Current status and advances of immunotherapy in nasopharyngeal carcinoma.

The general immune landscape of nasopharyngeal carcinoma (NPC) renders immunotherapy suitable for patients with NPC. Immune checkpoint inhibitors (ICIs) based on programmed death-1/programmed death ligand-1 (PD-1/PD-L1) blockade have made a breakthrough with the approval of PD-1 inhibitor for refractory recurrence and/or metastatic (R/M NPC) and the approval of PD-1 inhibitor in combination with gemcitabine and cisplatin as first line for R/M NPC in 2021 in China. The incorporation of ICIs into the treatment paradigms of NPC has become a clinical hot spot and many prospective clinical studies are ongoing. In this review, we provide a comprehensive overview of the rationale for immunotherapy in NPC and current status, advances and challenges of immunotherapy in NPC based on published clinical data, and ongoing trials. We focus on the clinical application and advances of PD-1 inhibitor monotherapy and its combination with chemotherapy and summarize the clinical explorations of other immunotherapy approaches, for example, combination of PD-1/PD-L1 inhibitors with antiangiogenic inhibitor with molecular targeted agents, cancer vaccines, adaptive immunotherapy, and new ICI agents beyond PD-1/PD-L1 inhibitors in R/M NPC. We also describe the clinical studies' status and challenges of ICIs-based immunomodulatory strategies in local advanced NPC and pay attention to the biomarker application for personalized immunotherapy of NPC in the hope to provide insights for clinical practice and future clinical studies.

Optimizing Chemotherapy of Pancreatic Acinar Cell Carcinoma: Our Experiences and Pooled Analysis of Literature.

Background: Pancreatic acinar cell carcinoma (PACC) is rare, and its appropriate treatment remains unknown. We aim to explore the characteristics and optimal treatment of it. Methods: The data on clinicopathologic characteristics, molecular alteration, treatment, and survival of patients diagnosed with PACC at the Sun Yat-sen University Cancer Center from 2005 to 2020 were collected. The optimal treatment was explored by co-analyzing our results and published literatures. Results: Twenty-two PACC patients were enrolled. Eight of 17 non-metastatic patients received adjuvant chemotherapy. The patients receiving fluoropyrimidine-based regimen (n = 3) had a better median disease-free survival (mDFS) than those with gemcitabine-based regimen (n = 5) (unreached vs 27 months). Eight metastatic patients received first-line chemotherapy. Four patients received second-line chemotherapy. The objective response rate (ORR) of the fluoropyrimidine-based regimen was 85.7% (6/7), much better than that of the gemcitabine-based regimen (0/5). One patient who had responded to the first-line FOLFIRINOX (5-fluorouracil + oxaliplatin + leucovorin + irinotecan) regimen received olaparib as maintenance treatment for 5 months with good tolerance. Thirty-one published literatures, with a total of 86 cases, were included in the co-analysis. The ORR of the first-line fluoropyrimidine-based regimen (n = 47) was higher than that of gemcitabine-based regimen (n = 39) (59.6% vs 15.3%, P < .001). Eight of 11 patients treated with the FOLFIRINOX regimen achieved partial response (PR). Conclusions: For patients with metastasis, a fluorouracil-based regimen such as FOLFIRINOX may be preferred, and maintenance treatment of poly ADP-ribose polymerase (PARP) inhibitors after effective platinum-containing treatment for breast cancer susceptibility gene (BRCA) mutation patients must be assessed.

Association of Plasma Epstein-Barr Virus DNA With Outcomes for Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma Receiving Anti-Programmed Cell Death 1 Immunotherapy.

IMPORTANCE: Anti-programmed cell death 1 (anti-PD-1) immunotherapy features a durable response and improved survival in a small subset of patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). The association between plasma Epstein-Barr virus (EBV) DNA titer dynamics and efficacy of anti-PD-1 monotherapy has been reported, while its value in predicting long-term outcomes and monitoring disease progression is unclear for patients with RM-NPC who are receiving anti-PD-1 monotherapy. OBJECTIVE: To evaluate the role of plasma EBV DNA titers in prognosis prediction and surveillance of disease progression for patients with RM-NPC who are receiving anti-PD-1 monotherapy. DESIGN, SETTING, AND PARTICIPANTS: Patients with RM-NPC from the POLARIS-02 prospective clinical trial, the largest cohort to receive anti-PD-1 monotherapy, were included in this study. From December 22, 2016, to February 19, 2019, 17 participating centers in China screened 279 patients with RM-NPC; 190 patients were enrolled and followed up until February 19, 2020. Plasma EBV DNA was detected before treatment and every 4 weeks until disease progression. MAIN OUTCOMES AND MEASURES: Plasma EBV DNA as a predictor for progression-free survival (PFS), overall survival (OS), durable clinical benefit (defined as PFS of ≥6 months), and disease progression. RESULTS: Of 179 patients with RM-NPC receiving anti-PD-1 therapy, 148 (82.7%) were men, and the median age was 46 years (range, 22-71 years). A higher baseline EBV DNA titer was associated with shorter median OS (hazard ratio, 1.88; 95% CI, 1.22-2.89; P = .004). Patients with a ratio of the EBV DNA titer at week 4 to that at baseline (W4 to baseline ratio) greater than 0.5 had shorter median OS (hazard ratio, 2.18; 95% CI, 1.30-3.65; P < .001) than those with a W4 to baseline ratio of 0.5 or less. Patients with higher baseline EBV DNA titers had a lower durable clinical benefit rate than those with lower baseline EBV DNA titers (19 of 97 [19.6%] vs 27 of 71 [38.0%]; P = .01). Similarly, patients with a W4 to baseline ratio greater than 0.5 had a lower durable clinical benefit rate than those with a W4 to baseline ratio of 0.5 or less (9 of 86 [10.5%] vs 32 of 54 [59.3%]; P < .001). In addition, a significant EBV DNA titer increase was present at a median of 2.6 months (IQR, 0.9-4.5 months) prior to radiographic progression. CONCLUSIONS AND RELEVANCE: This study of plasma EBV DNA in patients with RM-NPC who are receiving anti-PD-1 monotherapy suggests that plasma EBV DNA could be a useful biomarker for outcomes and monitoring disease progression.

Photocatalytic CO2-to-Ethylene Conversion over Bi2S3/CdS Heterostructures Constructed via Facile Cation Exchange.

Solar-driven CO2 conversion to multicarbon (C2+) products has emerged as a key challenge, yet this calls for a systematic investigation on the overall reaction process and mechanism at an atomic level based on the rational design of highly selective photocatalysts. Herein, we report the synthesis of compact Bi2S3/CdS heterostructures via facile cation exchange, by which a unique pathway of CO2-to-C2H4 photoconversion is achieved. Specifically, the BCS-30 shows an optimal C2H4 production rate of 3.49 µmol h-1 g-1 based on the regulation of band structures and energy levels of photocatalysts by controlled growth of Bi2S3 at CdS surface. Both experimental and theoretical results (DFT calculations) identify Bi atoms as new catalytic sites for the adsorption of CO* and formation of *CO-*CO dimers that further hydrogenate to produce ethylene. Overall, this work demonstrates vast potentials of delicately designed heterostructures for CO2 conversion towards C2+ products under mild photocatalytic conditions.

The Impact of Mismatch Repair Status on Prognosis of Patients With Gastric Cancer: A Multicenter Analysis.

BACKGROUND: The clinical role of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) in gastric cancer (GC) is still controversial. We aimed to analyze the relationship between dMMR/MSI-H and clinicopathological features along with survival. METHODS: Patients who were diagnosed with GC at the three big cancer centers in China from 2015 to 2020 were evaluated retrospectively. MMR/MSI status was assessed using immunohistochemistry/PCR. Clinical and pathological data were collected from the medical record system. RESULTS: A total of 196 patients with dMMR/MSI-H status were enrolled for analysis. The prevalence of MSI-H/dMMR in GC was 6.6%. Another 694 proficient MMR (pMMR) GC patients were enrolled for comparison. Compared with pMMR patients, dMMR/MSI-H patients were associated with older age, female predominance, distal location in the stomach, earlier TNM stage, intestinal subtype, better differentiation, and more negative HER2 status. The median overall survival (OS) of the dMMR/MSI-H group was better than that of the pMMR/microsatellite stability (MSS) group (not reached vs. 53.9 months, p = 0.014). Adjuvant chemotherapy had no impact in both disease-free survival (DFS) and OS of dMMR/MSI-H patients (p = 0.135 and 0.818, respectively). dMMR/MSI-H patients had poorer response and progression-free survival (PFS) of first-line chemotherapy, though they were statistically significant (p = 0.361 and 0.124, respectively). CONCLUSIONS: dMMR/MSI-H GC patients have specific clinicopathological characteristics and better prognosis than pMMR patients.

Baseline lesion number as an efficacy predictive and independent prognostic factor and its joint utility with TMB for PD-1 inhibitor treatment in advanced gastric cancer.

BACKGROUND: We previously reported tumor mutation burden (TMB) as a potential prognostic factor for patients with advanced gastric cancer (AGC) receiving immunotherapy. We aimed to comprehensively understand the impact of tumor burden and TMB on efficacy and prognosis in immunotherapy-treated AGC patients. METHODS: A total of 58 patients with refractory AGC receiving PD-1 inhibitor monotherapy from a phase Ib/II clinical trial (ClinicalTrials.gov identifier: NCT02915432) were retrospectively included. Univariate and multivariate logistical regression analyses and the Cox proportional hazards model were performed for prognostic value of baseline factors. Factors reflecting baseline tumor burden, including baseline lesion number (BLN), the maximum tumor size (MTS) and the sum of target lesion size (SLS) were analyzed. The objective response rate (ORR) and disease control rate (DCR) were compared by Chi-square test. RESULTS: In univariate analysis, high BLN was associated with poor median progression-free survival (mPFS) [1.7 months versus 3.4 months; hazard ratio (HR), 2.696, p < 0.05] and median overall survival (mOS) (3.2 months versus 7.6 months; HR, 1.997, p < 0.05), while high TMB was a positive prognostic factor. In multivariable analysis, both BLN and TMB were independent prognostic factors for mOS (BLN: HR, 2.782, p < 0.05; TMB: HR, 0.288, p < 0.05), while MTS or SLS had no association with survival. Better ORR and DCR were observed in the low BLN group (15.4% versus 5.3%, p > 0.05; 86.96% versus 54.29%, p < 0.05). When combining BLN and TMB, the best efficacy and survival were observed in the BLNlowTMBhigh group (ORR: 37.5%, DCR: 62.5%, mPFS and mOS: not reached). The worst efficacy and survival were shown in the BNLhighTMBlow group [ORR: 0% (0/15); DCR: 13.3%; mPFS: 1.7 months; mOS: 2.7 months (all p < 0.05)]. CONCLUSIONS: BLN, rather than factors regarding baseline tumor size, is perhaps a potential predictor for benefit from immunotherapy and its combination with TMB could further risk-stratify patients with AGC receiving immunotherapy.

Adiponectin antagonises LPS-regulated secretion of inflammatory factors in airway epithelial cells, and its expression is regulated by many factors.

Many studies have shown that adiponectin is closely related to chronic obstructive pulmonary disease (COPD), but the specific role of adiponectin in COPD is still not well understood. Adiponectin and IL-6 expression in patients with acute exacerbation of COPD (AECOPD) was detected by ELISA. Human bronchial epithelial cells (HBECs) were stimulated with TNF-α, IL-6, apoptotic cells or LPS. Then, the expression of adiponectin was detected by qRT-PCR and western blotting, and pro- and anti-inflammatory factors were detected by ELISA. Adiponectin expression in AECOPD patients increased after treatment. TNF-α and apoptotic cells promoted adiponectin expression in HBECs in a dose-dependent manner, and apoptotic cells significantly promoted adiponectin secretion. IL-6 also promoted adiponectin expression, but it inhibited adiponectin expression at high doses and with long treatment times. LPS inhibited adiponectin expression, but when HBECs were pretreated with anti-TNF-α and then treated with LPS, the expression and secretion of adiponectin increased significantly with increasing anti-TNF-α concentrations. Adiponectin stimulated the secretion of pro-inflammatory factors in HBECs, but this effect was not concentration dependent. Adiponectin promoted the secretion of anti-inflammatory factors in a dose-dependent manner. Although LPS also stimulated HBECs to secrete pro-inflammatory and anti-inflammatory factors, adiponectin inhibited LPS-induced pro-inflammatory factor secretion and enhanced anti-inflammatory factor secretion. Many factors regulate the expression and secretion of adiponectin, and adiponectin regulates the balance of the inflammatory response and inhibits further expansion of inflammation. SIGNIFICANCE OF THE STUDY: Many studies have shown that adiponectin is closely related to chronic obstructive pulmonary disease (COPD), but the specific role of adiponectin in COPD is still not well understood. Adiponectin expression in AECOPD patients increased after treatment. TNF-α, IL-6 and apoptotic cells promoted adiponectin expression in HBECs. Adiponectin stimulated the secretion of pro-inflammatory factors in HBECs, but this effect was not concentration dependent. Adiponectin promoted the secretion of anti-inflammatory factors in a dose-dependent manner. Adiponectin inhibited LPS-induced pro-inflammatory factor secretion and enhanced anti-inflammatory factor secretion. Therefore, many factors regulate the expression and secretion of adiponectin, and adiponectin regulates the balance of the inflammatory response and inhibits further expansion of inflammation.

Small airway immunoglobulin A profile in emphysema-predominant chronic obstructive pulmonary disease.

BACKGROUND: Due to airway remodeling and emphysematous destruction in the lung, the two classical clinical phenotypes of chronic obstructive pulmonary disease (COPD) are emphysema and bronchiolitis. The present study was designed to investigate the levels of small airway immunoglobulin A (IgA) in COPD with "emphysema phenotype." The study also evaluated the associations between the small airway IgA levels and the severity of disease by the extent of emphysema versus airflow limitation. METHODS: Thirty patients (20 with COPD and ten healthy smokers) undergoing lung resection surgery for a solitary peripheral nodule were included. The study was conducted from January 2015 to December 2018 in the Shanxi Dayi Hospital. The presence of small airway IgA expression was determined in the lung by immunohistochemistry. In vivo, Wistar rats were exposed to silica by intratracheal instillation. Rats were sacrificed at 15 and 30 days after exposure of silica (n = 10 for each group). We also evaluated airway IgA from rats. RESULTS: Small airway secretory IgA (sIgA), dimeric IgA (dIgA), and dIgA/sIgA of Global Initiative for Chronic Obstructive Lung Disease grade 1-2 COPD patients showed no difference compared with smoking control subjects (5.15 ±â€Š1.53 vs. 6.03 ±â€Š0.85; 1.94 ±â€Š0.66 vs. 1.67 ±â€Š0.04; 41.69 ±â€Š21.02 vs. 28.44 ±â€Š9.45, all P > 0.05). dIgA/sIgA level in the lung of COPD patients with emphysema showed higher levels than that of COPD patients without emphysema (51.89 ±â€Š24.81 vs. 31.49 ±â€Š9.28, P = 0.03). The percentage of low-attenuation area below 950 Hounsfield units was positively correlated with dIgA/sIgA levels (r = 0.45, P = 0.047), but not associated with the severity of disease by spirometric measurements (forced expiratory volume in the first second %pred, P > 0.05). Likewise, in the rat study, significant differences in sIgA, dIgA, dIgA/sIgA, mean linear intercept, mean alveoli number, and mean airway thickness of bronchioles (VV airway, all P < 0.01) were only observed between control rats and those exposed for 30 days. However, in the group exposed for 15 days, although the VV airway was higher than that in normal rats (27.61 ±â€Š2.26 vs. 20.39 ±â€Š1.99, P < 0.01), there were no significant differences in IgA and emphysema parameters between the two groups (all P > 0.05). CONCLUSION: Airway IgA concentrations in mild and moderate COPD patients are directly associated with the severity of COPD with "emphysema phenotype" preceding severe airway limitation. This finding suggests that small airway IgA might play an important role in the pathophysiology of COPD, especially emphysema phenotype.

Localized surface plasmon resonance enhanced visible-light-driven CO2 photoreduction in Cu nanoparticle loaded ZnInS solid solutions.

Visible-light-driven photocatalysts have shown tremendous prospects in solving the energy crisis and environmental problems, thanks to their wide spectral response and high quantum efficiency. Several strategies including the expansion of visible light response and the improvement of solar energy utilization and photocatalytic quantum efficiency via more effective separation of photogenerated carriers are the current focuses of research that direct the design and fabrication of viable photocatalysts. Herein, a series of composite photocatalysts assembled from plasmonic Cu nanoparticles (NPs) and Zn3In2S6 (ZIS) solid solutions were synthesized by means of a simple solvothermal method. In comparison with the pristine ZIS semiconductor, Cu NP loaded ZIS solid solutions showed greatly enhanced photocatalytic activity, selectivity and stability towards CO2 reduction under visible irradiation. Of note was that the optimized ZIS-Cu2 exhibited an enhanced CH4 production rate of ca. 292 µL g-1 h-1 and a selectivity of ca. 71.1%, which were among the highest numbers reported hitherto. The localized surface plasmon resonance (LSPR) effect, shown by surface Cu NPs, was believed to play a critical role in the enhanced CO2 photoreduction efficiency. More importantly, the introduction of plasmonic Cu NPs could restrain the recombination of photogenerated electron-hole pairs and promote the migration of photogenerated electrons to better participate in the photocatalytic CO2 reduction in the presence of water vapor. This work thus provides a facile means to design robust and flexible composite photocatalysts for visible-light-driven CO2 photoreduction with high efficiency.

CdZnS nanorods with rich sulphur vacancies for highly efficient photocatalytic hydrogen production.

A one-dimensional Cd0.6Zn0.4S nanorod (CZS NR) solid solution with rich sulfur vacancies achieved an excellent photocatalytic hydrogen production activity of 59.3 mmol h-1 g-1 under visible irradiation, which is the highest number observed for CdZnS solid solution nanomaterials to date.

Comparison of Serum Adiponectin in Smoke-induced Pulmonary Emphysema Rats Fed Different Diets.

BACKGROUND: Smoking and body mass index (BMI) are the key risk factors for chronic obstructive pulmonary disease (COPD). Adiponectin with both anti-inflammatory and pro-inflammatory properties is a vital modulator of inflammatory processes, which is expressed in epithelial cells in the airway in COPD-emphysema. The aim of this study was to examine the effects of adiponectin on tobacco smoke-induced emphysema in rats, which were fed different diets. METHODS: Seventy-six adult (6-8 weeks old) male Sprague-Dawley rats (average weight 220 ± 20 g) were exposed to smoke or smoke-free room atmosphere and fed different diets (regular, high-fat, or low-fat diets) for 6 months. The rats were randomly divided into six groups. They are nonsmoke-exposed regular diet (n = 10), nonsmoke-exposed high-fat diet (n = 14), nonsmoke-exposed low-fat diet (n = 14), smoke-exposed regular diet (n = 10), smoke-exposed high-fat diet (n = 14), and smoke-exposed low-fat diet groups (n = 14). A full 2 3 factorial design was used to evaluate the effect of independent variables on smoke exposure and different rearing methods. Serum adiponectin and inflammatory cytokines were measured by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum adiponectin levels in rats fed low-fat and regular diets exposed to smoke exposure were remarkably higher than that of rats exposed to room air while serum adiponectin levels of fat-rich diet rats exposed to tobacco smoke were lower than that of rats exposed to room air. Compared with regular diet or low-fat diet group, serum adiponectin levels in high-fat diet rats exposed to tobacco smoke were lower (t = 6.932, 11.026; all P < 0.001). BMI was inversely correlated with serum adiponectin levels (r = -0.751, P = 0.012). Serum interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and 4-hydroxy 2-nonenal (HNE) levels in rats exposed to low-fat or fat-rich diets were remarkably higher than that of rats exposed to normal diets (IL-6, t = 4.196, 3.480; P < 0.01, P = 0.001; TNF-α, t = 4.286, 3.521; P < 0.01, P = 0.001; 4-HNE, t = 4.298, 4.316; all P < 0.001). In nonhigh-fat diet rats exposed to tobacco smoke, serum adiponectin levels correlated positively with serum IL-6, TNF-α, and 4-HNE, bronchoalveolar lavage cell count, and mean linear intercept. In contrast, in high-fat diet rats, serum adiponectin levels correlated inversely with these parameters. CONCLUSIONS: In smoke-induced emphysema and fat-rich diet rat model, serum adiponectin level was decreased, and the anti-inflammatory effect was attenuated. By contrast, nonhigh-fat diet elevated serum adiponectin and enhanced the role of pro-inflammatory.

Different forms of adiponectin reduce the apoptotic and damaging effect of cigarette smoke extract on human bronchial epithelial cells.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, in which adiponectin may serve an important role. The present study investigated the role of adiponectin in the apoptotic and damaging effect of cigarette smoke extract (CSE) on human bronchial epithelial cells (16HBECs). An MTT assay showed that CSE significantly inhibited the proliferation of 16HBECs (F=1808.88, P<0.01). The 16HBECs were treated with different concentrations of high molecular weight (HMW) adiponectin and globular domain (gAd) adiponectin and it was observed that HMW and gAd dose-dependently inhibited the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-8, and the generation of 4-hydroxy-nonenal and reactive oxygen species (ROS) in 16HBECs, thereby blocking the upregulating effect of CSE on these factors. However, the inhibitory effect of gAd on TNF-α and IL-8 expression was stronger compared with that of HMW, but the suppressing effect of HMW on ROS production was superior compared with that of gAd. Further testing of apoptosis indicated that CSE and HMW promoted the apoptosis of 16HBECs. However, such effects of HMW declined with an increase in concentration. In contrast, gAd showed an inhibitory effect on apoptosis and inhibited the occurrence of CSE-induced apoptosis in a dose-dependent manner. Therefore, the present study demonstrated that different forms of adiponectin may have different mechanisms of action, suggesting that further exploration of their effects may open a new avenue for the treatment of COPD.

[Toxicity tests and their application in safety assessment of water quality].

The safety of water quality has important impacts not only on the health of ecological system, but also on the survival and development of human beings. The conventional assessment methods for water quality based on the concentration limits are not reliable. The toxicity tests can vividly reflect the whole adverse biological effects of multiple chemicals in water body, which has been regarded as a necessary supplement for conventional water quality assessment methods based on physicochemical parameters. Considering the chemical pollutants usually have various adverse biological effects, the ecotoxicity testing methods, including lethality, genotoxicity, endocrine disrupting effects, were classified according to the different toxicity types. Then, the potential applications of toxicity testing methods and corresponding evaluation indices in evaluating the toxicity characteristics of ambient water samples were discussed. Particularly, the safety assessment methods for water quality based on the toxicity tests, including potential toxicology, toxicity unit classification system, potential ecotoxic effect probe, and safety assessment of water quality based on toxicity test battery, were summarized. This paper not only systematically reviewed the progress of toxicity tests and their application in safety assessment of water quality, but also provided the scientific basis for the further development in the future.

Immunohistochemical alterations of cajal-like type of tubal interstitial cells in women with endometriosis and tubal ectopic pregnancy.

PURPOSE: The aim of the study was to observe alterations of pacemaker cells termed cajal-like type of tubal interstitial cells (t-ICC) in oviduct from early-stage EMs and tEP, discuss underlying mechanisms and potential role in tubal factor infertility (TFI). METHODS: Ten patients with early-stage EMs, 10 with unruptured tEP and 10 control subjects were included in this retrospective comparative study, received adnexectomy (salpingectomy) and/or hysterectomy. Paraffin-embedded full-thickness isthmic segment of oviduct specimens received immunohistochemistry with c-kit/CD117 antibody. Network distribution and area density of cells with features of t-ICC were analyzed. RESULTS: t-ICC was detected mainly in lamina propria and smooth muscle layers. t-ICC lost its network integrity, became less densely stained, sparse and almost invisible with relatively very rare connections in EMs and tEP, apparently differing in morphology of t-ICC from control, which demonstrated rich t-ICC immunostaining and intact network. Further quantitative analysis showed the area density of t-ICC decreased significantly in early-stage EMs and tEP compared with the control (73.9 ± 8.8 vs. 156 ± 18.3 mm(2); and 76 ± 7.4 vs. 156 ± 18.3 mm(2); both P < 0.001). CONCLUSIONS: We revealed that t-ICC underwent certain degree of cell damage, suggested that decreased expression of t-ICC network may be involved in early development of EMs and tEP, and might serve as an explanation for TFI in these patients.

Expression and significance of myeloid differentiation factor 88 in marrow dendritic cells in asthmatic rats with cigarette smoke exposure.

BACKGROUND: Smoking causes frequent asthma attacks, leading to a rapid decline in lung function in patients with asthma, and it can also reduce the therapeutic effect of glucocorticoids in patients with asthma. Therefore, the present study aimed to investigate the effect of cigarette smoke on the expression of myeloid differentiation factor 88 (MyD88) in marrow dendritic cells (DCs) in asthmatic rats, and to explore the molecular mechanism of cigarette smoke exposure on asthma by DCs. METHODS: Forty Wistar rats were randomly divided into the following groups: control, smoke exposure, asthma, and asthma combined with smoke exposure. The animal model was established, and then rat bone marrow-derived DCs were collected. Additionally, rat spleen lymphocytes and bone marrow-derived DCs were cultured together for mixed lymphocyte responses. Interferon (IFN)-gamma and interleukin (IL)-4, IL-10, and IL-12 expressions were determined by enzyme-linked immunosorbent assay (ELISA). MyD88 expression was determined by Western blotting. The proliferation of lymphocytes was examined with methyl thiazolyl tetrazolium (MTT) colorimetric assay. RESULTS: MyD88 expression was decreased in the asthma combined with smoke exposure group compared to the asthma group (P < 0.01), and IL-10 and IL-12 expressions were decreased in the asthma combined with smoke exposure group compared to control group (P < 0.01). In addition, DCs stimulating activity on allogeneic lymphocytes were significantly decreased in the smoke exposure combined with asthma group compared to the control and asthma groups (P < 0.01). After allogeneic mixed lymphocyte responses, IL-4 expression was increased and IFN-gamma was decreased in the asthma group and the asthma combined with smoke exposure group compared to control group (P < 0.01). IL-4 expression was increased and IFN-gamma was decreased in the asthma combined with smoke exposure group compared to the asthma group (P < 0.01). The study also showed that MyD88 expression was positively correlated with IL-12 and IFN-gamma expressions and the activity of lymphocytes (P < 0.01), and negatively correlated with IL-4 expression (P < 0.01). CONCLUSIONS: Smoking aggravates asthma by weankening immunological mechanism. MyD88-dependent pathways may play a role in the immunological balance and activation of lymphocytes.

Cigarette smoke extract stimulates rat pulmonary artery smooth muscle cell proliferation via PKC-PDGFB signaling.

Accumulating evidence suggests a direct role for cigarette smoke in pulmonary vascular remodeling, which contributes to the development of pulmonary hypertension. However, the molecular mechanisms underlying this process remain poorly understood. Platelet-derived growth factor (PDGF) is a potential mitogen and chemoattractant implicated in several biological processes, including cell survival, proliferation, and migration. In this study, we investigated the effect of cigarette smoke extract (CSE) on cell proliferation of rat pulmonary artery smooth muscle cells (rPASMCs). We found that stimulation of rPASMCs with CSE significantly increased cell proliferation and promoted cell cycle progression from G1 phase to the S and G2 phases. CSE treatment also significantly upregulated the mRNA and protein levels of PDGFB and PDGFRß. Our study also revealed that Rottlerin, an inhibitor of PKCδ signaling, prevented CSE-induced cell proliferation, attenuated the increase of S and G2 phase populations induced by CSE treatment, and downregulated PDGFB and PDGFRß mRNA and protein levels in rPASMCs exposed to CSE. Collectively, our data demonstrated that CSE-induced cell proliferation of rPASMCs involved upregulation of the PKCδ-PDGFB pathway.

Increased expression of the von Hippel-Lindau gene in the implantation site of human tubal pregnancy.

The objective of this study was to investigate the expression of the von Hippel-Lindau (VHL) gene in tissues of human fallopian tube and tubal pregnancy. Twenty patients undergoing salpingectomy for tubal pregnancy were recruited into the study group. Tissues of tubal pregnancy were separated into both the implantation and non-implantation sites as the implantation group and the non-implantation group, respectively. Samples of ampullary fallopian tube during mid-secretory phase were collected from twenty patients with benign uterine disease as the control group. Immunohistochemistry, real-time reverse transcription polymerase chain reaction, and Western blotting analysis were performed to detect expressions of VHL mRNA and protein. The results showed that VHL immunostaining appeared in the cytoplasm of tubal epithelial cells. Expression of VHL mRNA in the implantation group was higher than that in the non-implantation group or the control group (P < 0.01). Intensity of VHL protein in the implantation group was increased compared with that in the non-implantation group (P < 0.05) or in the control group (P < 0.01). There was no difference on expressions of VHL mRNA and protein between the non-implantation group and the control group (P > 0.05). In conclusion, VHL mRNA and protein are present in human tubal tissues. The VHL gene expression is increased in the implantation site of tubal pregnancy, and locally elevated expression of the VHL gene might be associated with human tubal pregnancy.

[The role of 4-hydroxynonenal in assessment of chronic obstructive pulmonary disease severity].

OBJECTIVE: To measure the levels of 4-hydroxynonenal (4-HNE), TNF-α and IL-6 in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and stable COPD, and therefore to explore the role of 4-HNE in the assessment of COPD severity. METHODS: A total of 242 patients with AECOPD, 182 males and 60 females, age 54 - 89 (mean 72 ± 8) years, 57 outpatients with stable COPD, 55 males and 2 females, age 38 - 76 (mean 60 ± 8) years, and 67 healthy controls, 49 males and 18 females, age 42 - 86 (mean 66 ± 10) years, were included in the study. Based on whether there were respiratory failure, chronic pulmonary heart disease or a history of smoking, the patients with AECOPD were divided into different subgroups. Patients with stable COPD were divided into different subgroups based on lung function or whether there was a history of smoking. The serum 4-HNE, TNF-α and IL-6 concentrations were measured by using enzyme-linked immune sorbent assay (ELISA). RESULTS: The serum 4-HNE levels in patients with AECOPD or stable COPD (16 ± 4) mg/L, (15 ± 5) mg/L were higher than those in healthy controls (12 ± 4) mg/L (both P < 0.01). After control for age, the serum 4-HNE levels in patients with AECOPD were significantly higher than those in stable COPD (F = 7.93, P < 0.01). There were no differences in the serum 4-HNE among AECOPD patients of current smokers, non-smokers and ex-smokers (16 ± 4) mg/L, (17 ± 3) mg/L, (17 ± 4) mg/L. The serum 4-HNE in AECOPD patients with chronic pulmonary heart disease were particularly higher (17 ± 4) mg/L vs (15 ± 4) mg/L (F = 1.23, P < 0.01). There were no differences in the serum 4-HNE between stable COPD patients of current smokers and ex-smokers (14 ± 5) mg/L, (16 ± 4) mg/L (t = -1.44, P > 0.05). In patients with stable COPD, the serum 4-HNE levels were significantly correlated with FEV(1)% (r = -0.345, P < 0.01) and IL-6 (r = 0.363, P < 0.01). CONCLUSIONS: The serum levels of 4-HNE in COPD patients with different smoking status were all significantly elevated, particular in patients with acute exacerbation and with pulmonary heart disease. In patients with stable COPD, the 4-HNE levels were negatively correlated with FEV(1)% and positively with serum IL-6 levels. It may be a valuable biomarkers for the assessment of COPD severity.

Aberrant expression of the von Hippel-Lindau gene in human endometrial hyperplasia and endometrial carcinoma.

INTRODUCTION: The purpose of this study was to determine whether aberrant expression of the von Hippel-Lindau (VHL) gene in human hyperplastic and malignant endometrial tissues was involved in endometrial carcinogenesis. METHODS: Fresh tissue samples of endometrial hyperplasia consisting of simple (n = 26), complex (n = 23), and atypical hyperplasia (n = 20); endometrial carcinoma (n = 17); and normal endometrium (n = 40) were measured using Western blotting and real-time reverse transcription polymerase chain reaction. Paraffin-embedded sections of endometrial hyperplasia (n = 90), endometrial carcinoma (n = 30), and normal endometrium (n = 60) were detected by immunohistochemical method. RESULTS: Von Hippel-Lindau staining was present in the cytoplasm of epithelial cells and stroma. A decreased expression of VHL mRNA in endometrial hyperplasia from simple, complex, to atypical hyperplasia was observed. There were statistical differences on VHL messenger RNA (mRNA) levels among simple, complex, and atypical hyperplasia (P < 0.01). The VHL mRNA levels in endometrial carcinoma were significantly lower than those in normal endometrium, simple hyperplasia, or complex hyperplasia (P < 0.01) but similar to those in atypical hyperplasia (P > 0.05). Von Hippel-Lindau protein levels by Western blotting and staining intensity by immunohistochemistry were coincident with the VHL mRNA levels. CONCLUSIONS: Aberrant expression of the VHL gene is associated with the risk of endometrial hyperplasia progressing to endometrial carcinoma, and its expression levels are useful as a predictive indicator for endometrial carcinoma.