The interaction between DNA methylation and tumor immune microenvironment: from the laboratory to clinical applications.

DNA methylation is a pivotal epigenetic modification that affects gene expression. Tumor immune microenvironment (TIME) comprises diverse immune cells and stromal components, creating a complex landscape that can either promote or inhibit tumor progression. In the TIME, DNA methylation has been shown to play a critical role in influencing immune cell function and tumor immune evasion. DNA methylation regulates immune cell differentiation, immune responses, and TIME composition Targeting DNA methylation in TIME offers various potential avenues for enhancing immune cytotoxicity and reducing immunosuppression. Recent studies have demonstrated that modification of DNA methylation patterns can promote immune cell infiltration and function. However, challenges persist in understanding the precise mechanisms underlying DNA methylation in the TIME, developing selective epigenetic therapies, and effectively integrating these therapies with other antitumor strategies. In conclusion, DNA methylation of both tumor cells and immune cells interacts with the TIME, and thus affects clinical efficacy. The regulation of DNA methylation within the TIME holds significant promise for the advancement of tumor immunotherapy. Addressing these challenges is crucial for harnessing the full potential of epigenetic interventions to enhance antitumor immune responses and improve patient outcomes.

Comprehensive landscape and interference of clonal haematopoiesis mutations for liquid biopsy: A Chinese pan-cancer cohort.

Tumour-derived DNA found in the plasma of cancer patients provides the probability to detect somatic mutations from circulating cell-free DNA (cfDNA) in plasma samples. However, clonal hematopoiesis (CH) mutations affect the accuracy of liquid biopsy for cancer diagnosis and treatment. Here, we integrated landscape of CH mutations in 11,725 pan-cancer patients of Chinese and explored effects of CH on liquid biopsies in real-world. We first identified 5933 CHs based on panel sequencing of matched DNA of white blood cell and cfDNA on 301 genes for 5100 patients, in which CH number of patients had positive correlation with their diagnosis age. We observed that canonical genes related to CH, including DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2 and SF3B1, were dominant in the Chinese cohort and 13.29% of CH mutations only appeared in the Chinese cohort compared with the Western cohort. Analysis of CH gene distribution bias indicated that CH tended to appear in genes with functions of tyrosine kinase regulation, PI3K-Akt signalling and TP53 activity, suggesting unfavourable effects of CH mutations in cancer patients. We further confirmed effect of driver genes carried by CH on somatic mutations in liquid biopsy of cancer patients. Forty-eight actionable somatic mutations in 17 driver genes were considered CH genes in 92 patients (1.80%) of the Chinese cohort, implying potential impacts of CH on clinical decision-making. Taken together, this study exhibits strong evidence that gene mutations from CH interfere accuracy of liquid biopsies using cfDNA in cancer diagnosis and treatment in real-world.

Regulation of BTG3 by microRNA-20b-5p in non-small cell lung cancer.

The present study aimed to evaluate microRNA- 20b-5p (miR-20b-5p) expression in non-small cell lung cancer (NSCLC), and investigate the effects of miR-20b-5p expression on NSCLC cell proliferation and migration. Reverse transcription-quantitative polymerase chain reaction was performed to measure the expression level of miR-20b-5p in NSCLC tissues and cell lines. Cell Counting Kit-8 and wound healing assays were used to measure cell proliferation and migration. A dual-luciferase reporter assay was performed to validate B-cell translocation gene 3 (BTG3) as a target of miR-20b-5p. It was identified that the expression level of miR-20b-5p is elevated in NSCLC tissues and cell lines. miR-20b-5p overexpression was revealed to promote NSCLC cell proliferation and migration. Furthermore, BTG3 was identified as a direct target of miR-20b-5p, and BTG3 overexpression reversed a miR-20b-5p mimic-induced increase in cell proliferation and migration. In summary, the present study revealed that miR-20b-5p promotes NSCLC cell proliferation and migration by targeting BTG3, which may assist with the development of a novel therapeutic target for the treatment of NSCLC.

The ideal methods for the management of rib fractures.

The clinical treatment choices for multiple rib fractures and flail chest are controversial. For example, among conservative treatment and surgical treatment, different studies have different conclusions and recommendations. Furthermore, early clinical research was mainly focused on the treatment of flail chest due to its severity. Nowadays, the treatment for multiple rib fractures patients without a flail chest is drawing an increased clinical interest. However, we are facing many challenges for the treatment of rib fractures, such as insufficient understanding of the available treatment options, lack of clinical research, lack of the internationally recognized clinical indication for the surgical stabilization of rib fractures (SSRF), and the constant controversies and debates in terms of treatment options, surgery timing, and surgical techniques. All these challenges make it difficult to select the most appropriated clinical decisions for the proper treatment of a rib fracture, resulting in a seriously hindered development of novel rib fractures treatment choices. The concepts and ideas for traditional rib fractures treatment are relatively old, and even have some misunderstandings or errors. With the emergence of more and more research, the understandings of the rib fractures treatment has gradually improved; for example, the benefits provided to patients under the open reductions and internal fixation of fractures treatment. In this article, we outlined the new concepts in rib fractures treatment, which mainly included four parts, damage control, pain management, fixation selection, and quality of life. We hope these concepts help practitioners better manage rib fracture patients.

MDM2 promotes epithelial-mesenchymal transition through activation of Smad2/3 signaling pathway in lung adenocarcinoma.

BACKGROUND: Mouse double minute 2 (MDM2) contributes to cancer metastasis and epithelial-mesenchymal transition (EMT). This study aimed to investigate small mothers against decapentaplegic (Smad) signaling in MDM2-mediated EMT in lung adenocarcinoma (LAC). MATERIALS AND METHODS: Expression patterns of MDM2 in LAC tissues, adjacent tissues, and cell lines (BEAS-2B, PC9, H1975, and A549) were detected. We then overexpressed MDM2 in PC9 cells and knocked it down in H1975 cells. To explore whether MDM2 activates EMT through the Smad2/3 signaling pathway, Smad2 and Smad3 were also silenced by siRNA in H1975 cells. Male BALB/c nude mice were used in in vivo model to validate the effects of MDM2 on LAC cells. RESULTS: MDM2 was significantly upregulated in LAC tissues compared with adjacent tissues. The expression of MDM2 was relatively higher in PC9 cells and relatively lower in H1975 cells compared with A549 cells. Overexpression of MDM2 significantly increased cell proliferation, migration, and invasion in LAC cells, while inhibiting apoptosis in PC9 cells. On the contrary, silencing of MDM2 significantly inhibited the expression of EMT-related genes N-cadherin and vimentin, while promoting the expression of E-cadherin and ß-catenin. In vivo, MDM2 knockdown inhibited tumor growth. In addition, the expression of Smad2/3 was correlated with MDM2 in H1975 cells transfected with Smad2 and Smad3 siRNAs, which inhibited EMT progress. CONCLUSION: MDM2 can activate the Smad2/3 signaling pathway, which promotes the proliferation and EMT progress of LAC cells.

Biomarkers for early diagnosis, prognosis, prediction, and recurrence monitoring of non-small cell lung cancer.

Despite advances in the management of non-small cell lung cancer, it remains to be the leading cause of cancer-related deaths worldwide primarily because of diagnosis at a late stage with an overall 5-year survival rate of 17%. A reduction in mortality was achieved by low-dose computed tomography screening of high-risk patients. However, the benefit was later challenged by the high false positive rate, resulting in unnecessary follow-ups, thus entailing a burden on both the health care system and the individual. The diagnostic dilemma imposed by imaging modalities has created a need for the development of biomarkers capable of differentiating benign nodules from malignant ones. In the past decade, with the advancements in high-throughput profiling technologies, a huge amount of work has been done to derive biomarkers to supplement clinical diagnosis. However, only a few of them have efficient sensitivity and specificity to be utilized in clinical settings. Therefore, there is an urgent need for the development of sensitive and specific means to detect and diagnose lung cancers at an early stage, when curative interventions are still possible. Due to the invasiveness of tissue biopsies and inability to capture tumor heterogeneity, nowadays enormous efforts have been invested in the development of technologies and biomarkers that enable sensitive and cost-effective testing using substrates that can be obtained in a noninvasive manner. This review, primarily focusing on liquid biopsy, summarizes all documented potential biomarkers for diagnosis, monitoring recurrence treatment response.

Functional role of lncRNA DB327252 in lung cancer.

BACKGROUND: Lung cancer becomes a concerning health issue and is considered one of the most deadly cancers in the worldwide. Most recently, long non-coding RNAs (lncRNAs) are newfound non-coding RNAs that are thought as one of the major players in a range of biological processes of human diseases. Although lncRNAs are involved in numerous cancer types, the precise understandings of lncRNAs' functional roles and mechanisms in lung cancer are limited. In this study, we looked for lung cancer related lncRNAs. METHODS: The quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) technique was utilized to investigate the lncRNA DB327252 expression in 91 paired clinical lung cancer tissues and related cell lines. Moreover, its biological functions were also evaluated in the development of lung cancer. RESULTS: The results indicated that the expression of DB327252 was up-regulated in lung cancer tissues compared to the cancer-adjacent normal tissues (P<0.05); and the up-regulated expression is likely to relate to those with bigger tumor size, adenocarcinoma and advanced TNM stage (P<0.05). In addition, the knockdown of DB327252 inhibited the growth and proliferation of tumor cell in vitro and in vivo. According to the observation from our study, we found that the knockdown of the DB327252 expression, led to G0/G1 phase cell-cycle arrested, colony formation suppressed in vitro, and tumor growth inhibited in a nude mouse xenograft model. Our experimental results also suggest that lncRNA DB327252 may be a lncRNA related to lung cancer and acts an important role in A549 and 16HBE-T cancer cells, which provides evidence that DB327252 has an oncogene-like function in lung cancer. CONCLUSIONS: The lncRNA DB327252 is up-regulated in lung cancer, and its expression implies that it was probable related to biologic functions of lung cancer.

Subcostal thoracoscopic extended thymectomy for patients with myasthenia gravis.

BACKGROUND: Extended thymectomy is indicated for patients with myasthenia gravis (MG) when drug-resistance or dependence is seen. We have employed a technique for subcostal thoracoscopic extended thymectomy (STET) on patients with MG. METHODS: Clinical data of 15 eligible patients who underwent STET in our department from February 2015 to November 2015 by the same surgical team were retrospectively analyzed. The operation time, blood loss, duration of postoperative hospital stay, thoracic drainage periods were concerned. RESULTS: All the surgeries were finished successfully without conversion to sternotomy. Mean operation time was 157.53±40.31 min (range, 73-275 min). Mean blood loss was 56.33±7.07 mL (range, 10-200 mL). Mean pleural drainage volume in the first 24 hours was 72.67±17.68 mL (range, 0-250 mL). Mean postoperative thoracic drainage periods were 1.20±0.71 days (range, 0-3 days). Mean duration of postoperative hospital stay was 6.13±0.71 days (range, 3-22 days). CONCLUSIONS: This procedure showed satisfactory results for patients with MG. Moreover, the STET approach is more easily for surgeons to fully reveal the bilateral phrenic nerve and the upper thymic poles. We believe that STET is a satisfactory procedure for performing extended thymectomy in well selected patients.

A specific groove design for individualized healing in a canine partial sternal defect model by a polycaprolactone/hydroxyapatite scaffold coated with bone marrow stromal cells.

The reconstruction of sternal defects remains clinically challenging for thoracic surgeons. Here we aimed to explore the individualized reconstruction of partial sternal defects with new biodegradable material in a large animal model. We used the fused deposition modeling (FDM) technique to manufacture polycaprolactone/hydroxyapatite (PCL/HA) tissue scaffolds with individualized grooves to repair the sternal defect. The defects were surgically created in a sternocostal joint of eighteen Beagle dogs. The animals were separated into three groups (n = 6): Blank group, PCL/HA group, and PCL/HA/BMSCs group. Radiographic examination, histological, and histomorphometric analyses were performed to evaluate the result. In the blank group, the defect site couldn't maintain its original integrity due to no bone union. In the PCL/HA group and PCL/HA/BMSCs group, it was observed that the scaffolds retained their shapes without significant degradation at 12 weeks. Both groups could observe new bone-union by radiographic and histological examination. And PCL/HA/BMSCs would be more mineralized tissue area at implant sites (p < 0.05). These results reveal that using the FDM technique to manufacture the PCL/HA scaffolds with specific grooves could repair the sternal defect satisfactorily. Furthermore the scaffolds with BMSCs-seeded could enhance the amount of bone ingrowth and seemed to be more promising.