Benralizumab efficacy and safety in severe asthma: A randomized trial in Asia.

BACKGROUND: Benralizumab is indicated as add-on therapy in patients with uncontrolled, severe eosinophilic asthma; it has not yet been evaluated in a large Asian population with asthma in a clinical trial. OBJECTIVE: To evaluate the efficacy and safety of benralizumab in patients with severe asthma in Asia. METHODS: MIRACLE (NCT03186209) was a randomized, Phase 3 study in China, South Korea, and the Philippines. Patients aged 12-75 years with severe asthma receiving medium-to-high-dose inhaled corticosteroid/long-acting ß2-agonists, stratified (2:1) by baseline blood eosinophil count (bEOS) (≥300/µL; <300/µL), were randomized (1:1) to benralizumab 30 mg or placebo. Endpoints included annual asthma exacerbation rate (AAER; primary endpoint), change from baseline at Week 48 in pre-bronchodilator (BD) forced expiratory volume in 1 second (pre-BD FEV1) and total asthma symptom score (TASS). Safety was evaluated ≤ Week 56. RESULTS: Of 695 patients randomized, 473 had baseline bEOS ≥300/µL (benralizumab n = 236; placebo n = 237). In this population, benralizumab significantly reduced AAER by 74% (rate ratio 0.26 [95% CI 0.19, 0.36], p < 0.0001) and significantly improved pre-BD FEV1 (least squares difference [LSD] 0.25 L [95% CI 0.17, 0.34], p < 0.0001) and TASS (LSD -0.25 [-0.45, -0.05], p = 0.0126) versus placebo. In patients with baseline bEOS <300/µL, there were numerical improvements in AAER, pre-BD FEV1, and TASS with benralizumab versus placebo. The frequency of adverse events was similar for benralizumab (76%) and placebo (80%) in the overall population. CONCLUSIONS: MIRACLE data reinforces the efficacy and safety of benralizumab for severe eosinophilic asthma in an Asian population, consistent with the global Phase 3 results.

A pilot study on Paxlovid therapy for hemodialysis patients with severe acute respiratory syndrome coronavirus 2 infections.

We aimed to investigate the safety and efficacy of nirmatrelvir/ritonavir (Paxlovid) therapy for hemodialysis-dependent patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Thirteen hemodialysis patients infected with the Omicron variant of SARS-CoV-2 from April 3 to May 30, 2022, were recruited. Laboratory parameters and chest CT (computed tomography) imaging were analyzed. The treatment group included six patients who received 150 mg/100 mg of Paxlovid orally once daily for 5 days, whereas the control group included seven patients who received basic treatment. No serious adverse reactions or safety events were recorded. Four control patients progressed to moderate disease, and none in the treatment group showed progression of chest CT findings (P < 0.05). Paxlovid therapy tended toward early viral clearance and low viral load on Day 8. Moreover, 83.3% of the patients in the treatment group and 57.1% of the patients in the control group turned negative within 22 days. In the Paxlovid treatment group, we found significantly increased levels of lymphocytes (P=0.03) and eosinophils (P=0.02) and decreased levels of D-dimer on Day 8 compared with those on Day 1. Paxlovid therapy showed a potential therapeutic effect with good tolerance in hemodialysis patients. The optimal dose and effectiveness evaluation must be further investigated in a largeer cohort.

Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome.

BACKGROUND: Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN, in DS-associated transcriptional regulation and phenotypic modulation. METHODS: We performed assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq) to explore the difference of chromatin accessibility between DS derived amniocytes (DSACs) and controls. We then combined the annotated differentially expressed genes (DEGs) and enriched transcriptional factors (TFs) targeting the promoter region from ATAC-seq results with the DEGs in RNA-seq, to identify key genes and pathways involved in alterations of biological processes and pathways in DS. RESULTS: Binding motif analysis showed a significant increase in chromatin accessibility of genes related to neural cell function, among others, in DSACs, which is primarily regulated by members of the activator protein-1 (AP-1) transcriptional factor family. Further studies indicated that MX Dynamin Like GTPase 1 (MX1), defined as one of the key effector genes of I-IFN, is a critical upstream regulator. Its overexpression induced expression of AP-1 TFs and mediated inflammatory response, thus leading to decreased cellular viability of DS cells. Moreover, treatment with specific AP-1 inhibitor T-5224 improved DS-associated phenotypes in DSACs. CONCLUSIONS: This study demonstrates that MX1-mediated AP-1 activation is partially responsible for cellular dysfunction of DS. T-5224 effectively ameliorated DS-associated phenotypes in DSACs, suggesting it as a potential treatment option for DS patients.

Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary-lung axis.

The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.

Three-way contact analysis characterizes the higher order organization of the Tcra locus.

The generation of highly diverse antigen receptors in T and B lymphocytes relies on V(D)J recombination. The enhancer Eα has been implicated in regulating the accessibility of Vα and Jα genes through long-range interactions during rearrangements of the T-cell antigen receptor gene Tcra. However, direct evidence for Eα physically mediating the interaction of Vα and Jα genes is still lacking. In this study, we utilized the 3C-HTGTS assay, a chromatin interaction technique based on 3C, to analyze the higher order chromatin structure of the Tcra locus. Our analysis revealed the presence of sufficient information in the 3C-HTGTS data to detect multiway contacts. Three-way contact analysis of the Tcra locus demonstrated the co-occurrence of the proximal Jα genes, Vα genes and Eα in CD4+CD8+ double-positive thymocytes. Notably, the INT2-TEAp loop emerged as a prominent structure likely to be responsible for bringing the proximal Jα genes and the Vα genes into proximity. Moreover, the enhancer Eα utilizes this loop to establish physical proximity with the proximal Vα gene region. This study provides insights into the higher order chromatin structure of the Tcra locus, shedding light on the spatial organization of chromatin and its impact on V(D)J recombination.

Effective omalizumab treatment influenced eosinophil function in severe allergic asthmatics.

Background: Omalizumab is an effective anti-immunoglobulin E (IgE) treatment for allergic asthma. Eosinophil plays a critical role in the pathogenesis of allergic airway inflammation. This study aimed to explore the influence of effective omalizumab treatment on circulating eosinophils. Methods: Allergic asthmatics enrolled in the study were treated with omalizumab for at least 16 weeks and exhibited a good or excellent response according to the global evaluation of treatment effectiveness (GETE) assessed by each patient and specialist physician. For eosinophil functional evaluation, peripheral blood eosinophils were separated; and examined the expression of human leukocyte antigen (HLA)-DR and co-stimulatory molecules cluster of differentiation (CD) 80, CD86 and CD40 by Flow Cytometry and serum were to measure the concentration of eotaxin-1 before and after 16 weeks of omalizumab treatment. Results: Totally 32 allergic asthma patients who responded positively to omalizumab treatment were included. Omalizumab responders showed a significant decline in the expression of co-stimulatory molecules CD40, CD80, and CD86 on peripheral eosinophils and in serum eotaxin-1 concentration after treatment. Negative correlations (r=-0.61, P=0.048) were observed between the change in CD80+ eosinophils and the change in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC)% predicted and maximal expiratory flow (MEF) 25% after omalizumab treatment. Omalizumab improved FEV1/FVC% predicted (3.88, P=0.033), fractional exhaled nitric oxide (FeNO, -22.24, P=0.028), asthma control test (ACT, 4.22, P<0.001), mini asthma quality of life questionnaire (mini-AQLQ, -14.44, P=0.019), Leicester cough questionnaire (LCQ, 3.03, P=0.009) and visual analogue scale (VAS) for allergic symptoms (-13.00, P=0.001) in patients with severe allergic asthma statistically; reduced mini rhino-conjunctivitis quality of life questionnaire (mini-RQLQ, -8.50, P=0.047), and self-rating anxiety scale (SAS, -5.08, P=0.040) in allergic asthmatics with concomitant allergic rhinitis (AR) or anxiety, respectively. Conclusions: Our findings show a unique role of omalizumab in reducing co-stimulatory molecules expression on eosinophil and serum eotaxin-1 levels in severe allergic asthmatics accompanied by improvement of multiple clinical parameters of allergic diseases.

Prevention of exacerbation in patients with moderate-to-very severe COPD with the intent to modulate respiratory microbiome: a pilot prospective, multi-center, randomized controlled trial.

Introduction: Considering the role of bacteria in the onset of acute exacerbation of COPD (AECOPD), we hypothesized that the use of influenza-Streptococcus pneumoniae vaccination, oral probiotics or inhaled amikacin could prevent AECOPD. Methods: In this pilot prospective, muti-central, randomized trial, moderate-to-very severe COPD subjects with a history of moderate-to-severe exacerbations in the previous year were enrolled and assigned in a ratio of 1:1:1:1 into 4 groups. All participants were managed based on the conventional treatment recommended by GOLD 2019 report for 3 months, with three groups receiving additional treatment of inhaled amikacin (0.4 g twice daily, 5-7 days monthly for 3 months), oral probiotic Lactobacillus rhamnosus GG (1 tablet daily for 3 months), or influenza-S. pneumoniae vaccination. The primary endpoint was time to the next onset of moderate-to-severe AECOPD from enrollment. Secondary endpoints included CAT score, mMRC score, adverse events, and survival in 12 months. Results: Among all 112 analyzed subjects (101 males, 96 smokers or ex-smokers, mean ± SD age 67.19 ± 7.39 years, FEV1 41.06 ± 16.09% predicted), those who were given dual vaccination (239.7 vs. 198.2 days, p = 0.044, 95%CI [0.85, 82.13]) and oral probiotics (248.8 vs. 198.2 days, p = 0.017, 95%CI [7.49, 93.59]) had significantly delayed onset of next moderate-to-severe AECOPD than those received conventional treatment only. For subjects with high symptom burden, the exacerbations were significantly delayed in inhaled amikacin group as compared to the conventional treatment group (237.3 vs. 179.1 days, p = 0.009, 95%CI [12.40,104.04]). The three interventions seemed to be safe and well tolerated for patient with stable COPD. Conclusion: The influenza-S. pneumoniae vaccine and long-term oral probiotic LGG can significantly delay the next moderate-to-severe AECOPD. Periodically amikacin inhalation seems to work in symptomatic patients. The findings in the current study warrants validation in future studies with microbiome investigation.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT03449459.

Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers.

CD4+ and CD8+ double-positive (DP) thymocytes play a crucial role in T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRß. DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, regulatory T cells, or invariant nature kill T cells (iNKT) in response to TCR signaling. Chromatin organizer SATB1 is highly expressed in DP cells and is essential in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing shows that Satb1 deletion changes the cell identity of DP thymocytes and down-regulates genes specifically and highly expressed in DP cells. Super-enhancers regulate the expressions of DP-specific genes, and our Hi-C data show that SATB1 deficiency in thymocytes reduces super-enhancer activity by specifically decreasing interactions among super-enhancers and between super-enhancers and promoters. Our results reveal that SATB1 plays a critical role in thymocyte development to promote the establishment of DP cell identity by globally regulating super-enhancers of DP cells at the chromatin architectural level.

Automated interpretation of the pulmonary function test by a portable spirometer in Chinese adults.

INTRODUCTION: A portable spirometer is a promising alternative to a traditional pulmonary function test (PFT) spirometer for respiratory function evaluation. OBJECTIVES: This study aimed to investigate the accuracy of automated interpretation of the PFT measured by a portable Yue Cloud spirometer in Chinese adults. METHODS: The PFT was performed to evaluate subjects prospectively enrolled at Ruijin Hospital (n = 220). A Yue Cloud spirometer and a conventional Jaeger MasterScreen device were applied to each patient with a 20-min quiescent period between each measurement. Pulmonary function parameters, including forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF), maximal expiratory flow at 25%, 50%, and 75% of the FVC (MEF25, MEF50, and MEF75, respectively), and maximal mid-expiratory flow (MMEF), were compared by correlation analyses and Bland-Altman methods. The Yue Cloud spirometer automatically interpreted the PFT results, and a conventional strategy was performed to interpret the PFT results obtained by the Jaeger machine. Concordance of the categorization of pulmonary dysfunction, small airway dysfunction, and severity was analyzed by the kappa (κ) statistic. RESULTS: Significantly similar correlations of all variables measured with the two spirometers were observed (all p < 0.001). No significant bias was observed in any of the measured spirometer variables. A satisfactory concordance of pulmonary function and severity classification was observed between the automated interpretation results obtained with the Yue Cloud spirometer vs. a conventional spirometer interpretation strategy (all κ > 0.80). CONCLUSION: The portable Yue Cloud spirometer not only yields reliable measurements of pulmonary function but also can automatically interpret the PFT results.

Role of IL-25 on Eosinophils in the Initiation of Th2 Responses in Allergic Asthma.

Background: Eosinophils act as a secondary antigen-presenting cell (APC) to stimulate Th cell responses against antigens. IL-25 plays a significant role in eosinophil activation in allergic asthma. The role of IL-25 on the classic APC functions of dendritic cells has been elucidated. However, whether IL-25 facilitates eosinophils for antigen presentation is unknown. Objective: To elucidate the role of IL-25 on eosinophils antigen presenting function during allergic asthma and its related mechanism. Methods: Eosinophils from allergic asthma subjects were cultured with IL-25 and HDM to identify the co-stimulator molecules expression. Co-cultures of patient eosinophils and autologous naïve CD4+ T cells in the same culture system were to explore whether eosinophils had the capacity to promote Th cell differentiation in response to IL-25 engagement. In asthma mouse model, IL-25-/- mice were exposed to HDM to investigate the effect of IL-25 on eosinophils during the sensitization phase. The impact of IL-25 on the capacity for eosinophils taking up antigens was evaluated. Mouse bone marrow derived eosinophils (BmEOS) were co-cultured with naïve CD4+T cells sorted from spleens under HDM and IL-25 stimulation to identify T cell differentiation. Results: IL-25 upregulated HLA-DR, PD-L1, and OX-40L expression on eosinophils from allergic asthma patients. IL-25 and HDM co-sensitized eosinophils promoted Th2 differentiation. In mouse model, IL-25-/- mice experienced restrained allergic pulmonary inflammation and reduced eosinophils recruitment and antigen uptake capacity during the early sensitization phase. In vitro, IL-25 promoted antigen uptake by eosinophils. In BmEOS and naïve CD4+T cells co-culture, IL-25 accreted the proportion of CD4+Th2 cells, which was absent in CD4+T cells culture alone. Conclusion: Our data identify a novel role of IL-25 in enhancing eosinophils antigen uptake and co-stimulator molecules expression to induce Th2 priming in the context of allergic inflammation.

Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation.

BACKGROUND: Organisms have orchestrated coagulation and immune systems. Although a link between inflammation and haemostasis has been reported in asthma, the interaction mechanism has not been completely elucidated. Here, we investigated the direct link between the mammalian immune and coagulation systems. METHODS: Mice were administered protease or antigens intranasally to induce airway inflammation with or without thrombin inhibitors treatment. The effects of thrombin and its inhibitors on interleukin (IL)-33 were investigated both in vivo and in vitro. Peripheral blood mononuclear cells (PBMCs) and plasma from asthma patients are collected to verify the correlation between thrombin and group 2 innate lymphocytes (ILC2s). RESULTS: Low-molecular-weight heparin (LMWH, an indirect inhibitor of thrombin) restrained both papain- and fungus-induced type 2 immune responses in mice by inhibiting IL-33 cleavage. Upon examining the potential thrombin protease consensus sites, we found that IL-33 was directly cleaved by thrombin at specific amino acids (R48 and R106) to generate a mature form of IL-33 with potent biological activity. In addition, we found that bivalirudin TFA (a direct inhibitor of thrombin) inhibited a variety of type 2 inflammatory responses, such as those in house dust mite (HDM)- and ovalbumin (OVA)-mediated pulmonary inflammation models. We found that plasma thrombin-antithrombin complex (TATc) levels in asthma patients were positively associated with the number and function of IL-33-responder group 2 innate lymphocytes (ILC2s) among peripheral blood mononuclear cells (PBMCs) from asthma patients. CONCLUSION: The data suggested that thrombin inhibitors administration could be effective in treating lung inflammation by regulating ILC2s via IL-33 maturation, indicating that targeting thrombin is a potential way to treat allergic diseases.

Diffusing capacity in chronic obstructive pulmonary disease assessment: A meta-analysis.

To achieve a multidimensional evaluation of chronic obstructive pulmonary disease (COPD) patients, the spirometry measures are supplemented by assessment of symptoms, risk of exacerbations, and CT imaging. However, the measurement of diffusing capacity of the lung for carbon monoxide (DLCO) is not included in most common used models of COPD assessment. Here, we conducted a meta-analysis to evaluate the role of DLCO in COPD assessment.The studies were identified by searching the terms "diffusing capacity" OR "diffusing capacity for carbon monoxide" or "DLCO" AND "COPD" AND "assessment" in Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, and Web of Science databases. The mean difference of DLCO % predict was assessed in COPD patient with different severity (according to GOLD stage and GOLD group), between COPD patients with or without with frequent exacerbation, between survivors and non-survivors, between emphysema dominant and non-emphysema dominant COPD patients, and between COPD patients with or without pulmonary hypertension.43 studies were included in the meta-analysis. DLCO % predicted was significantly lower in COPD patients with more severe airflow limitation (stage II/IV), more symptoms (group B/D), and high exacerbation risk (group C/D). Lower DLCO % predicted was also found in exacerbation patients and non-survivors. Low DLCO % predicted was related to emphysema dominant phenotype, and COPD patients with PH.The current meta-analysis suggested that DLCO % predicted might be an important measurement for COPD patients in terms of severity, exacerbation risk, mortality, emphysema domination, and presence of pulmonary hypertension. As diffusion capacity reflects pulmonary ventilation and perfusion at the same time, the predictive value of DLCO or DLCO combined with other criteria worth further exploration.

Exosomal miR-1275 Secreted by Prostate Cancer Cells Modulates Osteoblast Proliferation and Activity by Targeting the SIRT2/RUNX2 Cascade.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the second leading cause of cancer mortality among men worldwide. Modulation of osteoblast activity is involved in PCa metastasis, and miR-1275 is also reported to regulate PCa metastasis; however, the association between cancer-derived exosomal miR-1275 and osteoblast activity is unclear. Here, we isolated exosomes from PC3-derived conditioned medium by ultracentrifugation. We found that miR-1275 could be transferred from PCa cells to osteoblasts via exosomes. Exosomal miR-1275 significantly accelerated the proliferation of osteoblasts and the expression levels of osteoblast-specific genes, such as osteocalcin (OCN), type I collagen (COL-1), and osteopontin (OPN). Moreover, exosomal miR-1275 increased the expression of RUNX2, a master modulator of osteoblast activity, by down-regulation of SIRT2, which in turn influenced the growth and activity of osteoblasts. Our findings indicate that PCa-derived exosomal miR-1275 promotes the proliferation and activity of osteoblasts via modulation of SIRT2/Runx2 signaling.

Lnc-STYK1-2 regulates bladder cancer cell proliferation, migration, and invasion by targeting miR-146b-5p expression and AKT/STAT3/NF-kB signaling.

BACKGROUND: Epigenetic modulation by noncoding RNAs substantially contributes to human cancer development, but noncoding RNAs involvement in bladder cancer remains poorly understood. This study investigated the role of long noncoding RNA (lncRNA) lnc-STYK1-2 in tumorigenesis in cancerous bladder cells. METHODS: Differential lncRNA and mRNA profiles were characterized by high-throughput RNA sequencing combined with validation via quantitative PCR. Bladder cancer cell proliferation was assessed through MTS, and bladder cancer cell migration and invasion were assessed through a Transwell system. The in vivo tumorigenesis of bladder cancer cells was evaluated using the cancer cell line-based xenograft model. The dual-luciferase reporter assay verified the association of miR-146b-5p with lnc-STYK1-2 and the target gene. Protein abundances and phosphorylation were detected by Western blotting. RESULTS: Alterations in lncRNA profiles, including decreased lnc-STYK1-2 expression, were detected in bladder cancer tissues compared with adjacent noncancerous tissues. lnc-STYK1-2 silencing effectively promoted proliferation, migration, and invasion in two bladder cancer cell lines, 5637 and T24, and their tumorigenesis in nude mice. lnc-STYK1-2 siRNA promoted miR-146b-5p and reduced ITGA2 expression in bladder cancer cells. Moreover, miR-146b-5p suppressed ITGA2 expression in bladder cancer cells through direct association. Also, lnc-STYK1-2 directly associated with miR-146b-5p. Finally, miR-146b-5p inhibitors abrogated the alterations in bladder cell functions, ITGA2 expression, and phosphorylation of AKT, STAT3, and P65 proteins in 5637 and T24 cells induced by lnc-STYK1-2 silencing. CONCLUSION: lnc-STYK1-2 inhibited bladder cancer cell proliferation, migration, and tumorigenesis by targeting miR-146b-5p to regulate ITGA2 expression and AKT/STAT3/NF-kB signaling.

Phase separation of Epstein-Barr virus EBNA2 protein reorganizes chromatin topology for epigenetic regulation.

Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases. It was reported that EBNA2 regulates gene expression by reorganizing chromatin and manipulating epigenetics. Recent studies showed that liquid-liquid phase separation plays an essential role in epigenetic and transcriptional regulation. Here we show that EBNA2 reorganized chromatin topology to form accessible chromatin domains (ACDs) of the host genome by phase separation. The N-terminal region of EBNA2, which is necessary for phase separation, is sufficient to induce ACDs. The C-terminal domain of EBNA2 promotes the acetylation of accessible chromatin regions by recruiting histone acetylase p300 to ACDs. According to these observations, we proposed a model of EBNA2 reorganizing chromatin topology for its acetylation through phase separation to explain the mechanism of EBNA2 hijacking the host genome by controlling its epigenetics.

Absolute Neutrophil Count in the Peripheral Blood Predicts Prognosis in Lung Cancer Patients Treated with Anlotinib.

PURPOSE: Anlotinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis and cell proliferation. It is widely used as a third-line therapy for lung cancer. However, reliable prognostic biomarkers for predicting the efficacy of anlotinib are lacking. We conducted a retrospective study to investigate the prognostic value of serological inflammatory biomarkers in anlotinib treatment. PATIENTS AND METHODS: Patients with advanced lung cancer treated with anlotinib monotherapy were enrolled. Cox regression was conducted to analyze the significant factors related to progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was compared based on the median cut-off value of the significant inflammation index. Meanwhile, we created survival curves to compare the two groups and performed receiver operating characteristic curve analysis to assess the predictive ability of the inflammation index. RESULTS: Among a total of 71 patients, the median PFS was 5.5 months and the median OS was 9.5 months. The ORR and disease control rate were 16.9% and 84.5%, respectively. According to univariate and multivariate analyses, absolute neutrophil count (ANC) was the only indicator associated with both PFS (hazard ratio [HR] =1.095, 95% confidence interval [CI] 1.030-1.163, P=0.003) and OS (HR=1.057, 95% CI 1.003-1.113, P=0.037). In the group with ANC ≥4.58, the ORR was relatively lower (8.1% vs 26.5%, P=0.057), but not statistically significant; PFS and OS were relatively shorter (median PFS 5.0 [95% CI 4.4-9.6] vs 7.0 months [95% CI 4.4-5.7], P=0.024 and median OS 7.3 [95% CI 4.7-10.0] vs 17.6 months [95% CI 12.3-22.9], P < 0.001). ANC had a relatively high discriminatory ability to predict 10-month survival, with an area under the curve of 0.729, sensitivity of 82.5%, and specificity of 67.7%. CONCLUSION: Elevated pre-treatment ANC was associated with a poor prognosis. Patients with lower peripheral blood levels of ANC might benefit from anlotinib.

Insights into gut microbiome and its functional pathways in asthma patients through high-throughput sequencing.

Aim: To describe gut microbiome and functional genes of asthma. Patients & methods: Fecal microbiome in controls, asthma patients with and without inhaled corticosteroid (ICS) treatment was determined. Results: Patients with ICS had lower abundance of Alloprevotella, unclassified_f_Lachnospiraceae and Lachnospiraceae_NC2004_group, higher abundance of Sutterella and Sphingomonas than patients without ICS. In all the asthma patients, there are microbial differences in aging distribution, different gender and different asthmatic phenotypes. Asthma patients without ICS treatment had more microbial genes related to geraniol degradation, ethylbenzene degradation and bladder cancer than controls; 15 pathways showed significant difference between asthma patients with and without ICS treatment. Conclusion: We found gut dysbiosis in asthma and different functional pathways associated with both asthma and ICS.

METTL3-Mediated N6-Methyladenosine Modification Is Involved in the Dysregulation of NRIP1 Expression in Down Syndrome.

Down syndrome (DS) is a common genetic condition in which a person is born with an extra copy of chromosome 21. Intellectual disability is the most common characteristic of DS. N6-methyladenosine (m6A) is a common RNA modification that is implicated in many biological processes. It is highly enriched within the brain and plays an essential role in human brain development. However, the mRNA m6A modification in the fetal brain of DS has not been explored. Here, we report m6A mRNA profiles and mRNA expression profiles of fetal brain cortex tissue from DSs and controls. We observed that the m6A modification in DS brain tissues was reduced genome-wide, which may be due to decreased the m6A methyltransferase like 3 (METTL3) protein expression. The nuclear receptor-interacting protein 1 (NRIP1/RIP140) is coded by a highly conserved chromosome 21 (Hsa21) gene. Overexpression of NRIP1 is associated with mitochondrial dysfunction in DS. The NRIP1 mRNA increased in fetal brain tissues of DS, whereas the m6A modification of the NRIP1 mRNA significantly decreased. METTL3 knockdown reduced the m6A modification of NRIP1 mRNA and increased its expression, and an increase in NRIP1 m6A modification and a decrease in its expression were observed in METTL3-overexpressed cells. The Luciferase reporter assay confirmed that METTL3 regulates NRIP1 expression in an m6A-dependent manner. The decay rate of NRIP1 mRNA was significantly reduced in METTL3-knockdown cells but increased in METTL3-overexpressed cells. We proposed that the m6A modification of NRIP1 mRNA in DS fetal brain tissue is reduced, reducing its transcript degradation rate, resulting in abnormally increased expression of NRIP1, at least partially, in the DS brain. It provides a new mechanism for the molecular pathology of DS and leads to a new insight that may become therapeutically relevant.