This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment of stage Ⅲ-N2 EGFR-mutant NSCLC patients. The medical records of patients with Ⅲ-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the observation group, and those who received EGFR-TKI monotherapy were included in the control group. A total of 74631 EGFR-mutant NSCLC patients were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (p =0.495). MPR was observed in 20.0% (3/15) and 10.5% (4/38) of patients in the combination and monotherapy groups, respectively (p =0.359). No patients achieved PCR in the combination group, while three attained PCR in the monotherapy group. The two groups did not differ in N2 downstaging rate (p =0.459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (p = 0.832). Adverse events observed were consistent with those commonly associated with the two treatments. Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for NSCLC patients of EGFR-mutant stage III-N2, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.
Nestin is an intermediate filament protein expressed in neural progenitor cells and in developing skeletal muscle. Nestin has been widely used as a neural progenitor cell marker. It is well established that the specific expression of the nestin gene in neural progenitor cells is conferred by the neural-specific enhancer located in the second intron of the nestin gene. However, the transcriptional mechanism of nestin expression in developing muscle is still unclear. In this study, we identified a muscle cell-specific enhancer in the first intron of mouse nestin gene in mouse myoblast C2C12 cells. We localized the core enhancer activity to the 291-661 region of the first intron, and showed that the two E-boxes in the core enhancer region were important for enhancer activity in differentiating C2C12 cells. We also showed that MyoD protein was involved in the regulation of nestin expression in the myogenic differentiation of C2C12 cells.
Abstract Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13 mutant trachea phenotypes. These results provide insights into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
To investigate whether homocysteine (Hcy) participates the proliferation of the spontaneously hypertensive rat(SHR) vascular smooth muscle cell (VSMCs) and the molecular mechanism.The rat's arota were removed. The primary SHR VSMCs were isolated and cultured in vitro, then the SHR VSMCs were divided into four groups: (1) control group, (2) Hcy group, (3) 18alpha-glycyrrhetinic acid (GA) group, (4) Hcy + 18alpha-GA group. We detected proliferation of the SHR VSMCs by MTT and flow cytometry. The expression and co-localization of the connexin (Cx) 43 and Cx40 proteins in the SHR VSMCs were deteced by immunofluorescence. The expression of the Cx43 and Cx40 proteins in SHR VSMCs were detected by Western blot. The molecular dye transfer method (scrape dye transfer method) was applied to detect the gap junction function in the SHR VSMCs.(1) The Cx43 and Cx40 proteins expression in the SHR VSMCs were positive, confocal microscopy supported the co-localization of Cx43 and Cx40 in the cytoplasm. (2) The S value deteced by cell cycle and A value detected by MTT in the Hcy group were increased obviously compared with those in the control group (P < 0.05), decreased in 18alpha-GA group (P < 0.05). Compared with the Hcy group, the S and A value in the Hcy + 18alpha-GA group were significantly decreased, respectively (P < 0.05). (3) The expression of Cx43 and Cx40 proteins in Hcy group were increased compared with the control group (P < 0.05), decreased in 18alpha-GA group (P < 0.05). Compared with the Hcy group, the expression of Cx43 and Cx40 proteins in the Hcy + 18alpha-GA group were significantly decreased, respectively (P < 0.05). (4) The function of gap junction detected by scrape dye transfer method in the Hcy group were enhanced compared with the control group (P < 0.05), weakened in the 18alpha-GA group (P < 0.05). Compared with the Hcy group,the function of gap junction in the Hcy + 18alpha-GA group was significantly weakened (P < 0.05).Hcy can enhance the function of gap junctional to stimulate the proliferation of SHR VSMCs through the expression of Cx43 and Cx40 proteins promoted.
e21140 Background: Limited data is known regarding osimertinib plus anlotinib as first line treatment in EGFRm advanced NSCLC patients. Earlier we have reported that osimertinib in combination with anlotinib was well tolerated. Here we further present the efficacy and safety profile of the combined therapy. Methods: In this phase Ib/IIa, open-label study, treatment-naïve patients with an activating EGFR mutation, advanced or metastatic lung adenocarcinoma were eligible. Patients with stable CNS metastases were allowed to enroll. Patients were treated with anlotinib at dose of 8mg, 10mg and 12mg, all patients received osimertinib 80mg. Primary endpoint was objective response rate (ORR) by investigator using RECIST v1.1. Secondary endpoints include disease control rate (DCR), depth of response, median progression free survival, overall survival rate at 12 months and safety profile. Data cut-off: Nov. 23 rd , 2021. Results: From November 2020 through June 2021, 25 patients were enrolled in the study and started treatment. Median age was 59 years (38-77years), 11 (44%) were female, 24 (96%) were ECOG PS 1. 24 (96%) patients were stage IV and 6 (24%) had CNS metastases. At DCO, 18 (72%) patients remained on treatment. Among 23 response evaluable patients, the overall ORR was 65.2% (95%CI 42.7,83.6), DCR was 95.7% (95%CI 78.0,99.9) and median depth of response was -40.7% (range, -70.6 to 49.7). Adverse events (AEs) were observed in 21 (84%) patients. The most common AEs were platelet count decreased (56.5%), thyroid-stimulating hormones increased (39.1%) and diarrhea (30.4%), no unexpected AEs occurred. Grade≥3 AEs and SAEs were experienced by 5 (20%) and two (8.0%) patients, respectively. Dose reduction occurred in 8 (32%) patients and all were related to anlotinib. There was no fatal AE event reported in this study. Conclusions: Osimertinib in combination with anlotinib as first-line treatment for naïve EGFRm advanced NSCLC patients showed encouraging antitumor activity with manageable safety profile. The study is ongoing and more results will be updated in the future. Clinical trial information: NCT04770688.
A tripolarization and low-profile planar antenna is designed, prototyped, and tested for WLAN application. The developed three-port antenna provides three orthogonal polarization radiations. Two slot-coupled microstrip antennas and a disk-loaded monopole are integrated into one structure. The total height of the antenna is 5.8 mm. Obtained gain for the two slot-coupled directive elements at 2.42 GHz is 7 dBi, while the gain for the monopole omnidirectional element is 2.5 dBi. The bandwidths of the three elements are 2.352.52, 2.32.54, and 2.382.49 GHz, respectively. Simulation results of the radiation patterns are presented and validated by experimental measurements.
The present study aimed to investigate the association of CD45RO+, CD8+, CCR7+ and FOXP3+ tumor-infiltrating lymphocytes (TILs) with the clinicopathological features as well as survival of patients with lung adenocarcinoma.Ninety patients with lung adenocarcinoma who underwent surgery were recruited in the present study. Lung adenocarcinoma tissues and paired adjacent lung tissues were obtained from all participants, and immunohistochemistry was performed to detect the expression of CD45RO, CD8, CCR7 and FOXP3. After multiplying the staining intensity score by the labeling frequency score, the immunohistochemical results were divided into three groups: TILs low, TILs intermediate and TILs high.CD45RO+, CD8+ and CCR7+ infiltrating lymphocytes were markedly increased in lung adenocarcinoma (all P<0.001) while FOXP3+ infiltrating lymphocytes were reduced (P<0.001) compared with than in adjacent tissues. CD45RO+ TILs were negatively associated with tumor size (P=0.002), lymph node metastasis (P<0.001) and TNM stage (P<0.001). CD8+ TILs were also negatively correlated with lymph node metastasis (P=0.016). Kaplan-Meier curve analysis revealed that CD45RO+ TILs were positively associated with longer disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001). Univariate and multivariate Cox's proportional hazards regression confirmed that CD45RO+ TILs (high) independently predicted longer DFS (P=0.002) and OS (P=0.009).The present study demonstrates that CD45RO+ TILs are negatively correlated with tumor size, lymph node metastasis and TNM stage and that CD45RO+ TILs (high) can be regarded as a novel and promising biomarker for prolonged DFS and OS in lung adenocarcinoma patients.
Currently, many detection methods have high sensitivity to the diagnosis of lung cancer. However, some postoperative patients with pulmonary nodules are eventually diagnosed as having benign nodules. The ideal evaluation of an individual with a pulmonary nodule would expedite therapy for a malignant nodule and minimize testing for those with a benign nodule.This case-control study is designed to explore the relationship between ACE1 rs4646994 polymorphism and the risk of lung cancer in patients with pulmonary nodules, for which 400 individuals with lung cancer and benign pulmonary nodules were included. A DNA extraction kit was used to extract DNA from peripheral blood. The relationship between ACE1 rs4646994 and the risk of lung cancer in patients with pulmonary nodules was determined by the chi-square test, logistic regression analysis and cross analysis.The results showed that after adjusting for age and gender confounding factors, the risk of lung cancer in patients with pulmonary nodules carrying the DD genotype was more than three times that of the I carriers (II + ID) genotype (OR = 3.035, 95% CI, 1.252-7.356, p = 0.014). There was no significant difference between lung squamous cell carcinoma and lung adenocarcinoma in the polymorphism of ACE1 rs4646994 (p > 0.05). We also found that the ACE1 rs4646994 DD genotype frequency was inversely correlated with the risk of EGFR mutation in lung adenocarcinoma patients.Our study indicated that ACE1 rs4646994 polymorphism increases the risk of lung cancer in patients with pulmonary nodules from China.
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