Treatment efficacy of HER2-mutant lung adenocarcinoma by immune checkpoint inhibitors: a multicenter retrospective study.

BACKGROUND: Despite the remarkable clinical advance of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, there are limited studies focused on evaluating efficacy of ICIs for patients with human epidermal growth factor receptor 2 (HER2)-mutant lung adenocarcinoma. METHODS: We conducted a multicenter retrospective study of patients with HER2-mutant lung adenocarcinoma who received ICIs therapy at Shanghai Pulmonary Hospital, Shanghai Chest Hospital and the First Affiliated Hospital of Wenzhou Medical University between 2016 and 2021. Response was defined with reference to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: Among the 26 patients enrolled in our study, the overall objective response rate (ORR) was 38.5%, disease control rate (DCR) was 84.6% and median progression-free survival (PFS) was 7.4 months. Majority of patients were treated with immunochemotherapy combination regimens (16/26, 61.5%), with a median PFS of 8.4 months. Among the 9 patients receiving ICIs-based therapy as first-line treatment, 5 patients had partial response (PR) and 4 patients had stable disease (SD), with a median PFS of 9.1 months. Of the entire cohort, 5 patients who received ICIs before epidermal growth factor receptor (EGFR)/HER2-targeting drugs achieved a median PFS of 8.4 months. CONCLUSION: Our retrospective study provides clinical evidence that front line of ICIs-based therapy is also worth considering for the treatment to improve survival outcomes of patients with HER2-mutant lung adenocarcinoma.

Recurrent pneumothorax and intrapulmonary cavitary lesions in a male patient with vascular Ehlers-Danlos syndrome and a novel missense mutation in the COL3A1 gene: a case report.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant hereditary collagen disease caused by a defect or deficiency in the pro-α1 chain of type III procollagen encoded by the COL3A1 gene. Patients with vEDS rarely present with multiple pneumothoraces. The clinical features of this disease are not familiar to clinicians and are easily missed. We report a patient with a novel missense mutation in the COL3A1 gene (NM_000090.3: c.2977G > A) and hope to provide clinicians with valuable information. CASE PRESENTATION: We reported the case of a young man presenting with frequent episodes of pneumothorax and intrapulmonary cavities and nodular lesions without arterial or visceral complications. His skin was thin and transparent, and the joints were slightly hypermobile. Whole-exome sequencing (chip capture high-throughput sequencing) revealed a heterozygous missense mutation in exon 41 of the COL3A1 gene (NM_000090.3: c.2977G > A), confirming the diagnosis of vEDS. vEDS remains a very rare and difficult diagnosis to determine. CONCLUSION: When a patient presents with recurrent pneumothorax, intrapulmonary cavities and nodular lesions, thin and transparent skin, and hypermobile joints, clinicians should consider the diagnosis of vEDS.

Arbutin attenuates LPS-induced lung injury via Sirt1/ Nrf2/ NF-κBp65 pathway.

The main goal of this study was to evaluate the effects of arbutin (AR) on lipopolysaccharide (LPS)-induced lung injury. A lung injury rat model was established by intravenous LPS administration. We found that levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6) in both serum and lung tissue were significant increased after LPS challenge. In addition, pathological conditions were examined in rat lungs, and it was demonstrated that AR-pretreatment reduced LPS-induced malondialdehyde (MDA) levels and increased LPS-induced superoxide dismutase (SOD) activity. Moreover, the expression of sirtuin1 (SIRT1), nuclear erythroid factor 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) as well as the phosphorylation of NF-κBp65 and IκBα were increased with LPS-induced lung injury, and were significantly restored by AR treatment. Together, our results indicated that SIRT1 is a potential therapeutic target in LPS-induced lung injury, and that AR may be a novel therapeutic in patients with acute lung injury.

Antioxidant mitoquinone ameliorates EtOH-LPS induced lung injury by inhibiting mitophagy and NLRP3 inflammasome activation.

Chronic ethanol abuse is a systemic disorder and a risk factor for acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). However, the mechanisms involved are unknown. One explanation is that ethanol produces damaging reactive oxygen species (ROS) and disturbs the balance of mitochondria within the lungs to promote a pro-injury environment. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate EtOH-LPS-induced lung injury. To test this, we investigated the effects of mitochondria-targeted ubiquinone, Mitoquinone (MitoQ) on ethanol-sensitized lung injury induced by LPS. Lung inflammation, ROS, mitochondria function, and mitophagy were assessed. We demonstrated that chronic ethanol feeding sensitized the lung to LPS-induced lung injury with significantly increased reactive oxygen species ROS level and mitochondrial injury as well as lung cellular NLRP3 inflammasome activation. These deleterious effects were attenuated by MitoQ administration in mice. The protective effects of MitoQ are associated with decreased cellular mitophagy and NLRP3 inflammasome activation in vivo and in vitro. Taken together, our results demonstrated that ethanol aggravated LPS-induced lung injury, and antioxidant MitoQ protects from EtOH-LPS-induced lung injury, probably through reducing mitophagy and protecting mitochondria, followed by NLRP3 inflammasome activation. These results will provide the prevention and treatment of ethanol intake effects with new ideas.

The epidemic of erythromycin-resistant Bordetella pertussis with limited genome variation associated with pertussis resurgence in China.

BACKGROUND: The resurgence of Bordetella pertussis infections leading to whooping cough is a concern in many parts of the world. The number of pertussis cases in China has increased significantly since 2013. RESEARCH DESIGN AND METHODS: In this study, whole-genome sequencing analysis was performed for 388 B. pertussis strains isolated in China from the 1970s to 2018, combining 594 published strains from around the world. RESULTS: This study revealed that lineage V diverged about 50 years ago in China, while lineage IV is dominant in the other countries. It also revealed that the erythromycin-resistant sub-lineages Va, Vb, and Vc with limited genomic variation emerged 11 ~ 12 years ago. These three sub-lineages were identified after the co-purified acellular vaccines (cp-ACVs) completely replaced the previous whole cell vaccines (WCVs) after the national immunization program of 2012. It suggests that the cp-ACVs cannot induce immunity that is potent enough to restrict the spread of the lineage V, antibiotic abuse further favors the spread of this lineage in China. CONCLUSIONS: These findings demand a reassessment of the immunization strategy and development of new vaccines in China to stop the resurgence and drug resistance of B. pertussis.

Protective effects of hesperetin on lipopolysaccharide-induced acute lung injury by targeting MD2.

Inflammation plays an important role in acute lung injury (ALI). Hesperetin (HES), a natural flavanone and an aglycone of hesperidin, has established potent anti-inflammatory activity. The aim of this study was to evaluate the potential protective effect of HES on lipopolysaccharide (LPS)-induced ALI in mice and to illuminate its possible directly target. Results indicated that HES pretreatment significantly attenuated LPS-induced pulmonary pathological injury, total protein concentration, markedly decreased the number of neutrophils and the levels of inflammatory cytokines, TNF-α and IL-6, in ALI model in vivo and in vitro. Meanwhile, pretreatment with HES dramatically reduced myeloperoxidase (MPO) activity in LPS-induced ALI mice. Additionally, using molecular docking and co-immunoprecipitation assay, HES showed a directly bind with myeloid differentiation 2 (MD2), in which HES could inhibit MAPK activation, regulate IκB degradation, block the interaction MD2 and its co-receptor Toll-like receptor 4 (TLR4). Taken together, HES showed a significantly protective effect against LPS-induced ALI, which might be associated with MD2 protein. These results attested HES worthy of further progress into an adjunctive potential drug for the treatment for ALI.

Dynamics of Plasma EGFR T790M Mutation in Advanced NSCLC: A Multicenter Study.

BACKGROUND: Droplet digital polymerase chain reaction (ddPCR) is an emerging technology for quantitative cell-free DNA oncology applications. However, a ddPCR assay for the epidermal growth factor receptor (EGFR) p.Thr790Met (T790M) mutation suitable for clinical use remains to be established with analytical and clinical validations. OBJECTIVE: We aimed to develop and validate a new ddPCR assay to quantify the T790M mutation in plasma for monitoring and predicting the progression of advanced non-small-cell lung cancer (NSCLC). METHODS: Specificity of the ddPCR assay was evaluated with genomic DNA samples from healthy individuals. The inter- and intraday variations of the assay were evaluated using mixtures of plasmid DNA containing wild-type EGFR and T790M mutation sequences. We assessed the clinical utility of the T790M assay in a multicenter prospective study in patients with advanced NSCLC receiving tyrosine kinase inhibitor (TKI) treatment by analyzing longitudinal plasma DNA samples. RESULTS: We set the criteria for a positive call when the following conditions were satisfied: (1) T790M mutation frequency > 0.098% (3 standard deviations above the background signal); (2) at least two positive droplets in duplicate ddPCR reactions. Among the 62 patients with advanced NSCLC exhibiting resistance to TKI treatment, 15 had one or more serial plasma samples that tested positive for T790M. T790M mutation was detected in the plasma as early as 205 days (median 95 days) before disease progression, determined by imaging analysis. Plasma T790M concentrations also correlated with intervention after disease progression. CONCLUSIONS: We developed a ddPCR assay to quantify the T790M mutation in plasma. Quantification of longitudinal plasma T790M mutation may allow noninvasive assessment of drug resistance and guide follow-up treatment in TKI-treated patients with NSCLC. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02804100.

Paeoniflorin inhibits pulmonary artery smooth muscle cells proliferation via upregulating A2B adenosine receptor in rat.

Paeoniflorin (PF), which is the main active ingredient in the root of Paeonia Radix, has many pharmacological effects. Here, we investigated the effect of PF on rat pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions and explored the mechanisms of the effects. The anti-proliferative effect of PF increased in a dose dependent manner. At the highest dose (20 µmol/L), the anti-proliferative effect of PF peaked at 24 h after administration. However, the selective A2B adenosine receptor (A2BAR) antagonist MRS1754 abolished it. PF increased A2BAR mRNA levels from 0.0763±0.0067 of ß-actin mRNA levels (hypoxia group) to 0.1190±0.0139 (P<0.05) measured by Real Time Reverse Transcription-Polymerase Chain Reaction. A2BAR protein expression measured by Western Blot was also increased. PF inhibited the proliferation of PASMCs by blocking cell cycle progression in the S phase. These data indicated that activation of A2BAR might be involved in the anti-proliferative effect of PF on PASMCs under hypoxic conditions. The results suggested that a new mechanism of PF could be relevant to the management of clinical hypoxic pulmonary hypertension.