First-Line Treatment Options for PD-L1-Negative Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

BACKGROUND: First-line treatment strategies for programmed death-ligand 1 (PD-L1) negative non-small cell lung cancer (NSCLC) patients include chemotherapy and combination with anti-angiogenesis drugs and/or immune checkpoint inhibitor. We conducted a Bayesian network meta-analysis to evaluate the efficacy of these therapeutic options. METHODS: We included phase III randomized controlled trials comparing two or more treatments in the first-line setting for NSCLC, including data in PD-L1-negative patients. First-line strategies were compared and ranked based on the effectiveness in terms of overall survival (OS) and progression-free survival (PFS). A rank was assigned to each treatment after Markov Chain Monte Carlo analyses. RESULTS: Fourteen trials involving 14 regimens matched our eligibility criteria. For OS, none of the treatment were significantly more effective than chemotherapy. Nivolumab plus ipilimumab plus chemotherapy was probably the best option based on analysis of the treatment ranking (probability = 30.1%). For PFS, nivolumab plus chemotherapy plus bevacizumab, atezolizumab plus chemotherapy plus bevacizumab, and atezolizumab plus chemotherapy were statistically superior to chemotherapy in pairwise comparison. Nivolumab plus chemotherapy plus bevacizumab was likely to be the preferred option based on the analysis of the treatment ranking (probability = 72.9%). CONCLUSIONS: Nivolumab plus chemotherapy, in combination with angiogenesis inhibition or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), had maximal benefits for NSCLC patient of PD-L1-negative expression. These findings may facilitate individualized treatment strategies. Safety at an individual patient level should be considered in decision making. Further validation is warranted.

Resveratrol downregulates TNF-α-induced monocyte chemoattractant protein-1 in primary rat pulmonary artery endothelial cells by P38 mitogen-activated protein kinase signaling.

Background: To evaluate the effects of resveratrol to monocyte chemoattractant protein-1 (MCP-1) and the role of p38 mitogen-activated protein kinase (MAPK) in this process in vitro. Materials and methods: Animal acute pulmonary thromboembolism (PTE) model: rat model was established by infusion of an autologous blood clot into the pulmonary artery through a polyethylene catheter. One hundred and thirty-two rats were randomly and equally divided into ten groups: rats-control (untreated), rats-1% DMSO, rats-TNF-α, rats-TNF-α + resveratrol, rats-TNF-α +C1142, rats-TNF-α+SB203580, rats-TNF-α+resveratrol + SB203580, rats-resveratrol only, rats-C1142 only, and rats-SB203580 only. Rat pulmonary artery endothelial cells (RPAs) tests: RPAs were isolated from above animal and designated as: RPAs-control, RPAs-1% DMSO control, RPAs-TNF-α, RPAs-TNF-α + resveratrol, RPAs-TNF-α + C1142, RPAs-TNF-α + SB203580, RPAs-TNF-α + resveratrol + SB203580, RPAs-resveratrol only, RPAs-C1142 only, and RPAs-SB203580 only. Each group was further divided into 1, 4, and 8 hrs time point for evaluation (n=6 rats per time point) except RPAs-TNF-α + SB203580, RPAs-TNF-α + resveratrol + SB203580, RPAs-C1142 and RPAs-SB203580 only, which were evaluated at 8 hrs time point. At each time point, mRNA and protein expressions of RPAs of MCP-1 were measured. The phosphorylation of p38 MAPK (p-pMAPK) of RPAs was also detected. Results: We found that the RPAs-TNF-α elicited significant increases in MCP-1 expression and phosphorylation of p38 mitogen-activated protein kinase (p-p38 MAPK). Furthermore, the MCP-1 expressions of RPAs-Resveratrol, RPAs-C1142, and RPAs-SB203580 were significantly down-regulated, which was associated with robustly suppressed TNF-α-induced p-p38MAPK expression. Conclusion: Our findings suggested that MCP-1 was involved in the formation of TNF-α-induced inflammatory response, and resveratrol could down-regulate the expression of MCP-1 via TNF-α- inhibition, which might contribute to the decline of acute PTE-induced PH in vivo.

Seawater inhalation induces acute lung injury via ROS generation and the endoplasmic reticulum stress pathway.

Seawater (SW) inhalation can induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In the present study, SW induced apoptosis of rat alveolar epithelial cells and histopathological alterations to lung tissue. Furthermore, SW administration increased generation of reactive oxygen species (ROS), whereas pretreatment with the ROS scavenger, N­acetyl­L­cysteine (NAC), significantly decreased ROS generation, apoptosis and histopathological alterations. In addition, SW exposure upregulated the expression levels of glucose­regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP), which are critical proteins in the endoplasmic reticulum (ER) stress response, thus indicating that SW may activate ER stress. Conversely, blocking ER stress with 4­phenylbutyric acid (4­PBA) significantly improved SW­induced apoptosis and histopathological alterations, whereas an ER stress inducer, thapsigargin, had the opposite effect. Furthermore, blocking ROS with NAC inhibited SW­induced ER stress, as evidenced by the downregulation of GRP78, phosphorylated (p)­protein kinase R­like ER kinase (PERK), p­inositol­requiring kinase 1α (IRE1α), p­50 activating transcription factor 6α and CHOP. In addition, blocking ER stress with 4­PBA decreased ROS generation. In conclusion, the present study indicated that ROS and ER stress pathways, which are involved in alveolar epithelial cell apoptosis, are important in the pathogenesis of SW­induced ALI.

MiR-23a-5p modulates mycobacterial survival and autophagy during mycobacterium tuberculosis infection through TLR2/MyD88/NF-κB pathway by targeting TLR2.

Autophagy plays a pivotal role in activating the antimicrobial host defense against Mycobacterium tuberculosis (M.tb.). The emerging roles of microRNAs (miRNAs) in regulating immune responses have attracted increasing attention in recent years. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the influence of miR-23a-5p on the activation of macrophage autophagy during M.tb. infection in bone marrow-derived macrophages (BMDMs) and murine RAW264.7 cells. Here, we demonstrated that M.tb.-infection of macrophages lead to markedly enhanced expression of miR-23a-5p in a time- and dose-dependent manner. Furthermore, forced expression of miR-23a-5p accelerated the survival rate of intracellular mycobacteria, while transfection with miR-23a-5p inhibitors attenuated mycobacterial survival. More importantly, overexpression of miR-23a-5p dramatically prevented M.tb.-induced activation of autophagy in macrophages, whereas inhibitors of miR-23a-5p remarkably accelerated M.tb.-induced autophagy. Mechanistically, miR-23a-5p is able to modulate TLR2/MyD88/NF-κB signaling activity by targeting TLR2 in RAW264.7 cells in response to M.tb.-infection. Collectively, these findings demonstrated that miR-23a-5p modulated the innate host defense by promoting mycobacteria survival and inhibiting the activation of autophagy against M.tb. through TLR2/MyD88/NF-κB pathway by targeting TLR2, which may provide a promising therapeutic target for tuberculosis.

Suppressive effects of intrathecal paeoniflorin on bee venom-induced pain-related behaviors and spinal neuronal activation.

Recently, paeoniflorin (PF) administered systemically was found to have analgesic effects against inflammatory pain and hypersensitivity in a naloxone-reversible manner. In the present study, we adopted intrathecal administration to evaluate whether PF has direct antinociceptive actions at the spinal level. Pain-related behaviors and spinal c-Fos expression were induced by subcutaneous injection of bee venom (BV) into one hind paw of a rat. Intrathecal pretreatment of PF resulted in an inhibition of the BV-induced persistent spontaneous nociception and partially suppressed the occurrence of both thermal and mechanical hypersensitivity. Moreover, the PF-produced antinociception was completely reversed by naloxone. We further evaluated the intrathecal effects of the drug on the BV-induced c-Fos expression. The result showed that intrathecal PF preconditioning was effective to suppress spinal c-Fos expression in both superficial (lamina I-II) and deep (lamina IV-VI) layers of the L(4-5) dorsal spine. This result showed that PF has a direct pharmacological action in the spinal cord dorsal horn via activation of opioid receptors.

Tanshinone IIA attenuates seawater aspiration-induced lung injury by inhibiting macrophage migration inhibitory factor.

Inflammation takes responsibility for the seawater aspiration-induced lung injury. Tanshinone IIA (TIIA) can protect lipopolysaccharide-induced lung injury in mice through the inhibition of inflammation, but it is not reported whether TIIA have a protective effect on lung injury induced by seawater aspiration. Macrophage migration inhibitory factor (MIF) plays an important role in acute lung injury. In this study, we observed the effect of TIIA on the seawater aspiration-induced lung injury and the role of MIF in it. Seawater was aspirated into trachea of rats to make the lung injury model. TIIA was administered to investigate its beneficial effect on seawater-induced acute lung injury. The results showed that seawater aspiration led to hyoxemia, pulmonary edema, neutrophil infiltration, and lung histopathologic changes, with the elevated MIF expression in the lung tissues and plasma. However, these changes were attenuated by TIIA. In macrophage cells we also demonstrated that TIIA could inhibit MIF expression, nuclear factor κB (NF-κB) activity and release of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) induced by seawater. Besides, pretreatment with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), the MIF antagonist, elevated NF-κB and cytokines induced by seawater were also reduced markedly. Furthermore, rMIF treatment alone increased the phosphorylation level of NF-κB and release of cytokines, which was almost abolished by TIIA. Taken together, our results suggested that TIIA exert a protective effect on the seawater aspiration-induced lung injury partly through downregulation of MIF and the subsequent NF-κB activity, as well as expression of IL-6 and TNF-α.

Sodium tanshinone iia sulfonate attenuates seawater aspiration-induced acute pulmonary edema by up-regulating Na(+),K(+)-ATPase activity.

Relieving pulmonary edema is the key of a successful treatment to seawater drowning. Sodium tanshinone IIA sulfonate (STS) has been observed to reduce lung edema from lipopolysaccharide (LPS)-induced lung injury. In this study the authors investigated whether STS attenuates seawater aspiration-induced acute pulmonary edema, and examined the effects of sodium-potassium adensosine triphosphatase (Na(+),K(+)-ATPase) on it. Seawater was instilled through an endotracheal tube. The anesthetized and spontaneously breathing rats received STS intraperitoneally after seawater aspiration. Pao(2), lung wet-to-dry weight ratio, and pulmonary microvascular permeability were tested. The authors explored the effects of STS on the expression and activity of Na(+),K(+)-ATPase in vivo and in vitro. Additionally, the authors investigated the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in the stimulation of Na(+),K(+)-ATPase by STS. The results showed that STS significantly improved hypoxemia, attenuated lung edema, and alleviated seawater-induced lung injury in vivo. Both in vivo and in vitro, it was observed that STS up-regulated the expression and activity of Na(+),K(+)-ATPase. ERK1/2 inhibitor partially blocked the effects of STS on Na(+),K(+)-ATPase activity in alveolar type II cells following seawater incubation. These results indicated that STS could improve seawater aspiration-induced acute pulmonary edema by up-regulating Na(+),K(+)-ATPase activity, and the ERK1/2 signaling pathway may be involved in it.

Tanshinone IIA suppresses lung injury and apoptosis, and modulates protein kinase B and extracellular signal-regulated protein kinase pathways in rats challenged with seawater exposure.

1. Tanshinone IIA (TIIA) is one of the main active components of the Chinese herb, Danshen. In the present study, we investigated the role of apoptosis in seawater exposure-induced acute lung injury (ALI), and explored the effects of TIIA on lung injury, apoptosis, and protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK) pathways in seawater-challenged rats. The rats were randomly divided into four groups: (i) naive group, no drug was given; (ii) TIIA control group, TIIA (50 mg/kg) was given intraperitoneally; (iii) seawater (SW) group, seawater (4 mL/kg) was given; and (iv) TIIA/SW group, TIIA (50 mg/kg) was injected intraperitoneally 10 min after seawater instillation. 2. The results showed that TIIA treatment significantly improved seawater exposure-induced lung histopathological changes, alleviated the decrease in PaO(2) , and reduced lung oedema, vascular leakage and cell infiltration. As shown by terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) assay, seawater exposure induced apoptosis in lung tissue cells. Furthermore, seawater exposure also changed apoptosis-related factors Bcl-2 and caspase-3, and caused a reduction in the activation of Akt and ERK1/2 pathways. Furthermore, TIIA treatment decreased the number of apoptotic cells, reversed changes in Bcl-2 and caspase-3, and upregulated the activation of Akt and ERK1/2 in seawater-challenged rats. 3. In conclusion, the data suggest that apoptosis might play an important role in seawater exposure-induced lung injury and that TIIA could significantly attenuate the severity of ALI and apoptosis in seawater-challenged rats, which is possibly through modulation of Akt and ERK1/2 pathways.

[Joint application of 7 interventional pulmonology methods in early diagnosis of lung cancer].

OBJECTIVE: To evaluate the combination of 7 interventional pulmonology methods in early diagnosis of lung cancer. METHODS: A total of 467 patients with thoracic and pulmonary lesions (include hilum pulmonis lymphadenectasis, mediastinal lymphadenectasis, pulmonary scobination, lump, lamellar infiltration, small amount of pleural fluid and pleural scobination) had negative results via exfoliative cytology, bacteriology and routine bronchoscopy. All these patients had ultrathin bronchoscopy with biopsy and brushing. For those 155 cases whose foci were located at porta pulmonis, inner zone or median zone, the authors applied ultrathin bronchoscopy with biopsy and brushing guided by X-ray. For those 95 cases whose foci were located at median zone or outer zone and unconnected with chest wall, per cutem lung puncture needle aspiration was employed under the guidance of X-ray. For those 102 cases whose foci were tightly connected with pleural membrane, per cutem lung puncture biopsy was employed under the guidance of type-B ultrasonic. For those 59 cases with suspected central airway foci, auto-fluorescence bronchoscopic biopsy and brushing were employed. For those 67 cases with hilum pulmonis or mediastinal lymphadenectasis, endobronchial ultrasonic transbronchial needle aspiration (EBUS-TBNA) was employed. For those 23 cases with small amount of pleural fluid or pleural scobination, electronic thoracoscopic biopsy and brushing were employed. RESULTS: It was found that 118 cases were diagnosed by ultrathin bronchoscopic biopsy and brushing with a positive rate of 25.3% (118/467), 105 cases by ultrathin bronchoscopy with biopsy and brushing guided by X-ray with a positive rate of 67.7% (105/155), 63 cases by per cutem lung puncture needle aspiration under the guidance of X-ray with a positive rate of 66.3% (63/95), 69 cases by per cutem lung puncture biopsy under the guidance of type-B ultrasound with a positive rate of 67.6% (69/102), 18 cases by auto-fluorescence bronchoscopic biopsy and brushing with a positive rate of 35.3% (18/51), 52 cases by EBUS-TBNA with a positive rate of 77.6% (52/67), 12 cases by electronic thoracoscopic biopsy and brushing with a positive rate of 52.2% (12/23). The total positive diagnostic rate was 93.6% (437/467). And the diagnostic rate of < or = stage II lung cancer (3 cases carcinoma in situ, 84 stage I a, 63 stage Ib, 65 stage IIa and 44 stage IIb) was 82.7% (259/313). CONCLUSION: Joint application of these 7 interventional bronchoscopic techniques can significantly boost the rate of early diagnosis of lung cancer.

[Efficacy and safety of argon plasma coagulation in the treatment of obstructive tracheobronchial stenosis].

OBJECTIVE: To evaluate the efficacy and safety of argon plasma coagulation (APC) in the treatment of large airway obstruction. METHODS: Totally 389 patients with treacheobronchial stenosis were treated with APC (ARCO3000 type) by bronchoscopy. The stenoses were caused by carcinomas (203 cases, 52.2%), metastatic tumors (67 cases, 17.2%), benign tumors (18 cases, 4.6%), granulomas (93 cases, 23.9%) and other lesions (8 cases, 2.1%). The rate of recanalization, relief of the symptoms, and complications were analyzed. RESULTS: 1121 times of APC treatment were performed in the 389 patients. Complete recanalization was achieved in 138 cases (35.5%), partial in 143 (36.8%), mild in 55 (14.1%) and none in 53 (13.6%). The major complications included: super-ventricular tachycardia in 136 cases (34.9%), bleeding in 51 (13.1%), decrease in blood oxygen saturation in 48 (12.3%), asphyxia in 33 (8.5%), ventricular or super-ventricular arrhythmia in 24 (6.2%), short-term aggravation of airway obstruction in 18 (4.6%), and tracheal perforation in 3 (0.78%). All those complications were treated with various measures and no patient died of the complications during the procedure. CONCLUSION: Argon plasma coagulation is effective and relatively safe in relieving the obstruction and dyspnea in patients with large airway obstruction caused by various reasons. However, for the patients with severe airway obstruction, argon plasma coagulation sometimes may cause severe or even lethal complications. Critical consideration of the indication, operators' skill and taking more precautions during the procedure are required to ensure the safety of argon plasma coagulation treatment.

[Effect of IL-4 on ABCG2 expression in human lung adenocarcinoma cell lines].

AIM: To investigate the effect of IL-4 on the expression of ABCG2 in lung adencarcinoma cell lines. METHODS: The ABCG2 mRNA and protein expression was determined by semi-quantitative RT-PCR and Western blot respectively. RESULTS: The ABCG2 mRNA and protein was detectable in lung adencarcinoma cell lines A549 and SPC-A-1. But IL-4 stimulation did not significantly affect the ABCG2 mRNA and protein expression in lung adencarcinoma cell lines. CONCLUSION: IL-4 does not regulate ABCG2 expression in human lung adencarcinoma cell lines.

[Exploration of serum endothelin-1 as a marker of early radiation lung injury].

AIM: To explore the possibility of endothelin-1(ET-1) as a serological marker of early diagnosis and progression of radiation induced lung injury. METHODS: One hundred and ninety female rats were randomly divided into control group (group C) and experimental groups, namely, radiation group (group R), fluvastatin treatment group (group Flu), retinoic acid treatment group (group Ra) and dexemethasone treatment group (group Dex). The chests of rats in experimental groups were exposed to radiation by linear accelerator after anesthesia. The radiation dose for each rat was 15Gy, 2Gy per minute, and radiation distance was 1 meter. The next day after radiation, fluvastatin (20 mg. kg(-1). d(-1) ) was administered orally in group Flu, retinoic acid (20 mg. kg(-1). d(-1)) in group Ra and dexemethasone (3.33 mg. kg(-1). d(-1)) in group Dex. The rats in group C and group R were medicated with the equal volume of normal saline. On the 5th, 15th, 30th, and 60th day after radiation, five rats were randomly chosen from each group respectively. The sera were harvested by decapitation or cardiopuncture and at the same time, lung tissues were cut off. The levels of serum ET-1 and LN were detected by radioimmunological assay(RIA). The pathologic changes of lung tissue were observed under light microscope. RESULTS: Compared to the control group, serum ET-1 level began to increase on the 5th day after exposure to radiation and reached the peak on the 60th day in group R. The levels of laminin and hyaluronic acid began to rise on the 30th day and the 60th day respectively. The elevation of serum ET-1 level in group R was obviously earlier than that in other groups and correlated to extent of lung injury. CONCLUSION: The serum ET-1 can be used as a marker of early diagnosis and dynamic changes of radiation lung injury.