Preventive and Therapeutic Effects of Crocetin in Rats with Heart Failure.

Gardenia is both a food and medicine plant. It is widely used for cardiovascular protection, and its main bioactive ingredient is crocetin. This study aims to observe the therapeutic effects of crocetin on chronic heart failure in rats induced by various etiologies. It further compares the efficacy differences between preventative and treatment administration, varying dosages, and treatment durations, to provide improved guidance for medication in heart failure rats and determine which categories of chronic heart failure rats might benefit most from crocetin. Chronic heart failure models induced by abdominal aorta constriction, renal hypertension, and coronary artery ligation were constructed. By examining cardiac function, blood biochemistry, and histopathology, the study assessed the preventive and therapeutic effects of crocetin on load-induced and myocardial ischemia-induced heart failure. The results showed that in all three models, both treatment and preventative administration of crocetin significantly improved chronic heart failure in rats, especially in preventative administration. The results indicate crocetin may be beneficial for improving symptoms and functional capacity in rats with heart failure. Furthermore, long-term administration was more effective than short-term administration across all three rat models, with therapeutic onset observed over 6 weeks.

Identifying the pathophysiological traits of obstructive sleep apnea during dexmedetomidine sedation.

Dexmedetomidine (DEX) has been described as a safe sedative in clinical practice, but its effects on the pathophysiological traits of obstructive sleep apnea (OSA) are unclear. We estimated the effects of DEX sedation on the four key pathophysiological traits of OSA (pharyngeal collapsibility, dilator muscle function, arousal threshold, and loop gain) in adult patients with OSA by conducting a secondary analysis of a prospective diagnostic trial. Pathophysiological traits estimated from polysomnography and the respiratory parameters under natural sleep and DEX-induced sleep were compared. Bivariate and multivariate linear regression analyses were used to estimate the relationship between pathophysiological traits and OSA severity for both sleep states. Adult patients with OSA had a significantly higher pharyngeal collapsibility (Vpassive : 44.9 [15.7 to 53.8] vs. 53.3 [34.2 to 66.3] %eupnea , p < 0.001), arousal threshold (178.5 [132.5 to 234.6] vs. 140.5 [123.2 to 192.3] %eupnea , p < 0.001), and loop gain (LG1: 0.74 ± 0.25 vs. 0.60 ± 0.17, p < 0.001; LGn: 0.52 ± 0.12 vs. 0.44 ± 0.08, p < 0.001) during DEX-induced sleep compared with natural sleep. There was no significant difference in dilator muscle function or PSG respiratory parameters between natural versus DEX-induced sleep states. Bivariate regression analysis showed varying degrees of correlation between OSA traits and severity. Multiple regression analysis indicated that collapsibility was the strongest predictor of the apnea-hypopnea index for both sleep states. Dexmedetomidine sedation in patients with OSA increased the pharyngeal collapsibility without impairing dilator muscle function, while elevating arousal threshold and increasing loop gain.

Upfront Surgery Versus Definitive Radiotherapy: Competing Risk Analyses in Early Stage Oropharyngeal Cancer.

OBJECTIVE: To compare the survival outcomes of early-stage oropharyngeal cancer (OPC) patients treated with upfront surgery versus definitive radiotherapy (RT). STUDY DESIGN: Retrospective observational study. SETTING: Publicly available database. METHODS: A total of 1877 patients with T1-2N0-1M0 OPC were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts. RESULTS: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 2.29; 95% confidence interval [CI], 1.42-3.68; p = .001) and noncancer mortality (adjusted SHR, 2.74; 95% CI, 1.50-5.02; p = .001). In the HPV-positive cohort, definitive RT and upfront surgery could achieve similar cancer-specific and noncancer survival outcomes. CONCLUSION: Upfront surgery is associated with lower cancer-specific and noncancer mortality in HPV-negative early-stage OPC patients. However, in the setting of HPV-positive early-stage OPC with better prognosis, the 2 treatment modalities have similar efficacy in terms of cancer-specific and noncancer survival outcomes. In the future, carefully designed prospective clinical trials are needed to confirm our findings.

CD69 and SBK1 as potential predictors of responses to PD-1/PD-L1 blockade cancer immunotherapy in lung cancer and melanoma.

Background: PD-1/PD-L1 blockade is a promising immunotherapeutic strategy with the potential to improve the outcomes of various cancers. However, there is a critically unmet need for effective biomarkers of response to PD-1/PD-L1 blockade. Materials and methods: Potential biomarkers of response to PD-1/PD-L1 blockade were obtained from the Cancer Treatment Response gene signature Database (CTR-DB). A comprehensive pan-cancer analysis was done on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Correlations between gene expression and infiltration by immune cells were assessed using TIMER, EPIC, MCPcounter, xCell, CIBERSORT, and quanTIseq. Immunophenoscore (IPS) was used to assess the potential application of the biomarkers to all TCGA tumors. Results: Analysis of CTR-DB data identified CD69 and SBK1 as potential biomarkers of response to PD-1/PD-L1 blockade. Correlation analysis revealed that in various TCGA cancer datasets, CD69 expression level correlated positively with most immune checkpoints and tumor-infiltrating immune cells, while SBK1 expression level correlated negatively with infiltrating immune cells. IPS analysis demonstrated the ability of CD69 and SBK1 to predict PD-1/PD-L1 blockade responses in various cancers. Conclusion: CD69 and SBK1 are potential predictors of response to cancer immunotherapy using PD-1/PD-L1 blockade. These biomarkers may guide treatment decisions, leading to precise treatment and minimizing the waste of medical resources.

Effect of Bilateral Vocal Fold Microsuturing on Voice Quality Improvement in Patients With Anterior Glottic Webs: A Retrospective Observational Study.

PURPOSE: This study was performed to introduce a modified procedure involving a combination of bilateral vocal fold mucosal flaps and microsurgical sutures for the management of anterior glottic webs and to study its efficacy in decreasing the recurrence rate and improving voice quality. METHODS: We retrospectively reviewed 102 patients with anterior glottic webs who underwent surgical treatment by a carbon dioxide laser incision with or without microsurgical suturing in our hospital from May 2014 to April 2021. We focused on the reoperation rate and the voice outcomes based on the 30-item Voice Handicap Index. RESULTS: This study included 102 patients with anterior glottic webs, which were caused by papilloma excision and endoscopic laryngocarcinoma resection in 97 (95.1%) of the 102 patients; less common causes were infection and traumatic injury. All incisions were performed along the midline with a carbon dioxide laser under microscopy and a self-retaining laryngoscope; 37 (36.3%) patients underwent microsurgical suturing and 65 (63.7%) patients did not. The microsuture group had a lower reoperation rate (χ2= 7.069, P = 0.0078) and higher voice quality (t = 2.054, P = 0.0462) than the non-microsuture group. CONCLUSIONS: We introduced a modified procedure that can both decrease the recurrence rate and improve the voice quality in patients with anterior glottic webs. Hence, this combination therapy involving bilateral vocal fold mucosal flaps and microsurgical sutures is worthy of clinical application and promotion.

Exposure-Response Analysis and Mechanism of Ginkgolide B's Neuroprotective Effect in Acute Cerebral Ischemia/Reperfusion Stage in Rat.

Ginkgolide B (GKB) is a well-established neuroprotectant for acute ischemia stroke. However, its cerebral exposure and real-time response remain elusive in acute ischemia/reperfusion stage, and it hinders its usage in therapeutic window of ischemia stroke. Therefore, we investigate the exposure-response relationship of GKB (10 mg/kg, intravenously (i.v.)) as well as its neuroprotective mechanism in acute ischemia/reperfusion rats. Cerebral and plasma exposure of GKB is comparatively explored in both of normal rats and acute ischemia/reperfusion rats. Correspondingly, neurological function and brain jury indexes were assessed at each time point, and superoxide dismutase (SOD), malondialdehyde (MDA), platelet activator factor (PAF) and thromboxane A2 (TXA2) are indexed as pharmacological response to GKB. Exposure-response relationships are analyzed by using linear regression. Additionally, cerebral expressions of proteins in PAF-regulated pathways are tested at each time point. Results show cerebral and plasma concentrations of GKB are much higher in acute ischemia/reperfusion rats than those in normal rats. Cerebral infarction, neurological function (NF) score, abnormal PAF and excessive MDA are significantly alleviated in 24 h after GKB injection, and PAF is reduced in exposure-response manner with significant concentration-response relationship (R2 = 0.9123). Regarding downstream proteins in intracellular PAF-regulated pathway, GKB progressively inhibits Bax, Caspase-3, p-p65 and p-IKK, while gradually restoring LC3B, p62 and p-mammalian target of rapamycin (mTOR) to the basic level within 24 h. Conclusively, GKB exhibits greater cerebral exposure in acute ischemia/reperfusion rats and neuroprotective effect through reducing PAF in exposure-response manner and mediating PAF-regulated intracellular signaling pathways. Our finding highlights clinical implications of GKB in therapeutic time window of ischemic stroke.

Ferroptosis Driver SOCS1 and Suppressor FTH1 Independently Correlate With M1 and M2 Macrophage Infiltration in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: To investigate the role of ferroptosis, an iron-dependent form of non-apoptotic cell death, in the head and neck squamous cell carcinoma (HNSCC) immune microenvironment. MATERIALS AND METHODS: A list of ferroptosis-related genes was obtained from the FerrDb database. Gene expression data were acquired from the cancer genome atlas (TCGA) and analyzed using the R language. Protein-protein interaction analysis was conducted using STRING and GeneMANIA. The correlations between gene expression levels and a patient's survival were analyzed using GEPIA, the Kaplan-Meier estimate, and a multivariate Cox proportional hazards model. The expression results were verified using Oncomine and Human Protein Atlas data. We used the TIMER, GEPIA2, GEPIA2021, and TIMER2 databases to investigate the relationships between gene expression and infiltrating immune cells. RESULTS: Analysis of differentially expressed genes (DEGs) identified nine each ferroptosis drivers and ferroptosis suppressors, among which four genes correlated with survival as follows: two drivers (SOCS1, CDKN2A) associated with better survival and two suppressors (FTH1, CAV1) associated with poorer survival. Multivariate Cox survival analysis identified SOCS1 and FTH1 as independent prognostic factors for HNSCC, and their higher expression levels were verified using Oncomine and HPA data. The results acquired using TIMER, GEPIA2, GEPIA2021, and TIMER2 data revealed that the driver SOCS1 and the suppressor FTH1 independently correlated with M1 and M2 macrophage infiltration. CONCLUSIONS: The ferroptosis driver SOCS1 and suppressor FTH1 are independent prognostic factors and that correlate with M1 and M2 macrophage infiltration in HNSCC. Targeting ferroptosis-immunomodulation may serve as a strategy to enhance the activity of immunotherapy.

IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer.

Regulatory T cells (Tregs) are immunosuppressive cells involved in antitumor immunity. However, the regulation of Treg generation by inflammation in the tumor microenvironment has not been carefully investigated. Here, we demonstrated that IL-21-polarized inflammation was enriched in the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC) and that IL-21 could promote PD-L1-induced Treg generation in a PD-1-dependent manner. Moreover, generated Tregs showed a greater ability to suppress the proliferation of tumor-associated antigen (TAA)-specific T cells than naturally occurring Tregs. Importantly, an anti-PD-1 antibody could inhibit only Treg expansion induced by clinical tumor explants with high expression of IL-21/PD-L1. In addition, neutralizing IL-21 could enhance the anti-PD-1 antibody-mediated inhibitory effect on Treg expansion. Furthermore, simultaneous high expression of IL-21 and PD-L1 was associated with more Treg infiltrates and predicted reduced overall and disease-free survival in patients with HNSCC. These findings indicate that IL-21 in the tumor microenvironment may promote PD-L1-induced, Treg-mediated immune escape in a PD-1-dependent manner and that an IL-21 neutralization strategy may enhance PD-1 blockade-based antitumor immunotherapy by targeting Treg-mediated immune evasion in patients with high expression of IL-21 and PD-L1.

Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors.

Ferritin is the most important iron storage form and is known to influence tumor immunity. We previously showed that expression of ferritin light chain (FTL) and ferritin heavy chain (FTH1) subunits is increased in head and neck squamous cell carcinoma (HNSC). Here, we analyzed solid tumor datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases to investigate correlations between FTL and FTH1 expressions and (i) patient survival, using univariate, multivariate, Kaplan-Meier and Receiver Operator Characteristic analysis; and (ii) tumor-infiltrating immune cell subsets, using the bioinformatics tools Estimation of Stomal and Immune cells in Malignant Tumor tissues, Microenvironment Cell Population-counter, Tumor Immune Estimation Resource, and Tumor Immunology Miner. We found that FTL and FTH1 are upregulated and downregulated, respectively, in most of the human cancers analyzed. Tumor FTL levels were associated with prognosis in patients with lower grade glioma (LGG), whereas FTH1 levels were associated with prognosis in patients with liver hepatocellular carcinoma, HNSC, LGG, and kidney renal papillary cell carcinoma. In many cancers, FTL and FTH1 levels was significantly positively correlated with tumor infiltration by tumor-associated macrophages and T regulatory cells. These results suggest an important role for FTL and FTH1 in regulating tumor immunity to solid cancers.

Acute and subacute inhalation toxicity assessment of WS-23 in Sprague-Dawley rats.

2-isopropyl-N,2,3-trimethylbutyramide (WS-23) is a well-known artificial synthesis cooling agent widely used in foods, medicines, and tobaccos. As a commonly cooling agent in e-cigarette liquids, WS-23 has led to concerns about the inhalation toxicity with the prosperous of e-cigarettes in recent years. Thus, the aim of this study is to assess the acute and subacute inhalation toxicity of WS-23 in Sprague-Dawley (SD) rats according to the Organization for Economic Cooperation and Development (OECD) guidelines. In the acute toxicity study, there was no mortality and behavioral signs of toxicity at the limit test dose level (340.0 mg/m3 ) in the exposure period and the following 14-day observation period. In the subacute inhalation toxicity study, there was no significant difference observed in the body weights, feed consumption, and relative organ weights. Haematological, serum biochemical, urine, and bronchoalveolar lavage fluid (BALF) analysis revealed the non-adverse effects after 28-day repeated WS-23 inhalation (342.85 mg/m3 ), accompanied by slight changes in few parameters which returned to normal during the 28-day recovery period. The histopathologic examination also did not show any differences in vital organs. In conclusion, the maximum tolerated dose for WS-23 acute inhalation is not less than 340.0 mg/m3 , and the No Observed Adverse Effect Level (NOAEL) of WS-23 subacute inhalation was determined to be over 342.85 mg/m3 .

The interval between onset and admission predicts disease progression in COVID-19 patients.

BACKGROUND: The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19). METHODS: A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively. RESULTS: Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients. CONCLUSIONS: The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems.

Dexmedetomidine-induced polysomnography as a diagnostic method in obstructive sleep apnea: a reliable alternative method?

BACKGROUND: Under-diagnosis of obstructive sleep apnea (OSA) is common because of the demanding and time-consuming nature of polysomnography (PSG). Herein, we assessed the utility of a short daytime dexmedetomidine-induced PSG for diagnosis of OSA in adults. METHODS: This was a single-center, prospective, diagnostic trial. We evaluated 86 patients using a full overnight PSG and a short diurnal drug-induced PSG (DIPSG). DIPSG was induced by continuous intravenous dexmedetomidine infusion. Sedation depth was monitored and maintained using the Narcotrend index (50-70). Diagnostic performance for DIPSG with different apnea-hypopnea index (AHI) cut-off values were calculated. Bland-Altman plots used for analysis. Sleep architecture and position were compared. RESULTS: We studied 47 OSA patients and 39 healthy volunteers. Sensitivity and specificity for detection of OSA by DIPSG were 92% and 79%, respectively, for an AHI cut-off value of 5, 90% and 77%, respectively, for an AHI cut-off value of 15, and 95% and 85%, respectively, for an AHI cut-off value of 30. The DIPSG bias was -5 (-25; 15) for AHI and -3 (-13; 7) for minimal oxygen saturation. N2 sleep was increased (32.9% vs. 50.75%, respectively; p < 0.01) and REM sleep was decreased (21.35% vs. 1.24%, respectively; p < 0.01) during DIPSG. Twenty-eight (33%) participants had postural shifts during DIPSG. No significant adverse events were observed during DIPSG. CONCLUSIONS: Dexmedetomidine-induced PSG had a good sensitivity and specificity, and can be used as a screening tool for diagnosis of OSA in adults. CHINESE CLINICAL TRIAL REGISTRATION: ChiCTR1900024044.

DZNep attenuates allergic airway inflammation in an ovalbumin-induced murine model.

BACKGROUND: Growing evidence shows that enhancer of zeste homolog 2 (EZH2) plays a role in various physiological functions and cancer pathogenesis. However, its contribution to allergic diseases remains controversial. We sought to investigate the role of EZH2 in the pathogenesis of allergic airway inflammation. METHODS: 3-Deazaneplanocin A (DZNep), an indirect inhibitor of EZH2, was administered via intraperitoneal injection in an ovalbumin (OVA)-induced murine model of allergic airway inflammation. The expression of EZH2 in the allergic airway tissues was examined by immunohistochemistry (IHC) and western blot. The inflammatory cell infiltration and the goblet cell hyperplasia in the murine nose and lung were detected by hematoxylin and eosin (H&E) staining and periodic acid-Schiff (PAS) staining. Levels of cytokines, including IL-4, IFN-γ, IL-6, and IL-10, were evaluated in the bronchoalveolar lavage fluid (BALF) using Enzyme-linked immune sorbent assay (ELISA). RESULTS: EZH2 expression was inhibited by DZNep treatment (P < 0.05). The administration of DZNep significantly inhibited the inflammatory cell infiltration (P < 0.0001) and goblet cell hyperplasia (P < 0.001). Moreover, it suppressed the secretion of IL-4 (P < 0.0001) and IL-6 (P < 0.01) in the BALF. CONCLUSIONS: Our findings demonstrate that DZNep attenuates allergic airway inflammation and could be a new therapeutic option for allergic rhinitis and asthma.

Leptin Promoted IL-17 Production from ILC2s in Allergic Rhinitis.

BACKGROUND: Interleukin-17 plays important roles in allergic diseases. Several studies proved that leptin promoted Th17 immune responses by inducing RORγt transcription. ILC2 is an important member of the early stage of immune response. Therefore, we aimed to explore the effect of leptin on the IL-17 production by ILC2 in AR in this study. METHODS: Fifteen AR patients and fifteen healthy controls were enrolled. Serum leptin levels were measured, and their correlation with the frequency of IL-17+ ILC2 cells was analyzed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. ILC2 was stimulated by leptin, and the expression of IL-17, IL-5, and IL-13 was detected by ELISA. The correlated pathways were confirmed by real-time PCR. RESULTS: We found that serum leptin and the frequency of IL-17-producing ILC2s in AR were significantly higher compared with those in controls. After being incubated with leptin, the frequency of IL-17+ ILC2 cells and IL-17 production from ILC2 was upregulated compared with that in controls. We also found that leptin induced RORγt and Ahr expression by ILC2. Moreover, leptin-induced IL-17-producing ILC2 concomitantly expressed IL-5 and IL-13. CONCLUSIONS: Our data provide preliminary evidence that leptin-induced IL-17 production from ILC2 cells is dependent on RORγt and Ahr expression and the blockade of leptin may be a promising target for the treatment of AR.

[Analysis on new research and development ideas and technical points of traditional Chinese medicine for prevention and treatment of chronic heart failure].

Chronic heart failure(CHF), a serious and end stage of various heart diseases, is a common chronic cardiovascular disease in the 21 st century. Literature data show that the 5-year mortality rate of hospitalized patients with heart failure is as high as 50%. Nowadays, the development of drugs treating heart failure has become a hot spot, meanwhile, traditional Chinese medicine(TCM) has shown the advantages in the treatment of chronic heart failure. In this article, four stages to develop traditional Chinese medicine for chronic heart failure were proposed. Firstly, discuss and screen ideas and methods with regard to the development of TCM and its prescriptions based on clinical needs. Secondly, study the preparation process and quality control method by referring to the existing clinical background of TCM prescriptions and analyzing the chemical compositions and pharmacological action characteristics of each herb in the prescription. Then, design non-clinical evaluation programs and carry out researches on pharmacodynamics and toxicology by combining the experience of clinical use of TCM prescriptions and future clinical positioning, and gradually adjust and improve the programs during implementation. Finally, conduct clinical trial application(IND) by submitting registration application data which are base on the clinical drug experience, preclinical research pharmacy, main pharmacodynamics, safety test results of the prescription, clinical positioning, and reasonable clinical trial plan designed by the theory of TCM. After passing the IND technical review, the clinical trial study shall be officially launched to achieve the desired results and obtain effective Chinese patent medicines for heart failure treatment.

Treatment Principle Based on the Clinical Staging of Pharyngocutaneous Fistula.

OBJECTIVE: Studies on factors affecting pharyngocutaneous fistulas (PCFs) and PCF repair methods have been widely reported. However, the healing phases of PCF are unclear, and their elucidation could guide clinical treatment. METHODS: Clinical stages of the PCF healing process were identified by a retrospective study of 39 patients with head and neck cancer who developed a PCF. RESULTS: Different conservative treatments were performed in turn according to three defined stages of the PCF healing process: stage I (drainage and debriding period), stage II (pressure dressing period), and stage III (healing period). A 7-day course of antibiotic therapy was only performed in stage I in 23 patients. The PCF was cured in 30 (76.9%) of 39 patients; the remaining 9 patients underwent subsequent surgical interventions for PCF healing. CONCLUSION: The three stages of PCF healing have a certain reference value in guiding clinical treatments. Moreover, antibiotics should be used in stage I when signs of infection are present, but they should not be used in all three phases of conservative treatment.

The cost-effectiveness analysis of drug therapy versus surgery for symptomatic adenoid hypertrophy by a Markov model.

PURPOSE: Adenoid hypertrophy (AH) is common among young children. Adenoid-based surgery and drug therapy could be applied for symptomatic AH patients, yet the treatment decision is difficult to make due to the diverse cost and efficacy between these two treatments. METHODS: A Markov simulation model was designed to estimate the cost-effectiveness (CE) of the adenoid-based surgery and the drug therapy for symptomatic AH patients. Transition probabilities, costs and utilities were extracted from early researches and expert opinions. Simulations using two set of parameter inputs for China and the USA were performed. Primary outcome was cost per QALY gained over a 6-year period. Deterministic and probabilistic sensitivity analyses were also conducted. RESULTS: The utility for the surgery group and the drug group were 4.10 quality-adjusted life years (QALYs) and 3.58 QALYs, respectively. The cost of the surgery group was more than that of the drug group using model parameters specific to China ($1069.0 vs. $753.7) but was less for the USA ($1994.4 vs. $3977.7). Surgery was dominant over drug therapy when US specific parameters were used. Surgery group had an ICER of $604.0 per QALY when parameters specific to China was used. CONCLUSION: Surgery is cost-effective in the simulations for both China and the USA at WTP thresholds of $9633.1 and $62,517.5, respectively.

Ten-Eleven Translocation (TET) Enzymes Modulate the Activation of Dendritic Cells in Allergic Rhinitis.

Background: The prevalence of allergic rhinitis (AR) has increased in recent decades. Accumulating evidence indicates that aberrant DNA demethylation modulated by enzymes of ten-eleven translocation (TET) promotes an imbalanced immune response. Objective: This study aimed to explore TETs on the activation of dendritic cells (DCs) in AR. Methods: The levels of TETs in peripheral blood mononuclear cells (PBMCs), peripheral myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) from house dust mite (HDM)-sensitive AR patients and healthy volunteers (HC) were evaluated by qPCR and flow cytometry. The levels of 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in PBMCs were determined by DNA-5hmC and DNA-5mC ELISA. The major HDM allergen, Dermatophagoides pteronyssinus (Der p 1), was used to stimulate atopic monocyte-derived DCs (moDCs) to assess its effect on the TETs. TET1 knockdown effect on the activation of non-atopic and atopic moDCs was investigated. Results: TETs and global 5hmC were higher in PBMCs of AR than HC. So was TET1 in peripheral mDCs and pDCs of AR. In vitro, TET1 in atopic moDCs was significantly decreased by allergen challenge. Knockdown of TET1 in moDCs tended to induce CD86, CD80, and CD40 in AR but not in HC. TET1-knockdown moDCs significantly decreased the differentiation of activated regulatory T cells in AR. Conclusion: DCs from AR patients express higher TET1 and are susceptible to be activated by TET1 decrease, which can be triggered by allergen challenge. Collectively, this suggests a role for TET in the pathogenesis of AR and potential for novel TET1-related, preventive, and therapeutic targets.

Epigenetic Modification of Enhancer of Zeste Homolog 2 Modulates the Activation of Dendritic Cells in Allergen Immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is the only etiological and potentially curative therapy for allergic rhinitis (AR). OBJECTIVES: We sought to investigate the role of epigenetic regulator enhancer of zeste homolog 2 (EZH2) in the activation of dendritic cells (DCs) in AIT. METHOD: In this study, EZH2 expression in circulating myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were evaluated using flow cytometry. Clinical information from 56 AR patients receiving AIT was collected, including 30 subjects with subcutaneous immunotherapy (SCIT) and 26 subjects with sublingual immunotherapy (SLIT). In vitro, the effect of EZH2 inhibitor, 3 Deazaneplanocin A (DZNep), on the phenotypic and functional activation of monocyte-derived DCs (moDCs) was evaluated. RESULTS: EZH2 expression in circulating mDCs and pDCs were both negatively correlated to treatment time of AIT (r = -0.39, p = 0.003 and r = -0.47, p = 0.0002, respectively). Furthermore, there was a higher correlation between EZH2 expression and AIT treatment time in the SCIT group compared to that of the SLIT group in mDCs (r = -0.42, p = 0.02 vs. r = -0.23, p = 0.26)and pDCs (r = -0.52, p = 0.003 vs. r = -0.33, p = 0.10). In vitro, the co-stimulatory molecules on moDCs, such as CD80, CD86, and CD83, were significantly inhibited by DZNep in a dose-dependent manner. The -DC-driven T-cell proliferation was suppressed by DZNep (MD = 22.88, 95% CI 7.809-37.96, p < 0.05). CONCLUSIONS: Our study shows that EZH2, which is required in the activation of DCs, mediates the epigenetic modification in AIT and stresses the importance of patient adherence during AIT.

CD73 expression on effector T cells sustained by TGF-ß facilitates tumor resistance to anti-4-1BB/CD137 therapy.

Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73- effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-ß-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8+ T cells across several tumor models. TGF-ß blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.