Periodontal disease is the major cause of adult tooth loss and is commonly characterized by a chronic inflammation caused by infection of oral bacteria. Porphyromonas gingivalis ( P. gingivalis ) is one of the suspected periodontopathic bacteria and is frequently isolated from the periodontal pockets of patients with chronic periodontal disease. The lipopolysaccharide (LPS) of P. gingivalis is a key factor in the development of periodontitis. Gingival fibroblasts, which are the major constituents of gingival connective tissue, may directly interact with bacteria and bacterial products, including LPS, in periodontitis lesions. It is suggested that gingival fibroblasts play an important role in the host responses to LPS in periodontal disease. P. gingivalis LPS enhances the production of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF-␣ ) in gingival fibroblasts. However, the receptor that binds with P. gingivalisLPS on gingival fibroblasts remained unknown for many years. Recently, it was demonstrated that P. gingivalis LPS binds to gingival fibroblasts. It was also found that gingival fibroblasts express CD14, Toll-like receptor 4 (TLR4), and myeloid differentiation primary response gene 88 (MyD88). P. gingivalis LPS treatment of gingival fibroblasts activates several intracellular proteins, including protein tyrosine kinases, and up-regulates the expression of monocyte chemoattractant protein-1 (MCP-1), extracellular signal-regulated kinase 1 (ERK1), and signal-regulated kinase 2 (ERK2), IL-1 receptor-associated kinase (IRAK), nuclear factor-B (NF-B), and activating protein-1 (AP-1). These results suggest that the binding of P. gingivalis LPS to CD14 and TLR4 on gingival fibroblasts activates various second-messenger systems. In this article, we review recent findings on the signaling pathways induced by the binding of P. gingivalis LPS to CD14 and Toll-like receptors (TLRs) in gingival fibroblasts.

Background Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling. Objectives To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling. Methods The airways of Shp2flox/flox mice were infected with recombinant adenovirus vectors expressing a Cre recombinase–green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1. Results Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression. Conclusions SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation. Clinical Implications Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP2 represents a potentially novel therapeutic target for the treatment of asthmatics.

Dear Editor,Uncommon mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene account for 10%-15% of all EGFR mutations when considered as a whole group [1,2]. However, each variant confers heterogeneous clinical outcomes to different generations of EGFR tyrosine kinase inhibitors (TKIs) with G719X, L861Q, and/or S768I showing adequate sensitivity to EGFR inhibition [1][2][3]. Osimertinib, based on its superior survival outcomes, has become the preferred first-line treatment for patients diagnosed with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations [4]; however, its efficacy in patients harboring G719X, S768I, and/or L861Q mutations was comparable or even inferior to Afatinib [5]. Afatinib, a second-generation EGFR-TKI, has received approval for extended clinical indication in treating previously untreated patients with metastatic NSCLC harboring G719X, L861Q, and/or S768I based on the findings from the pooled analysis of three clinical trials (LUX-Lung 2/3/6) [2]. The real-world clinical efficacy of Afatinib for treating this patient subset has been consistently demonstrated by two large retrospective studies [6,7]. In China, chemotherapy remains a standard first-line treatment for this patient subset, with Afatinib available only as an off-label treatment option.Mefatinib is a novel, second-generation EGFR-TKI with promising clinical efficacy and safety for patients with common EGFR mutations [8]. Here, we report the results of the phase II open-label, single-arm, multicenter study investigating the efficacy and safety of Mefatinib as firstline therapy for patients with NSCLC harboring uncommon EGFR mutations (ChiCTR2000029058).