ABBV-319: A CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

Glucocorticoids are key components of the current standard-of-care regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B-cells and is up-regulated in B-cell malignancies. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple malignant B-cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when multiple MOAs are enabled. ABBV-319 also showed durable anti-tumor activity across multiple B-cell lymphoma PDX models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma post R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Global burden of atrial fibrillation/flutter: Trends from 1990 to 2019 and projections until 2044.

Aims: Atrial fibrillation/atrial flutter (AF/AFL) is a critical public health issue worldwide, and its epidemiological patterns have changed over the decades. This work aimed to assess the global trends of AF/AFL and attributable risks from 1990 to 2019. Methods and results: The present study utilized data from the Global Burden of Disease Study 2019 to examine the temporal trends, attributable risks, and projections of AF/AFL. The estimated annual percentage change (EAPC) and age-standardized rate (ASR) were employed for this purpose. The findings revealed that in 2019, AF/AFL accounted for 4.72 million incident cases, 59.70 million prevalent cases, 0.32 million deaths, and 8.39 million disability-adjusted life years (DALYs). Furthermore, the results indicated that males under 70 years of age had a higher incidence, prevalence, and DALYs than females, while the rates were similar for both genders between 70 and 74 years. However, this pattern was reversed in individuals over the age of 75, with females exhibiting a higher total incidence, prevalence, and DALYs than males. The age-standardized rates (ASRs) of prevalence, incidence, mortality, and DALYs increased with an increase in the socio-demographic index (SDI). The three primary contributors to AF/AFL were high systolic blood pressure, high body-mass index, and smoking. Majority of risk factors exhibited a unimodal distribution, with a peak between the ages of 50 and 70. Conclusions: The disease burden of AF/AFL is still severe worldwide and getting worse. To encourage prevention and treatment, systematic regional surveillance of AF/AFL should be put in place.

Pulmonary abscess combined with pulmonary vein thrombosis and stroke: A case report.

BACKGROUND: Although most stroke patients have underlying vascular risk factors, it is important to consider infectious causes of stroke in young adults without traditional risk factors or patients with cryptogenic stroke. Pulmonary vein thrombosis and air embolism can potentially cause cerebral infarction. However, the association between infection and pulmonary vein thrombosis or air embolism is often overlooked. In this case, we present a rare infectious cause of stroke and air embolism involving a pulmonary abscess and pulmonary vein thrombosis. CASE PRESENTATION: A 37-year-old male patient initially presented with right-sided pneumonia. During treatment at a local hospital, he developed headaches and left limb weakness. Subsequently, he was transferred to our hospital due to septic shock. Neurological evaluations revealed multiple brain foci and thrombosis in the right superior pulmonary vein. Following treatment with broad-spectrum antibiotics and anticoagulants, the patient's clinical symptoms and inflammatory markers showed improvement. However, a computed tomography scan revealed the formation of a pulmonary abscess, and the patient experienced coma and epilepsy after severe coughing with massive hemoptysis. Multiple air embolisms were observed in the brain computed tomography. Eventually, the patient's family chose to discharge him from the hospital. CONCLUSIONS: This case highlights the rare and complex etiologies of stroke associated with infection in a young patient. Early detection, diagnosis, and appropriate treatment of infected systemic embolism in young patients are crucial to prevent serious complications.

PAR1 regulates sepsis-induced vascular endothelial barrier dysfunction by mediating ERM phosphorylation via the RhoA/ROCK signaling pathway.

Sepsis begins with vascular endothelial barrier breakdown and causes widespread organ failure. Protease-activated receptor 1 (PAR1) is an important target for modulating vascular endothelial permeability; however, little research has been undertaken in sepsis, and its putative molecular mechanism remains unknown. The vascular endothelial permeability was examined by detecting FITC-dextran flux. F-actin was examined by immunofluorescence (IF). PAR1, ERM phosphorylation, and RhoA/ROCK signaling pathway expression in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) line were examined by IF and Western blot. To develop the sepsis model, cecal ligation and puncture (CLP) were conducted. The PAR1 inhibitor SCH79797 was utilized to inhibit PAR1 expression in vivo. Vascular permeability in main organs weres measured by Evans blue dye extravasation. The pathological changes in main organs were examined by HE staining. The expression of PAR1, ERM phosphorylation, and the RhoA/ROCK signaling pathway was examined using IF, immunohistochemical and WB in CLP mice. In vitro, in response to LPS stimulation of HUVECs, PAR1 mediated the phosphorylation of ERM, promoted F-actin rearrangement, and increased endothelial hyperpermeability, all of which were prevented by inhibiting PAR1 or RhoA. Additionally, inhibiting PAR1 expression reduced RhoA and ROCK expression. In vivo, we showed that inhibiting PAR1 expression will reduce ezrin/radixin/moesin (ERM) phosphorylation to relieve vascular endothelial barrier dysfunction and thereby ameliorate multiorgan dysfunction syndrome (MODS) in CLP-induced septic mice. This study revealed that PAR1-mediated phosphorylation of ERM induced endothelial barrier dysfunction, which in turn led to MODS in sepsis, and that the RhoA/ROCK signaling pathway underlay these effects.

Changing trends in gastric and colorectal cancer among surgical patients over 85 years old: A multicenter retrospective study, 2001-2021.

BACKGROUND: Whether patients over 85 years old with gastrointestinal cancer should undergo surgery remains controversial. We aimed to describe the changing trends of characteristics to provide more information to decision makers, and strive to find appropriate surgical plan. AIM: To describe the changing trends of characteristics to provide more information to decision makers, and strive to find appropriate surgical plan. METHODS: A total of 218 gastric cancer (GC) patients and 563 colorectal cancer (CRC) patients who underwent surgery between 2001 and 2021 were enrolled in this retrospective analysis. Changes in clinicopathological features, surgical treatments, and survival status were analyzed longitudinally at 5-year intervals. RESULTS: Only 14 GC patients underwent laparoscopic surgery where 219 CRC patients had this procedure. Cardia and esophagogastric junction cancer increased in GC patients, and the proportion of sigmoid colon cancer decreased in CRC patients. Pulmonary infection gradually became the most common postoperative complication, its incidence in period 4 reached 48.79%. However, the incidence of anastomotic leakage decreased from 26.79% to 9.38% (P < 0.01). Additionally, 30-d mortality significantly decreased from 32.14% to 9.01%. Increases were observed in 5-year overall survival (OS) in GC patients from period 1 to period 4 (18.18% vs 33.32%, respectively) and CRC patients (0 vs 36.32%, respectively). Disease-free survival (DFS) also increased in GC and CRC patients (7.14% vs 27.74% and 0 to 36.03%, respectively). The average survival time of GC patients following radial lymphadenectomy was higher than in patients that underwent limited lymphadenectomy (26 vs 22 mo, respectively), the same was seen in CRC patients (44 vs 33 mo, respectively). This advantage was particularly evident in patients with TNM I, but not in patients with TNM II/III period cancer. CONCLUSION: The safety as well as effectiveness of surgery in ultra-elderly patients is increasing. Radical lymphadenectomy has advantages in patients with TNM I gastrointestinal cancer, but not TNM II/III.

Effect of Hypoglycemic Drugs on Kisspeptin Expression in the Hypothalamic Arcuate Nucleus of PCOS Rats.

Background: To investigate the change in hypothalamic kisspeptin-1 (Kiss1) expression during the development of polycystic ovary syndrome (PCOS) and hypoglycemic drug intervention. Methods: Letrozole lavage was used to construct a polycystic ovary rat model. After successful modeling, we treated PCOS rats with metformin, pioglitazone, and acarbose, and we then observed changes in weight, estrus, glucose tolerance, insulin resistance, sex hormones, and hypothalamic kiss1 expression. Results: PCOS rats exhibited increased body weight, abnormal estrous cycle, impaired glucose tolerance, insulin resistance, increased testosterone level, increased luteinizing hormone level, and increased Kiss1 expression in the hypothalamus. However, intervention with metformin, pioglitazone, and acarbose improved the reproductive and metabolic disorders as well as reduced hypothalamic Kiss1 expression. Conclusion: The expression of hypothalamic Kiss1 may play an important role in the pathogenesis of PCOS. Metformin, pioglitazone, and acarbose may reduce the expression of hypothalamic Kiss1 by improving insulin resistance, thereby improving reproductive and metabolic disorders in PCOS rats.

Transverse magneto-optical behavior of nanoporous ferromagnetic film based on anodic aluminum oxide/aluminum template and its sensing application.

The transverse magneto-optical Kerr effect (TMOKE) has attracted widespread scientific interest because of its potential applications in biosensor technology, data storage, optical isolation, and telecommunications. More conventional architectures, including prism-based metal/magnetic multilayers and nanoarrays that integrate plasmonic and magnetic materials, are commonly used to amplify TMOKE through the high-quality propagation of the surface plasmon resonance optical mode. However, the main disadvantages of these architectures are their large ohmic losses and radiation damping, resulting in a large optical spectrum linewidth, which hinders the sensing performance. Here, we use a theoretical approach to show that it is possible to employ a low-loss Fabry-Perot optical mode on a magneto-optical platform for TMOKE signal and gaseous sensing enhancement by means of a single CoFeB ferromagnetic film directly overlayed on an already industrial anodic aluminum oxide/aluminum template. The proposed strategy can therefore potentially be exploited for high-precision and low-loss magneto-optical sensors.

Thrombocytosis in patients with spondyloarthritis: a case-control study.

OBJECTIVE: This study aimed to investigate the clinical and laboratory as well as radiological features of spondyloarthritis (SpA) patients with thrombocytosis and to explore risk factor for thrombocytosis in SpA patients and to assess the effect of antitumor necrosis factor-α (anti-TNF-α) therapy on platelet count in SpA patients with thrombocytosis. METHODS: A total of 145 patients with SpA were included in this study, and non-thrombocytosis was identified in 76 patients while thrombocytosis was found in 69 patients, 38 out of the 69 patients received anti-TNF-α therapy. Logistic regression analysis was performed to investigate risk factors that associated with thrombocytosis. The platelet count of patients in the thrombocytosis group treated with anti-TNF-α therapy on week 0, week 6 and week 12 were collected and compared with conventional therapy group. RESULTS: The proportion of hip involvement (60.86% vs 36.84%, p = 0.004), bath ankylosing spondylitis disease activity index score (4.24 ± 0.55 vs 3.69 ± 0.67, p < 0.001), erythrocyte sedimentation rate (62.22 ± 41.97 mm/hour vs 27.00 ± 25.93 mm/hour, p < 0.001), C-reactive protein (53.45 ± 47.45 mg/L vs 18.91 ± 31.09 mg/L, p < 0.001), fibrinogen (5.77 ± 1.48 g/L vs 4.01 ± 1.32 g/L, P < 0.001), white blood cells (8.15 ± 1.90 × 109/L vs 6.85 ± 2.39 × 109/L, p < 0.001) and neutrophils (5.08 ± 1.55 × 109/L vs 4.01 ± 2.04 × 109/L, p = 0.001) are higher in thrombocytosis group, but hemoglobin and albumin are lower compared to non-thrombocytosis group (122.88 ± 17.25 g/L vs 131.51 ± 16.03 g/L, p = 0.002; 37.19 ± 4.73 g/L vs 39.67 ± 3.99 g/L, p = 0.001, respectively). Multivariable logistic regression analysis indicated that higher white blood cells (OR, 1.644; 95% CI, 1.045-2.587; P = 0.032) and fibrinogen (OR, 2.169; 95% CI, 1.237-3.804; P = 0.007) were independently associated with thrombocytosis in SpA patients. The platelet count in the thrombocytosis group treated with anti-TNF-α therapy on week 6 and week 12 were statistically lower than week 0 (225.05 ± 60.58 × 109/L vs 368.26 ± 54.34 × 109/L, p < 0.001; 201.26 ± 51.48 × 109/L vs 368.26 ± 54.34 × 109/L, p < 0.001) and conventional therapy (week 6, 225.05 ± 60.58 × 109/L vs 370.00 ± 74.05 × 109/L, p < 0.001; week 12, 201.26 ± 51.48 × 109/L vs 303.13 ± 71.49 × 109/L, p < 0.001). CONCLUSION: SpA patients with thrombocytosis have a higher proportion of hip involvement and disease activity compared to non-thrombocytosis SpA patients. The potential risk factors for thrombocytosis in SPA patients were higher white blood cells and fibrinogen. Anti-TNF-α therapy can reduce the increased platelets more effectively and rapidly than conventional treatments in SpA patients with thrombocytosis.

SLC26A4 mutation in Pendred syndrome with hypokalemia: A case report.

RATIONALE: Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, inner ear malformations, goiter, and abnormal organification of iodide. It is caused by mutations in SLC26A4 gene, which encodes pendrin (a transporter of chloride, bicarbonate, and iodide). Pendred syndrome is a common cause of syndromic deafness, but the metabolic abnormalities it causes are often overlooked. Here, we report the case of a patient diagnosed with Pendred syndrome with hypokalemia. PATIENT CONCERNS: A 53-year-old deaf-mute woman was hospitalized due to severe limb asthenia. The emergency examination showed that her blood potassium level was 1.8 mmol/L. DIAGNOSES: Through the genetic test, we found a mutation of SLC26A4 gene in NM_000441: c.2027T>A, p.L676Q, as well as the SLC26A4 exon 5-6 deletion. These genetic variations pointed to Pendred syndrome (an autosomal recessive disorder that mainly affects the inner ear, thyroid, and kidney) which is a common cause of syndromic deafness. INTERVENTIONS: The patient was treated with potassium supplements and screened for the cause of hypokalemia. OUTCOMES: The patient was discharged after her potassium levels rose to the normal range. LESSONS: Patients with Pendred syndrome may also have certain metabolic abnormalities; thus, more attention should be paid to them during clinical diagnosis.

An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.

Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1-GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.

Dysregulated lncRNA and mRNA may promote the progression of ischemic stroke via immune and inflammatory pathways: results from RNA sequencing and bioinformatics analysis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are widely involved in gene transcription regulation and which act as epigenetic modifiers in many diseases. OBJECTIVE: To determine whether lncRNAs are involved in ischemic stroke (IS), we analyzed the expression profile of lncRNAs and mRNAs in IS. METHODS: RNA sequencing was performed on the blood of three pairs of IS patients and healthy controls. Differential expression analysis was used to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). Based on the co-expression relationships between lncRNA and mRNA, a series of bioinformatics analysis including GO and KEGG enrichment analysis and PPI analysis, were conducted to predict the function of lncRNA. RESULTS: RNA sequencing produced a total of 5 DElncRNAs and 144 DEmRNAs. Influenza A pathway and Herpes simplex infection pathway were the most significant pathways. EP300 and NFKB1 were the most important target proteins, and Human leucocyte antigen (HLA) family were the key genes in IS. CONCLUSIONS: Analysis of this study revealed that dysregulated lncRNAs in IS may lead to IS by affecting the immune and inflammation system.

Identification of MicroRNAs as potential biomarkers for detecting ischemic stroke.

BACKGROUND: Increasing epidemic of ischemic stroke (IS) makes it urgent to understand the pathogenesis and regulatory mechanism, previous studies have described microRNAs (miRNAs) is part of the brain's response to ischemia. OBJECTIVE: The aim of this study was to screen potential biomarkers for the prediction and novel treatment of IS. METHODS: Differentially expressed miRNAs were screened from three newly diagnosed IS patients and three controls by RNA sequencing technology. Furthermore, target prediction databases were then used to analysis the target genes of different expressed miRNAs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database were used to identify the functions and the main biochemical and signal pathways of differentially expressed target genes. RESULTS: Our results revealed that 27 miRNAs were differentially expressed in IS, among which, hsa-miR-659-5p was the most highly increased and was first found to be associated with IS. In addition, KEGG pathway analyses showed that differentially expressed miRNAs were mainly significantly enriched in lysosome pathway, cytokine-cytokine receptor interaction pathway, spliceosome pathway, base excision repair pathway. CONCLUSIONS: miRNAs were involved in IS pathogenesis, and hsa-miR-659-5p, hsa-miR-151a-3p and hsa-miR-29c-5p as the three highest |log2FoldChange| regulation in this study, which may be the biomarkers of IS and need further study.

Identification of Two Subsets of Murine DC1 Dendritic Cells That Differ by Surface Phenotype, Gene Expression, and Function.

Classical dendritic cells (cDCs) in mice have been divided into 2 major subsets based on the expression of nuclear transcription factors: a CD8+Irf8+Batf3 dependent (DC1) subset, and a CD8-Irf4+ (DC2) subset. We found that the CD8+DC1 subset can be further divided into CD8+DC1a and CD8+DC1b subsets by differences in surface receptors, gene expression, and function. Whereas all 3 DC subsets can act alone to induce potent Th1 cytokine responses to class I and II MHC restricted peptides derived from ovalbumin (OVA) by OT-I and OT-II transgenic T cells, only the DC1b subset could effectively present glycolipid antigens to natural killer T (NKT) cells. Vaccination with OVA protein pulsed DC1b and DC2 cells were more effective in reducing the growth of the B16-OVA melanoma as compared to pulsed DC1a cells in wild type mice. In conclusion, the Batf3-/- dependent DC1 cells can be further divided into two subsets with different immune functional profiles in vitro and in vivo.

Long-term follow-up of a case of MEN1 and literature review.

OBJECTIVE: To investigate the diagnosis and treatment of Multiple Endocrine Neoplasia Type 1 (MEN1), improve our understanding of the disease and highlight the importance of life-long follow-up of affected individuals. METHODS: A retrospective analysis was performed on 1 MEN1 patient with long-term follow-up at the First Affiliated Hospital of Anhui Medical University. RESULTS: A 51-year-old woman was diagnosed with MEN1 14 years ago, but exhibited a suspected disease course of at least 20 years. Prior to admission, the patient reported a cough lasting for two months. The patient's thyroid hormone, sex hormone, insulin, cortisol, parathyroid hormone, and ACTH circadian rhythm findings were within normal ranges. The patient exhibited elevated blood calcium levels. Examination led to the detection of thymoma and pancreatic neoplasms, whereas no obvious abnormalities were detected in her parathyroid gland or adrenal gland as determined via computed tomography (CT). Genetic analyses revealed a mutation in the MEN1 gene in this patient. As the patient had no relevant clinical symptoms, she refused surgical treatment, and follow-up was continued. It was learned through follow-up that the patient underwent anterior mediastinal lesion resection and partial rib resection in June 2020 because she re-examined the chest CT showed that the anterior mediastinal mass was significantly larger than that in 2019. Pathology suggested neuroendocrine tumors. The patient is currently recovering well. CONCLUSION: MEN1 is an uncommon condition in clinical settings, and it is important that clinicians be made aware of this disorder so that they can provide patients with appropriate and timely treatments.

Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients.

Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762.

Epidemiological study on severe acute respiratory syndrome coronavirus 2 virus transmission network in northeast China.

ABSTRACT: In this study, corona virus disease 2019 (COVID-19) transmission networks were built to analyze the epidemic situation of COVID-19 in Liaoning and Jilin provinces in early 2020. We explore the characteristics of the spread of COVID-19, and put forward effective recommendations for epidemic prevention and control. We collected demographic characteristics, exposure history, and course of action of COVID-19 cases. We described the demographic and case characteristics of these cases to show the basic characteristics of COVID-19 cases in both provinces. Combined with the spatial analysis of confirmed cases, the distribution law of the number of confirmed cases in different regions was analyzed. We exhibit the relationship among COVID-19 cases with a transmission network. The transmission characteristics of COVID-19 were analyzed through the transmission network. Mainly cases in Liaoning and Jilin provinces were imported cases from other provinces and the vast majority of these cases were related to Hubei province. The number of confirmed cases in different regions was positively correlated with their GDP and population. The main clinical symptoms of the cases were fever. Judge from the transmission network relationship between the 2 provinces, the transmission chain in Liaoning province contains fewer cases than that in Jilin province. The main transmission routes of the local cases in the 2 provinces were the family members, and the infection of the imported cases were mainly occurred in public places. It was estimated that the unidentified asymptomatic infected cases in the 2 provinces account for approximately 7.3% of the total number of infected cases. The length of the transmission chain suggests that the spread of COVID-19 can be effectively controlled with effective prevention measures.

VISTA is an activating receptor in human monocytes.

As indicated by its name, V-domain Ig suppressor of T cell activation (VISTA) is thought to serve primarily as an inhibitory protein that limits immune responses. VISTA antibodies can dampen the effects of several concomitantly elicited activation signals, including TCR and TLR activation, but it is currently unclear if VISTA agonism could singly affect immune cell biology. In this study, we discovered two novel VISTA antibodies and characterized their effects on human peripheral blood mononuclear cells by scRNA/CITE-seq. Both antibodies appeared to agonize VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. We also used pentameric VISTA to identify Syndecan-2 and several heparan sulfate proteoglycan synthesis genes as novel regulators of VISTA interactions with monocytic cells, adding further evidence of bidirectional signaling. Together, our study highlights several novel aspects of VISTA biology that have yet to be uncovered in myeloid cells and serves as a foundation for future research.

Causal associations of waist circumference and waist-to-hip ratio with type II diabetes mellitus: new evidence from Mendelian randomization.

Type II diabetes mellitus (T2DM) is a metabolic disease with high incidence, which has seriously affected human life and health. The associations among waist circumference (WC), waist-to-hip ratio (WHR), and T2DM were discovered in observational studies. However, the causality of these associations still remains unknown. The present study aims to apply two-sample Mendelian randomization (TSMR) using genetic variants as instrumental variables (IVs) to evaluate the causality among WC, WHR, and T2DM. The participants were from three independent studies in genome-wide association studies (GWAS) datasets, which included 127,997 Europeans for WC, 73,137 Europeans for WHR and 659,316 Europeans for T2DM. Furthermore, 16 were associated WC SNPs and eight were associated WHR SNPs as instrument variables were selected for TSMR using P < 5 × 10-8 standard. The pooled odd ratios (ORs) for the assessment of higher WC and WHR on the risk of T2DM for these SNPs were calculated using inverse variance weighted (IVW) method, and validated through extensively complementary analyses. The OR for T2DM per SD (cm) higher WC was 2.623 (95% CI 2.286-3.010, P = 5.000E-43), and the OR for T2DM per SD (cm) higher WHR was 1.751 (95% CI 1.122-2.733, P = 0.014). Consistent results for other methods were obtained. Furthermore, the range of OR fluctuation between WC and T2DM was from 2.623 to 2.986, while that between WHR and T2DM was from 0.990 to 2.931. Overall, these present results provide genetic support that suggests that the use of TSMR, and higher WC and WHR increased the T2DM risk among the European population.

Human Regulatory Dendritic Cells Develop From Monocytes in Response to Signals From Regulatory and Helper T Cells.

Dendritic cells (DCs) are powerful antigen presenting cells, derived from bone marrow progenitors (cDCs) and monocytes (moDCs), that can shape the immune response by priming either proinflammatory or tolerogenic immune effector cells. The cellular mechanisms responsible for the generation of DCs that will prime a proinflammatory or tolerogenic response are poorly understood. Here we describe a novel mechanism by which tolerogenic DCs are formed from monocytes. When human monocytes were cultured with CD4+FoxP3+ natural regulatory T cells (Tregs) and T helper cells (Th) from healthy donor blood, they differentiated into regulatory DCs (DC Reg ), capable of generating induced Tregs from naïve T cells. DC Reg exhibited morphology, surface phenotype, cytokine secretion, and transcriptome that were distinct from other moDCs including those derived from monocytes cultured with Th or with GM-CSF/IL-4, as well as macrophages (MΦ). Direct cell contact between monocytes, Tregs and Th, along with Treg-derived CTLA-4, IL-10 and TGF-ß, was required for the phenotypic differentiation of DC Reg , although only IL-10 was required for imprinting the Treg-inducing capacity of DC Reg . High ratios of Treg:Th, along with monocytes and DC Reg similar in function and phenotype to those induced in vitro, were present in situ in human colorectal cancer specimens. Thus, through the combined actions of Tregs and Th, monocytes differentiate into DCs with regulatory properties, forming a positive feedback loop to reinforce Treg initiated immune regulation. This mechanism may contribute to immune tolerance in tissues such as tumors, which contain an abundance of Tregs, Th and monocytes.