[Role of CTGF and PI3K/Akt signaling pathway in paraquat-induced mesenchymal changes in alveolar epithelial cells].

Objective: To investigate the role of connective tissue growth factor (CTGF) and PI3K/Akt signaling pathways in paraquat (PQ) -induced alterations in alveolar epithelial cell mesenchymalization (EMT) . Methods: In February 2023, RLE-6TN cells were divided into 2 groups, which were set as uncontaminated group and contaminated group (200 µmol/L PQ), and cellular EMT alteration, CTGF and PI3K/Akt signaling pathway related molecules expression were detected by cell scratch assay, qRT-PCR and western-blot assay. Using shRNA interference technology to specifically inhibit the expression of CTGF, RLE-6TN cells were divided into four groups: control group, PQ group (200 µmol/L PQ), interference group (transfected with a plasmid with shRNA-CTGF+200 µmol/L PQ), and null-loaded group (transfected with a plasmid with scramble- CTGF+200 µmol/L PQ), qRT-PCR and western blot were used to examine the alteration of the cellular EMT and the expression of molecules related to the activity of PI3K/Akt pathway. The PI3K/Akt signaling pathway was blocked by the PI3K inhibitor LY294002, and the expression of EMT-related molecules in cells of the control group, PQ group (200 µmol/L PQ), and inhibitor group (200 µmol/L PQ+20 µmol/L LY294002) was examined by qRT-PCR and western blot.The t-test was used to compare the differences between the two groups, while the analysis of variance (ANOVA) was applied to compare the differences among multiple groups. For further pairwise comparisons, the Bonferroni method was adopted. Results: The results of cell scratch test showed that compared with the uncontaminated group, RLE-6TN cells in the contaminated group had faster migration rate, lower mRNA and protein expression levels of E-Cadherin, and higher mRNA and protein expression levels of α-SMA, CTGF, PI3K and Akt, with statistical significance (P<0.05). After specific inhibition of CTGF expression, the mRNA and protein expression of CTGF, PI3K, Akt, and α-SMA in the cells of the interference group were significantly lower than that of the PQ group and the null-loaded group (P<0.05/6), whereas that of E-Cadherin was higher than that of the PQ group and the null-loaded group (P<0.05/6). Specifically blocking the PI3K/Akt signaling pathway, the mRNA and protein expression of PI3K, Akt and α-SMA in the cells of the inhibitor group was decreased compared with that of the PQ group (P<0.05/3), while the expression of E-Cadherin was elevated compared with that of the PQ group (P<0.05/3) . Conclusion: CTGF may promote PQ-induced alveolar epithelial cell EMT through activation of the PI3K/Akt signaling pathway. Inhibition of CTGF expression or blockade of PI3K/Akt signaling pathway activity can alleviate the extent of PQ-induced alveolar epithelial cell EMT.

SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.

BACKGROUND: SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined. PATIENTS AND METHODS: We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts. RESULTS: Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNFmut NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNFmut NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection. CONCLUSIONS: This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNFmut and TP53mut subgroups.

[The ninth edition of TNM staging for lung cancer: precise staging for precise diagnosis and treatment].

The ninth edition of TNM staging for lung cancer has been announced at the 2023 World Lung Cancer Congress and implemented from January 1, 2024. The focus of the ninth TNM staging change is dividing N2 into N2a and N2b, as well as M1c into M1c1 and M1c2. Although the T staging has not changed, it has played an important role in verifying the eighth edition of the T staging. The subdivision of stage N2 has led some patients with ⅢA of the eighth edition to experience ascending or descending stages, which will more accurately help to assess the condition and prognosis of patients with mediastinal lymph node metastasis, as well as the design of related clinical studies. Modifying the M1c staging will help define oligometastasis and explore new treatment models in the future. The ninth edition of the TNM staging system provides a more detailed division of different tumor loads, but there is no clear explanation for the staging of lung cancer after neoadjuvant therapy. Further data analysis is needed, and it is expected to be answered in the tenth edition of TNM staging.

[Introduction to the 9th edition of TNM classification for lung cancer].

Lung cancer is the second commonly diagnosed cancer and remained the leading cause of cancer-related death, with an estimated 1.8 million deaths in 2020. The identification of driver gene mutation and administration of corresponding tyrosine kinase inhibitor have improved overall survival and quality of life in advanced lung cancer patients. Check point inhibitor has revolutionized treatment strategy of driver gene negative advanced NSCLC patients. TNM staging system is the most widely used classification method, providing an international common language during academic communication and important tool for predicting prognosis and subsequent treatment decision making. Accumulating knowledge about prognostic factors in lung cancer promotes the update of TNM classification. In the World Conference on Lung Cancer (WCLC) held in Singapore, September, 2023, International Association for Study of Lung Cancer (IASLC) released the forthcoming 9th edition of TNM classification for lung cancer, which is supposed to be adopted at January, 2024. The manuscript discussed the history, data resource and limitation of the TNM staging system.

Imaging features of temporomandibular joint synovial chondromatosis with associated osseous degenerative changes.

Synovial chondromatosis (SC) of the temporomandibular joint (TMJ) is a rare benign disease associated with the formation of multiple cartilaginous nodules in the synovial tissue of the TMJ. This can result in pain, swelling, clicking, limited mouth opening, and osseous degenerative joint changes. A retrospective cross-sectional study was performed to summarize the clinical features, radiographic findings, and surgical and histopathological findings of TMJ SC patients who underwent open surgery over a 24-year period. A radiographic scoring system was used to evaluate osseous changes and correlate condyle and joint fossa degeneration. The study included 38 patients and focused on 38 joints. All 38 of these joints showed degenerative changes in the condyle, while 37 showed osseous degenerative changes in the articular fossa. The degree of condylar degenerative changes was related to the duration of the chief complaints (r = 0.342, P = 0.036) and the histopathological stage of the TMJ SC (r = 0.440, P = 0.006), while the degree of joint fossa degenerative changes was associated with the radiographic extent of the SC (r = 0.504, P = 0.001), type of calcification (r = 0.365, P = 0.024), and the histopathological stage (r = 0.458, P = 0.004).

[Prediction of microvascular invasion in hepatocellular carcinoma with magnetic resonance imaging using models combining deep attention mechanism with clinical features].

OBJECTIVE: To investigate the consistency and diagnostic performance of magnetic resonance imaging (MRI) for detecting microvascular invasion (MVI) of hepatocellular carcinoma (HCC) and the validity of deep learning attention mechanisms and clinical features for MVI grade prediction. METHODS: This retrospective study was conducted among 158 patients with HCC treated in Shunde Hospital Affiliated to Southern Medical University between January, 2017 and February, 2020. The imaging data and clinical data of the patients were collected to establish single sequence deep learning models and fusion models based on the EfficientNetB0 and attention modules. The imaging data included conventional MRI sequences (T1WI, T2WI, and DWI), enhanced MRI sequences (AP, PP, EP, and HBP) and synthesized MRI sequences (T1mapping-pre and T1mapping-20 min), and the high-risk areas of MVI were visualized using deep learning visualization techniques. RESULTS: The fusion model based on T1mapping-20min sequence and clinical features outperformed other fusion models with an accuracy of 0.8376, a sensitivity of 0.8378, a specificity of 0.8702, and an AUC of 0.8501 for detecting MVI. The deep fusion models were also capable of displaying the high-risk areas of MVI. CONCLUSION: The fusion models based on multiple MRI sequences can effectively detect MVI in patients with HCC, demonstrating the validity of deep learning algorithm that combines attention mechanism and clinical features for MVI grade prediction.

[Advances in the arthroscopic methods in managing temporomandibular joint disorders].

Temporomandibular joint disorders are common diseases characterized by joint clicking, limited mouth opening and pain, which have a huge impact on the patients' daily life. Conservative methods include medicine, physiotherapy and occlusal application. With the advancement of medical technology, the arthroscopy is becoming popular for its minimally invasion and high efficiency. This review focuses on the common arthroscopic methods, and provides an outlook of the arthroscopic surgery.

Early on-treatment tumor growth rate (EOT-TGR) determines treatment outcomes of advanced non-small-cell lung cancer patients treated with programmed cell death protein 1 axis inhibitor.

BACKGROUND: Tumor growth rate (TGR), denoted as percentage change in tumor size per month, is a well-established indicator of tumor growth kinetics. The predictive value of early on-treatment TGR (EOT-TGR) for immunotherapy remains unclear. We sought to establish and validate the association of EOT-TGR with treatment outcomes in patients with advanced non-small-cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 (programmed cell death protein 1/programmed death-ligand 1) therapy. PATIENTS AND METHODS: This bicenter retrospective cohort study included a training cohort, a contemporaneously treated internal validation cohort, and an external validation cohort. Computed tomography images were retrieved to calculate EOT-TGR, denoted as tumor burden change per month during a period between baseline and the first imaging evaluation after immunotherapy. Kaplan-Meier methodology and Cox regression analysis were conducted for survival analyses. RESULTS: In the pooled cohort (n = 172), 125 patients (72.7%) were males; median age at diagnosis was 58 (range 28-79) years. Based on the training cohort, we determined the optimal cut-off value for EOT-TGR as 10.4%/month. Higher EOT-TGR was significantly associated with inferior overall survival [OS; hazard ratio (HR) 2.93, 95% confidence interval (CI) 1.47-5.83; P = 0.002], worse progression-free survival (PFS; HR 2.44, 95% CI 1.46-4.08; P = 0.001), and lower objective response rate (3.3% versus 20.9%; P = 0.040) and durable clinical benefit rate (6.7% versus 41.9%; P = 0.001). Results were reproducible in the two validation cohorts for OS and PFS. Among 43 patients who had a best response of progressive disease in the training cohort, those with high EOT-TGR had worse OS (HR 2.64; P = 0.041) and were more likely to progress due to target lesions at the first tumor evaluation (85.2% versus 0.0%; P <0.001). CONCLUSIONS: Higher EOT-TGR was associated with inferior OS and immunotherapeutic response in patients with aNSCLC undergoing anti-PD-1/PD-L1 therapy. This easy-to-calculate radiologic biomarker may help evaluate the abilities of immunotherapy to prolong survival and assist in tailoring patients' management. TRIAL REGISTRATION: ClinicalTrials.govNCT04722406; https://clinicaltrials.gov/ct2/show/NCT04722406.

[Clinicopathological characteristics and molecular alterations of primary cardiac leiomyosarcoma: report of five cases].

Objective: To investigate the clinical, pathologic and radiologic features and molecular alterations in patients with primary cardiac leiomyosarcoma (PCLMS). Methods: Five cases of PCLMS were collected in Beijing Anzhen Hospital from January 2016 to December 2020. The clinical, pathologic and radiologic data, and molecular alterations were analyzed, and the patients were followed up. Results: All five patients were female, and had no history of leiomyosarcoma in other parts of the body. The age of patients ranged from 37 to 62 years (median 47 years). The main clinical symptoms were chest pain and dyspnea, one also presented with palpitation and lower limb weakness and one with dizziness. Two tumors were located in the left atrium, two in the right atrium, and one in the right ventricle, and they maximal diameter ranged from 2.5 to 14.0 cm (mean 6.2 cm). The neoplasms presented as medium-echo masses with a broad base in the echocardiography, and as a low-density, solid mass when detected by contrast-enhanced CT. Histologically, two tumors were well-differentiated and three were moderately and poorly differentiated, and two included extensive, loose myxoid stroma. Immunohistochemical staining showed that PCLMS was positive for SMA, desmin, MDM2, and epidermal growth factor receptor. Fluorescence in situ hybridization showed ALK gene rearrangement in two cases, and COL1A1-PDGFB fusion in three cases. All cases received surgical excision and two cases received chemotherapy. Three patients died within 0-11 months (mean survival of 7.7 months) and two patients were alive. Conclusions: PCLMS is a malignant tumor with a high recurrence rate and poor prognosis. These cases may provide useful information to improve the diagnosis and management of PCLMS.

[The role of neoadjuvant therapy in multimodality treatment of locally advanced esophageal squamous cell carcinoma: perspective from the NEOCRTEC5010 trial].

The efficacy of surgery alone for locally advanced esophageal cancer is poor, which requires the active participation of multimodality treatment. Neoadjuvant therapy, especially neoadjuvant chemoradiotherapy, could significantly lead to tumor downstage, bring higher radical resection rate and improve the prognosis. The NEOCRTEC5010 trial, a multicenter prospective randomized controlled trial on neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma has provided sufficient and valuable evidence for us, especially for some key questions after neoadjuvant chemoradiotherapy, such as perioperative complications, value of systemic lymphadenectomy, the post-operation recurrence pattern, pathological complete response, long-term prognosis and survival. In addition, the current development of tumor immunotherapy is so rapid that the role of immunotherapy in the first line treatment of advanced or relapsed/metastatic esophageal cancer has been confirmed. In the near future, neoadjuvant therapy based on immunnology-led combined with traditional chemoradiotherapy or chemotherapy is expected to become a new theraputic strategy to further improve the treatment efficacy of locally advanced esophageal squamous cell carcinoma. This paper focused on the classical research of neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma and the development of immunotherapy for esophageal cancer, aiming to improve the understanding of neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma. This will help to carry out optimal clinical work and to design better clinical study.

Synovial fluid levels of VEGF and FGF-2 before and after intra-articular injection of hyaluronic acid in patients with temporomandibular disorders: a short-term study.

Our purpose was to measure the temporomandibular joint (TMJ) synovial fluid (SF) levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) before and after intra-articular injection of hyaluronic acid (HA) and to investigate the possible mechanism involved in the therapeutic value of HA. We analysed the synovial fluid of 30 patients with unilateral internal derangement (ID) or osteoarthritis (OA) of the TMJ (confirmed by magnetic resonance imaging and cone-beam computed tomography) and recorded clinical signs and symptoms including maximal mouth opening, subjective joint pain, and joint noise at the patient's each visit. All clinical signs significantly improved after injection of HA, and there was no significant difference between ID and OA groups. In synovial fluid parameters, the concentration of VEGF was significantly higher before treatment with HA than after treatment, but there was no significant difference in the concentration of FGF-2 between before and after treatment. The study findings suggest intra-articular injection of HA may reduce the synovitis and improve the internal state of the TMJ in a short period.

LncRNA INHBA-AS1 promotes cell growth, migration, and invasion of oral squamous cell carcinoma by sponging miR-143-3p.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "LncRNA INHBA-AS1 promotes cell growth, migration, and invasion of oral squamous cell carcinoma by sponging miR-143-3p, by W.-Q. Ma, J. Chen, W. Fang, X.-Q. Yang, A. Zhu, D. Zhang, H.-L. Zhong, B. Yang, Z. Luo, published in Eur Rev Med Pharmacol Sci 2020; 24 (4): 1821-1828-DOI: 10.26355/eurrev_202002_20360-PMID: 32141551" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20360.

[A preliminary study on the registration of MRI and cone beam CT images of temporomandibular joint disc].

Objective: To evaluate the MRI and cone beam CT (CBCT) image registration methods of the temporomandibular joint (TMJ), and to explore the clinical application of the registered images and clinical diagnostic data for examining the relationship between the articular disc and condyle. Methods: Three patients with TMJ disc disposition were recruited at the Department of Oral and Maxillofacial Surgery, School of Stomatology, Wuhan University from January to March 2018. One patient was male, aged 30, and the others were females, aged 21 and 26 respectively. Three-dimensional (3D) images of CBCT and MRI of the TMJ were reconstructed and registered by using Mimics software. The images were then evaluated after the registration. The evaluation indicators selected were the area and volume of the articular disc, the position of the articular disc or the distance between the highest point of the condyle (point C) to the center point of the articular disc (point D), the distance between the last point of the joint disc (point P) to point C, as well as the angle between line CD and FH plane (∠DCF) at either opened- or closed-mouth condition. Results: The registration images of TMJ, at the closed- and opened-mouth positions of the 3 patients, showed the anatomical structures and interrelationships of the articular disc, articular nodules, joint fossa and condyle. Combined with clinical diagnosis, the difference of CD distances at the normal articular disc position was the minimum (1.94 mm), the difference of CD distances was small at the anterior disc displacement with non-reduction and larger with reduction. When the joint disc was in the opened-mouth position, ∠DCF angle was minimal (3.81°). The patients with anterior disc displacement with non-reduction showed the largest ∠DCF angle (48.03°). Conclusions: The position of the articular disc relative to the condyle and articular nodules, either at closed- or opened-mouth conditionds, could be accurately displayed after the image registration and fusion. The registration image not only could fully show the shape and position of the articular disc in different status from a 3D perspective, but also might provide basis for clinical study of TMJ disc displacement.

[Analysis of the effect of percutaneous vertebroplasty combined with (125)I seed implantation in the treatment of spinal metastatic epidural spinal cord compression].

Objective: To investigate the clinical efficacy of percutaneous vertebroplasty (PVP) combined with iodine-125 ((125)I) seed brachytherapy in the treatment of spinal metastatic epidural spinal cord compression (MESCC) and toassess the changes inthe grade of epidural spinal cord compression (ESCC) by magnetic resonance imaging (MRI). Methods: A total of 37 MESCC patients treated with PVP combined with (125)I seed brachytherapy in the interventional and vascular surgery department of Zhongda Hospital affiliated to Southeast University from January 2014 to June 2019 were retrospectively analyzed, including 23 cases of bilateral lower limbs paralysis. Total diseased vertebrae are 39 segments. Visual analogue scale (VAS) and paralysis of lower extremities were evaluated regularly before and after treatment, and VAS values at different follow-up time points were compared. At the same time, MRI was used to evaluate the changes of ESCC grade in the spinal canal and calculate the local lesion efficiency after operation. The postoperative local lesion efficiency at different follow-up times was compared. Results: PVP combined with (125)I seed implantation in all diseased vertebral bodies was successful. The average injection volume of polymethylmethacrylate (PMMA) was (3.2±1.3) ml/segment, the average number of (125)I seed implanted was (25.0±8.6) seeds/segment and the average radiation dose was (15.0±5.1) mCi/segment. The VAS before operation was 8.5, and postoperative VAS were respectively 3.6±1.3, 3.8±1.5, 3.4±1.4, 5.5±1.0, 5.9±1.4 at 5 days, 1 month, 3 months, 6 months, and 1 year after operation. The differences between all follow-up time points and preoperative VAS values were statistically significant (all P<0.001). Compared with 5 days, 1 month and 3 months after operation, VAS increased significantly at 6 months and 1 year after operation, and the difference was statistically significant (all P<0.001); there was no significant difference between the VAS value at 6 months after operation and 1 year after operation (P=0.405). At a follow-up of 3 months, 22 of 23 patients with paralysis of bilateral lower limbs regained the functions of autonomous walking and voiding; the effective rates of MESCC local lesions evaluated by MRI at 1 month, 3 months, 6 months, and>1 year were 89.7%, 91.9%, 90.6%, and 94.7%, respectively, and there was no statistically significant differences among those follow-up time points (all P>0.05). Conclusions: PVP combined with (125)I seed brachytherapy in the treatment of MESCC has significant improvement in immediate pain relief and spinal cord function. After combined treatment, MRI showed that the tumors around the spinal cord regressed dramatically, which could considerably reduce the MESCC grade and remain stable for a long time.

[Increased Notch receptors induces CD8(+) T cell exhaustion in patients with prostate cancer].

Objective: To investigate Notch receptor expression in CD8(+) T cells in patients with prostate cancer, and to assess the influence of Notch signaling pathway on the function of CD8(+)T cells inpatients with prostate cancer. Methods: Forty-five patients with prostate cancer, forty-one patients with nonbacterial prostatitis, and thirty healthy controls who were hospitalized or followed-up in Shanxi Provincial People's Hospital between November 2017 and June 2018 were enrolled. CD8(+)T cells were purified, and mRNA relative levels of Notch1-4 were semi-quantified by reverse transcriptional real-time PCR. CD8(+)T cells were stimulated with Notch signaling inhibitor γ-secretase inhibitor (GSI). mRNA relative levels of perforin, granzyme B, and FasL were semi-quantified by reverse transcriptional real-time PCR. Percentages of PD-1 and CTLA-4 positive cells were investigated by flow cytometry. Direct contact and indirect contact coculture systems were set up between CD8(+)T cells and prostate cancer cell line LAPC4 cells. The influence of Notch signaling inhibition to CD8(+)T cell cytotoxicitywas assessed by measuringtarget cell death and cytokine secretion. One-Way ANOVA, LSD-t test, and paired t test was used for comparison. Results: mRNA relative levels of Notch1~4 were elevated in CD8(+)T cells from prostate cancer patients when compared with those from healthy controls and nonbacterial prostatitis patients (all P<0.05). There was CD8(+)T cell exhaustion in prostate cancer patients, which presented as decreased mRNA relative levels of perforin, granzyme B, and FasL (all P<0.000 1), as well as increased percentage of PD-1(+)CD8(+) (19.3%±5.4%) and CTLA-4(+)CD8(+)(11.7%±3.9%) cells. CD8(+)T cells from prostate cancer patients induced LAPC cell death was downregulated in direct contact coculture system (28.8%±6.4% vs 37.2%±2.6%, P=0.015). IFN-γsecretion was also reduced ((61.7±10.6)ng/L vs (88.6±20.2)ng/L, P=0.003 2). Inhibition of Notch signaling by GSI increased mRNA of perforin, granzyme B, and FasL in CD8(+)T cells from prostate cancer patients (all P<0.01), while reduced percentage of PD-1(+)CD8(+)(12.6%±2.5% vs 17.4%±4.7%, P=0.005 9) and CTLA-4(+)CD8(+) (12.0%±1.0% vs 14.1%±3.1%, P=0.011)cells. Notch signaling inhibition promoted LAPC4 cell death (34.3%±7.2%, P=0.000 2) which induced by prostate cancer derived CD8(+)T cells, and increased IFN-γ production ((88.4±33.6)ng/L, P=0.008 3). Conclusion: Elevated Notch receptors induced CD8(+)T cells exhaustion in prostate cancer patients.