels of circulating cytokines and cytokine receptors were screened for their association with disease severity, survival and duration of illness of COVID-19.

Results

Our data confirmed previous results that neutrophil-to-lymphocyte ratio and circulating levels of IL-6 represent prominent biomarker for the prediction of disease severity and survival of COVID-19. However, this study shows for the first time that duration of illness in patients with severe COVID-19 is positively associated with serum levels of IL-8 (P=0.004) and soluble IL-2Rα (P=0.025).

Conclusion

The significant association of duration of illness with circulating levels of IL-8 and soluble IL-2Rα in patients with severe COVID-19 implicates that neutrophils and T cells are involved in the evolution of COVID-19.
Fermented Soybean Meal Replacement in the Diet of Lactating Holstein Dairy Cows: Modulated Rumen Fermentation and Ruminal Microflora
Authors: Wang Zuo , Yu Yuannian , Li Xinyao , Xiao Hongyan , Zhang Peihua , Shen Weijun , Wan Fachun , He Jianhua , Tang Shaoxun , Tan Zhiliang , Wu Duanqin , Yao Hui
Published: January 2021

This study was conducted to examine the influences of replacing soybean meal (SBM) with fermented soybean meal (FSBM) in the diet of lactating Holstein cattle on rumen fermentation and ruminal bacterial microbiome. Twenty-four lactating Chinese Holstein dairy cattle were assigned to each of the two treatments in a completely randomized design: the SBM group [the basal total mixed ration (TMR) diet containing 5.77% SBM] and the FSBM group (the experimental TMR diet containing 5.55% FSBM). This trial lasted for 54 days (14 days for adjustment and 40 days for data and sample collection), and samples of rumen liquid were collected on 34 d and 54 d, respectively. The results showed that replacing SBM with FSBM significantly increased the molar percentages of propionate (P < 0.01) and valerate (P < 0.05), but reduced the total volatile fatty acid (TVFA) concentration (P < 0.05), butyrate molar proportion (P < 0.05), and the acetate to propionate ratio (P < 0.01). The copy numbers of total bacteria (P < 0.05), Fibrobacter succinogenes (P < 0.01), Selenomonas ruminantium (P < 0.01), and Prevotella spp. (P < 0.05) in the FSBM group were greater, while the density of Prevotella ruminicola (P < 0.05) was lower than those in the SBM treatment. Additionally, Succiniclasticum ruminis and Saccharofermentans acetigenes were significantly enriched (P < 0.05) in the rumen fluid of FSBM-fed cows, despite the fact that there was no remarkable difference in the Alpha diversity indexes, structure and KEGG pathway abundances of the bacterial community across the two treatments. It could hence be concluded that the substitution of FSBM for SBM modulated rumen fermentation and rumen bacterial microbiota in lactating Holstein dairy cows. Further research is required to elucidate the relevant mechanisms of FSBM, and provide more insights into the application of FSBM in dairy cattle.
Optic Perineuritis and Its Association With Autoimmune Diseases
Authors: Li Hongyang , Zhou Hang , Sun Jiao , Wang Huihui , Wang Yanling , Wang Zhenchang , Li Jing
Published: January 2021

Background: Optic perineuritis (OPN) is a special optic neuropathy that has a distinct etiology from neuromyelitis optica spectrum disorders (NMOSDs) or multiple sclerosis (MS)-related optic neuritis (ON). The mechanisms of how this inflammation developed and invaded the nerve sheath remain unknown. This study is aimed to analyze the etiology and different clinical characteristics of OPN in a Chinese patient population.

Methods: Neuro-ophthalmological examination, orbit magnetic resonance imaging (MRI) and a series of blood samples were used in this retrospective observational cohort study to compare characteristics of OPN with idiopathic demyelination optic neuritis (IDON).

Results: Forty-four OPN cases (74 eyes) and 61 IDON cases (78 eyes) were analyzed. OPN cases included 33 cases (59 eyes) were associated with specific autoimmune diseases, 10 cases (13 eyes) were associated with infection diseases, 1 case was idiopathic disease. The causes of OPN with CTD were Graves' disease, Immunoglobulin G4-related disease (IgG-4 RD), granulomatosis with polyangiitis (GAP), systemic lupus erythematosus (SLE), Sarcoidosis, Rheumatoid arthritis, scleroderma, Behcet's disease, and gout. All patients received orbital MRI. Overall, 33 cases showed orbit fat infiltration. Specifically, nine cases with IgG-4 RD showed trigeminal nerve branch involvement, 12 cases with Graves' disease showed extraocular muscle belly enlargement, and 4 cases with GAP showed pterygopalatine fossa pseudotumor. Compared to IDON patients, OPN patients were older (p = 0.004) and more likely bilateral involvement 26 (78.79%) patients had bilateral involvement in OPN group vs. 17 (27.87%) in the IDON group (p < 0.001). Visual acuity scores using LogMAR testing was better in OPN patients compared to those with IDON, 0.55 ± 0.91 vs. 1.19 ± 1.24 (p < 0.001). Other ophthalmologic findings unique to the OPN group include 11 (33.33%) cases of ptosis, nine (27.27%) cases of diplopia, and 10 (30.30%) cases of exophthalmos, compared to zero cases of these conditions in the IDON group. Eight (13.11%) IDON patients also had multiple sclerosis (MS) and 7 (11.48%) patients had neuromyelitis which was significantly more than the zero patients in OPN group (p = 0.04).

Conclusions: OPN had distinct etiologies and clinical characteristics from IDON and is more often associated with autoimmune diseases. Using OPN characteristics to diagnose autoimmune diseases should prove useful for clinicians when presented with patients that have multiorgan dysfunction that include ophthalmologic findings.
Automatic Detection and Classification of Focal Liver Lesions Based on Deep Convolutional Neural Networks: A Preliminary Study
Authors: Zhou Jiarong , Wang Wenzhe , Lei Biwen , Ge Wenhao , Huang Yu , Zhang Linshi , Yan Yingcai , Zhou Dongkai , Ding Yuan , Wu Jian , Wang Weilin
Published: January 2021

With the increasing daily workload of physicians, computer-aided diagnosis (CAD) systems based on deep learning play an increasingly important role in pattern recognition of diagnostic medical images. In this paper, we propose a framework based on hierarchical convolutional neural networks (CNNs) for automatic detection and classification of focal liver lesions (FLLs) in multi-phasic computed tomography (CT). A total of 616 nodules, composed of three types of malignant lesions (hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastasis) and benign lesions (hemangioma, focal nodular hyperplasia, and cyst), were randomly divided into training and test sets at an approximate ratio of 3:1. To evaluate the performance of our model, other commonly adopted CNN models and two physicians were included for comparison. Our model achieved the best results to detect FLLs, with an average test precision of 82.8%, recall of 93.4%, and F1-score of 87.8%. Our model initially classified FLLs into malignant and benign and then classified them into more detailed classes. For the binary and six-class classification, our model achieved average accuracy results of 82.5 and73.4%, respectively, which were better than the other three classification neural networks. Interestingly, the classification performance of the model was placed between a junior physician and a senior physician. Overall, this preliminary study demonstrates that our proposed multi-modality and multi-scale CNN structure can locate and classify FLLs accurately in a limited dataset, and would help inexperienced physicians to reach a diagnosis in clinical practice.
Ubiquitin Carboxyl-Terminal Hydrolases and Human Malignancies: The Novel Prognostic and Therapeutic Implications for Head and Neck Cancer
Authors: Rong Chao , Zhou Ran , Wan Shan , Su Dan , Wang Shou-Li , Hess Jochen
Published: January 2021

Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), have been found in a variety of tumor entities and play distinct roles in the pathogenesis and development of various cancers including head and neck cancer (HNC). HNC is a heterogeneous disease arising from the mucosal epithelia of the upper aerodigestive tract, including different anatomic sites, distinct histopathologic types, as well as human papillomavirus (HPV)-positive and negative subgroups. Despite advances in multi-disciplinary treatment for HNC, the long-term survival rate of patients with HNC remains low. Emerging evidence has revealed the members of UCHs are associated with the pathogenesis and clinical prognosis of HNC, which highlights the prognostic and therapeutic implications of UCHs for patients with HNC. In this review, we summarize the physiological and pathological functions of the UCHs family, which provides enlightenment of potential mechanisms of UCHs family in HNC pathogenesis and highlights the potential consideration of UCHs as attractive drug targets.
A Quantitative Assessment of Pre-Operative MRI Reports in Glioma Patients: Report Metrics and IDH Prediction Ability
Authors: Cao Hang , Erson-Omay E. Zeynep , Günel Murat , Moliterno Jennifer , Fulbright Robert K.
Published: January 2021

Objectives

To measure the metrics of glioma pre-operative MRI reports and build IDH prediction models.

Methods

Pre-operative MRI reports of 144 glioma patients in a single institution were collected retrospectively. Words were transformed to lowercase letters. White spaces, punctuations, and stop words were removed. Stemming was performed. A word cloud method applied to processed text matrix visualized language behavior. Spearman’s rank correlation assessed the correlation between the subjective descriptions of the enhancement pattern. The T1-contrast images associated with enhancement descriptions were selected. The keywords associated with IDH status were evaluated by χ2 value ranking. Random forest, k-nearest neighbors and Support Vector Machine algorithms were used to train models based on report features and age. All statistical analysis used two-tailed test with significance at p <.05.

Results

Longer word counts occurred in reports of older patients, higher grade gliomas, and wild type IDH gliomas. We identified 30 glioma enhancement descriptions, eight of which were commonly used: peripheral, heterogeneous, irregular, nodular, thick, rim, large, and ring. Five of eight patterns were correlated. IDH mutant tumors were characterized by words related to normal, symmetric or negative findings. IDH wild type tumors were characterized words by related to pathological MR findings like enhancement, necrosis and FLAIR foci. An integrated KNN model based on report features and age demonstrated high-performance (AUC: 0.89, 95% CI: 0.88–0.90).

Conclusion

Report length depended on age, glioma grade, and IDH status. Description of glioma enhancement was varied. Report descriptions differed for IDH wild and mutant gliomas. Report features can be used to predict glioma IDH status.
The Role of Microglia in Glioblastoma
Authors: Geribaldi-Doldán Noelia , Fernández-Ponce Cecilia , Quiroz Roberto Navarro , Sánchez-Gomar Ismael , Escorcia Lorena Gómez , Velásquez Erika Puentes , Quiroz Elkin Navarro
Published: January 2021

Glioblastoma (GB), the most aggressive malignant glioma, is made up of a large percentage of glioma-associated microglia/macrophages (GAM), suggesting that immune cells play an important role in the pathophysiology of GB. Under physiological conditions, microglia, the phagocytes of the central nervous system (CNS), are involved in various processes such as neurogenesis or axonal growth, and the progression of different conditions such as Alzheimer’s disease. Through immunohistochemical studies, markers that enhance GB invasiveness have been shown to be expressed in the peritumoral area of ​​the brain, such as Transforming Growth Factor α (TGF-α), Stromal Sell-Derived Factor 1 (SDF1/CXCL12), Sphingosine-1-Phosphate (S1P) and Neurotrophic Factor Derived from the Glial cell line (GDNF), contributing to the increase in tumor mass. Similarly, it has also been described 17 biomarkers that are present in hypoxic periarteriolar HSC niches in bone marrow and in hypoxic periarteriolar GSC niches in glioblastoma. Interestingly, microglia plays an important role in the microenvironment that supports GB progression, being one of the most important focal points in the study of therapeutic targets for the development of new drugs. In this review, we describe the altered signaling pathways in microglia in the context of GB. We also show how microglia interact with glioblastoma cells and the epigenetic mechanisms involved. Regarding the interactions between microglia and neurogenic niches, some authors indicate that glioblastoma stem cells (GSC) are similar to neural stem cells (NSC), common stem cells in the subventricular zone (SVZ), suggesting that this could be the origin of GB. Understanding the similarities between SVZ and the tumor microenvironment could be important to clarify some mechanisms involved in GB malignancy and to support the discovering of new therapeutic targets for the development of more effective glioblastoma treatments.
Estrogen Receptor β1 Expression Patterns Have Different Effects on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors’ Treatment Response in Epidermal Growth Factor Receptor Mutant Lung Adenocarcinoma
Authors: Zhang Lijuan , Tian Meng , Lin Jiamao , Zhang Jianbo , Wang Haiyong , Li Zhenxiang
Published: January 2021

Estrogen receptor β (ERβ) can regulate cellular signaling through non-genomic mechanisms, potentially promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanisms underlying the ERβ-mediated resistance to EGFR TKIs remain poorly understood. In this study, we investigated the role of the interaction between ERβ1 and ERβ5 in non-genomic signaling in lung adenocarcinoma. We established PC9 cell lines stably overexpressing ERβ1 or ERβ1/ERβ5. Immunofluorescence revealed that ERβ5 overexpression partly retained ERβ1 in the cytoplasm. Immunoblotting analyses revealed that EGFR pathway activation levels were higher in PC9/ERβ1/5 cells than those in PC9/ERβ1 or control PC9 cells. In the presence of estradiol, PI3K/AKT/mTOR pathway activation levels were higher in ERβ1/5-expressing cells than those in ERβ1-expressing cells. Additionally, PC9/ERβ1/5 cells were less prone to the cytotoxic and pro-apoptotic effects of gefitinib compared with PC9/ERβ1 or control PC9 cells. Cytoplasmic ERβ1 was associated with poor progression-free survival in lung cancer patients treated with EGFR TKIs. These results suggest that cytoplasmic ERβ1 was responsible for EGFR TKI resistance slightly through non-genomic mechanism in EGFR mutant lung adenocarcinoma.
KIF21B Expression in Osteosarcoma and Its Regulatory Effect on Osteosarcoma Cell Proliferation and Apoptosis Through the PI3K/AKT Pathway
Authors: Ni Songjia , Li Jianjun , Qiu Sujun , Xie Yingming , Gong Kaiqin , Duan Yang
Published: January 2021

Osteosarcoma (OS) is the most common malignancy that occurs mainly during childhood and adolescence; however, no clear molecular or biological mechanism has been identified. In this study, we aimed to explore new biomarkers for the early diagnosis, targeted treatment, and prognostic determination of osteosarcoma. We first used bioinformatics analysis to show that KIF21B can be used as a biomarker for the diagnosis and prognosis of osteosarcoma. We then examined the expression of KIF21B in human osteosarcoma tissues and cell lines using immunohistochemistry, western blotting, and qRT-PCR. It was found that KIF21B expression was significantly upregulated in osteosarcoma tissues and cell lines. After knocking down the expression of KIF21B in the osteosarcoma cell lines 143B and U2-OS, we used cell fluorescence counting, CCK-8 assays, flow cytometry, and TUNEL staining to examine the effects of KIF21B on osteosarcoma cell proliferation and apoptosis. The results demonstrated that knocking down KIF21B in 143B and U2-OS cells could increase cell apoptosis, inhibit cell proliferation, and reduce tumor formation in nude mice. Subsequently, we used gene chips and bioinformatics to analyze the differential gene expression caused by knocking down KIF21B. The results showed that KIF21B may regulate OS cell proliferation and apoptosis by targeting the PI3K/AKT pathway. We then examined the expression of PI3K/AKT- and apoptosis-related proteins using western blotting. KIF21B knockdown inhibited the PI3K pathway, downregulated Bcl-2, and upregulated Bax. Moreover, the use of PI3K/AKT pathway agonists reversed the regulatory effect of KIF21B on the apoptosis and proliferation of 143B and U2-OS cells. In conclusion, our results indicated that KIF21B plays a key role in osteosarcoma. Low KIF21B expression might indirectly increase the apoptosis and inhibit the proliferation of osteosarcoma cells through the PI3K/AKT pathway.
Minimal Residual Disease Detection by Next-Generation Sequencing in Multiple Myeloma: A Comparison With Real-Time Quantitative PCR
Authors: Yao Qiumei , Bai Yinlei , Kumar Shaji , Au Elaine , Orfao Alberto , Chim Chor Sang
Published: January 2021

Here we compared clonotype identification by allele-specific oligonucleotide real-time quantitative-PCR (ASO RQ-PCR) and next-generation sequencing (NGS) in 80 multiple myeloma patients. ASO RQ-PCR was applicable in 49/55 (89%) and NGS in 62/78 (80%). Clonotypes identified by both methods were identical in 33/35 (94%). Sensitivity of 10−5 was confirmed in 28/29 (96%) by NGS while sensitivity of RQ-PCR was 10−5 in 7 (24%), 5 × 10−5 in 15 (52%), and 10−4 in 7 (24%). Among 14 samples quantifiable by ASO RQ-PCR, NGS yielded comparable results in 12 (86%). Applicability of NGS can be improved if immunoglobulin heavy-chain incomplete DJ primers are included.
Withaferin A Acts as a Novel Regulator of Liver X Receptor-α in HCC
Authors: Shiragannavar Varsha D. , Gowda Nirmala G. Sannappa , Kumar Divya P. , Mirshahi Faridoddin , Santhekadur Prasanna K.
Published: January 2021

Withaferin A, a steroidal lactone derived from the Withania somnifera plant has been known for its anti-cancerous effects on various types of cancer cells. However, its effect on the hallmarks of cancer such as proliferation, migration, invasion, and angiogenesis is still poorly understood. The antitumor property of Withaferin A and its molecular mechanism of action on hepatocellular carcinoma (HCC) cells is not yet completely established. In this study, we aimed to elucidate the novel molecular function of Withaferin A on HCC cells and its effect on various gene expression. Our results clearly showed that Withaferin A treatment to HCC cells inhibited proliferation, migration, invasion, and anchorage-independent growth. Further, we explored the Withaferin A target genes by blotting human angiogenesis, and cytokine arrays using conditioned media of Withaferin A treated QGY-7703 cells. We found that many of Nuclear factor kappa B (NF-κB), angiogenesis and inflammation associated proteins secretion is downregulated upon Withaferin A treatment. Interestingly, all these genes expression is also negatively regulated by nuclear receptor Liver X receptor-α (LXR-α). Here, we explored a novel mechanism that Withaferin-A activated LXR-α inhibits NF-κB transcriptional activity and suppressed the proliferation, migration, invasion, and anchorage-independent growth of these HCC cells. All these data strongly confirmed that Withaferin A is a potent anticancer compound and suppresses various angiogenesis and inflammatory markers which are associated with the development and progression of HCC. This beneficial and potential therapeutic property of Withaferin A will be very useful for the treatment of HCC.
Thiopurines: Recent Topics and Their Role in the Treatment of Inflammatory Bowel Diseases
Authors: Tominaga Keiichi , Sugaya Takeshi , Tanaka Takanao , Kanazawa Mimari , Iijima Makoto , Irisawa Atsushi
Published: January 2021

Ulcerative colitis (UC) and Crohn's disease (CD) are chronic inflammatory bowel diseases (IBD) of unknown etiology, characterized by repeated relapse and remission. The efficacy of thiopurine in IBD was first reported in the late 1960s. Thiopurines are used to alleviate the symptoms of IBD, especially UC. These drugs have a steroid-sparing potential and are widely used for the purpose of maintaining long-term remission in steroid-dependent cases. Therefore, thiopurines tend to be used long-term, but adverse events that accompany long-term use, such as lymphoproliferative disorders, must be monitored with care. In contrast, thiopurine plays a critical role in controlling the immunogenicity of biologics. Furthermore, although thiopurine is an old drug, new findings, including the prediction of serious adverse events such as severe alopecia and acute advanced leukopenia, by nudix hydrolase 15 gene polymorphism analysis, as well as the possibility of appropriate drug monitoring by detailed analysis of 6-thioguanine nucleotides have been clarified. However, the consequences of thiopurine withdrawal have not been determined and further studies, including randomized controlled trials, are necessary to answer the clinical question regarding the scenarios in which thiopurine withdrawal is possible.
A Novel Method to Identify Three Quality Grades of Herbal Medicine Ophiopogonis Radix by Microscopic Quantification
Authors: Yu Kunzi , Liu Wei , Zhang Nanping , Cheng Xianlong , Zhou Shiyu , Zuo Tiantian , Kang Shuai , Wei Feng , Ma Shuangcheng
Published: January 2021

Maidong, the root tuber of Ophiopogon japonicus (Thunb.) Ker Gawl., is a commonly used herbal medicine in China. There are three quality grades of Maidong according to traditional opinion and modern research studies: superior quality (Zhe-Maidong), medium quality (Chuan-Maidong), and poorest quality (Chuan-Maidong with paclobutrazol, which is a kind of plant growth regulator). However, no efficient way to distinguish the three quality grades of Maidong exists; thus, the herbal markets and botanical pharmacies are flooded with Chuan-Maidong with paclobutrazol. To ensure the safety and quality of Maidong, a comparative microscopic study was performed on three quality grades of Maidong. The result was to establish a microscopic quantification method based on the area ratio between xylem and pith to distinguish the three quality grades of Maidong. Subsequently, Maidong from regional markets was evaluated by this method. In this study, we developed a novel quantification method to identify the three quality grades of Maidong, which could in turn make efforts on the quality improvement of Maidong. Our study is the first to demonstrate that microscopic technology could be used to distinguish different quality grades of a specific herbal medicine.
Effects of Angiotensin II Type 1A Receptor on ACE2, Neprilysin and KIM-1 in Two Kidney One Clip (2K1C) Model of Renovascular Hypertension
Authors: Alawi Laale F. , Dhakal Sanjeev , Emberesh Sana E. , Sawant Harshal , Hosawi Anhar , Thanekar Unmesha , Grobe Nadja , Elased Khalid M.
Published: January 2021

Activation of the renin angiotensin system plays a pivotal role in the regulation of blood pressure, which is mainly attributed to the formation of angiotensin-II (Ang II). The actions of Ang II are mediated through binding to the Ang-II type 1 receptor (AT1R) which leads to increased blood pressure, fluid retention, and aldosterone secretion. In addition, Ang II is also involved in cell injury, vascular remodeling, and inflammation. The actions of Ang II could be antagonized by its conversion to the vasodilator peptide Ang (1–7), partly generated by the action of angiotensin converting enzyme 2 (ACE2) and/or neprilysin (NEP). Previous studies demonstrated increased urinary ACE2 shedding in the db/db mouse model of diabetic kidney disease. The aim of the study was to investigate whether renal and urinary ACE2 and NEP are altered in the 2K1C Goldblatt hypertensive mice. Since AT1R is highly expressed in the kidney, we also researched the effect of global deletion of AT1R on renal and urinary ACE2, NEP, and kidney injury marker (KIM-1). Hypertension and albuminuria were induced in AT1R knock out (AT1RKO) and WT mice by unilateral constriction of the renal artery of one kidney. The 24 h mean arterial blood pressure (MAP) was measured using radio-telemetry. Two weeks after 2K1C surgery, MAP and albuminuria were significantly increased in WT mice compared to AT1RKO mice. Results demonstrated a correlation between MAP and albuminuria. Unlike db/db diabetic mice, ACE2 and NEP expression and activities were significantly decreased in the clipped kidney of WT and AT1RKO compared with the contralateral kidney and sham control (p < 0.05). There was no detectable urinary ACE2 and NEP expression and activity in 2K1C mice. KIM-1 was significantly increased in the clipped kidney of WT and AT1KO (p < 0.05). Deletion of AT1R has no effect on the increased urinary KIM-1 excretion detected in 2K1C mice. In conclusion, renal injury in 2K1C Goldblatt mouse model is associated with loss of renal ACE2 and NEP expression and activity. Urinary KIM-1 could serve as an early indicator of acute kidney injury. Deletion of AT1R attenuates albuminuria and hypertension without affecting renal ACE2, NEP, and KIM-1 expression.