JAM2 is a prognostic biomarker and inhibits proliferation, metastasis and epithelial-mesenchymal transition in lung adenocarcinoma.

BACKGROUND: Junctional adhesion molecule 2 (JAM2) plays a pivotal role in various biological processes, including proliferation, metastasis and angiogenesis, contributing to tumor progression. While previous studies have highlighted the polarizing functions of JAM2 in different cancer types, its specific role in lung adenocarcinoma (LUAD) remains unclear. METHODS: In this study, we harnessed multiple public databases to analyze the expression and prognostic significance of JAM2 in LUAD. Using the Linkedomics database, Matescape database and R package, we explored the associated genes, the potential biological functions and the impact of JAM2 on the tumor microenvironment. Our findings from public databases were further validated using real-time quantitative PCR, western blot and immunohistochemistry. Additionally, in vitro experiments were conducted to assess the influence of JAM2 on LUAD cell proliferation, invasion, migration, apoptosis and epithelial-mesenchymal transition. Furthermore, we established a xenograft model to investigate the in vivo effects of JAM2 on tumorigenesis. RESULTS: Our results revealed a significant downregulation of JAM2 in LUAD, and patients with low JAM2 expression exhibited unfavorable overall survival outcomes. Functional enrichment analysis indicated that JAM2 may be associated with processes such as cell adhesion, extracellular matrix, cell junctions and regulation of proliferation. Notably, increased JAM2 expression correlated with higher tumor microenvironment scores and reduced immune cell abundance. Furthermore, overexpression of JAM2 induced apoptosis, suppressed tumor proliferation and exhibited potential inhibitory effects on tumor invasion and migration through the modulation of epithelial-mesenchymal transition. Additionally, in vivo experiments confirmed that JAM2 overexpression led to a reduction in tumor growth. CONCLUSION: Overall, our study highlights the clinical significance of low JAM2 expression as a predictor of poor prognosis in LUAD patients. Moreover, JAM2 was found to exert inhibitory effects on various aspects of tumor progression. Consequently, JAM2 emerges as a promising prognostic biomarker and a potential therapeutic target for LUAD patients.

TESC acts as a prognostic factor and promotes epithelial-mesenchymal transition progression in esophageal squamous carcinoma.

BACKGROUND: Tescalcin (TESC) is a critical regulator of cell differentiation and growth, promoting malignant progression in various tumors. However, the role of TESC in esophageal squamous carcinoma (ESCC) remains unclear. METHODS: Immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and western blot were utilized to identify the difference in TESC expression between ESCC tissues and normal tissues adjacent to the carcinoma. The relationship between TESC and several clinicopathological features was shown by the chi-square test. Log-rank analysis and Cox regression were used to detect the relationship between TESC and the prognosis in ESCC. Clone formation and cell count kit-8 (CCK-8) were applied to detect the impact of TESC on ESCC proliferation. Wound healing assay and transwell assay were used to confirm the influence of TESC on the invasion and migration. Spearman correlation coefficient was used to describe the correlation between TESC and epithelial-mesenchymal transition (EMT)-related protein expression in ESCC. Western blot was used to detect the effect of TESC on the expression of E-cadherin, N-cadherin, and Vimentin as well as AKT signaling pathway. Xenograft tumors were developed to test the pro-tumorigenic impacts of TESC in vivo. RESULTS: TESC was upregulated expression in ESCC tissues and was linked to poorer prognosis and worse tumor infiltration, TNM stage, and lymph node metastasis. Meanwhile, TESC was able to act as an independent prognostic factor in ESCC. TESC promoted tumor cell proliferation, invasion, migration, EMT progression, and activated the phosphorylation of the AKT pathway. Furthermore, TESC knockdown inhibited the growth of carcinoma in vivo. CONCLUSION: TESC is a predictive factor for poor prognosis in ESCC and may provide a new strategy for ESCC treatment.

FAM107A as a tumor suppressor in esophageal squamous carcinoma inhibits growth and metastasis.

BACKGROUND: Sequence similarity Family 107 member A (FAM107A) has been recognized as a tumor suppressor of various malignancies, which suppresses tumor proliferation and metastasis. Its specific role in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: Public datasets including Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus (GEO), quantitative real-time PCR (qRT-PCR), and Western blot were utilized for comparative analysis of FAM107A expression between ESCC and normal tissues. The link between FAM107A and clinicopathological features, as well as prognosis determined through χ2-test, log-rank analysis, and univariate and multivariate analyses, respectively. The impact of FAM107A on ESCC cell malignant behavior was confirmed through in vitro assays, including cell counting using the Cell Counting Kit-8 (CCK-8), clonal formation, wound healing, and transwell assays. Western blot analysis was employed to assess the effects of FAM107A on tumor epithelial-mesenchymal transition (EMT) and cell cycle-related proteins. Finally, xenograft tumors were developed to investigate the influence of FAM107A on ESCC growth in vivo. RESULTS: FAM107A exhibited low expression in ESCC tissues. Reduced FAM107A expression was associated with a poorer prognosis and unfavorable clinicopathological characteristics, such as degree of differentiation, T-stage, and N-stage. Overexpression of FAM107A suppressed ESCC cell proliferation, invasion, migration, the EMT process, and cell cycle progression. Finally, FAM107A overexpression inhibited tumor development in vivo. CONCLUSION: The decreased expression of FAM107A is indicative of a worse prognosis for ESCC patients. FAM107A exerts inhibitory impacts on malignant behavior and may hold promise as a therapeutic target for ESCC.

Tumor associated macrophages in esophageal squamous carcinoma: Promising therapeutic implications.

Esophageal squamous carcinoma (ESCC) is a prevalent and highly lethal malignant tumor, with a five-year survival rate of approximately 20 %. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising over 50 % of the tumor volume. TAMs can be polarized into two distinct phenotypes, M1-type and M2-type, through interactions with cancer cells. M2-type TAMs are more abundant than M1-type TAMs in the TME, contributing to tumor progression, such as tumor cell survival and the construction of an immunosuppressive environment. This review focuses on the role of TAMs in ESCC, including their polarization, impact on tumor proliferation, angiogenesis, invasion, migration, therapy resistance, and immunosuppression. In addition, we discuss the potential of targeting TAMs for clinical therapy in ESCC. A thorough comprehension of the molecular biology about TAMs is essential for the development of innovative therapeutic strategies to treat ESCC.

Three-Field Versus Two-Field Lymphadenectomy in Minimally Invasive Esophagectomy: 3-Year Survival Outcomes of a Randomized Trial.

BACKGROUND: Minimally invasive esophagectomy (MIE) has been used widely for the treatment of esophageal cancer. However, the optimal extent of lymphadenectomy for esophagectomy in MIE remains unclear. This trial aimed to investigate the 3-year survival and recurrence outcomes in a randomized controlled trial comparing MIE with either three-field lymphadenectomy (3-FL) or two-field lymphadenectomy (2-FL). METHODS: Between June 2016 and May 2019, 76 patients with resectable thoracic esophageal cancer were enrolled in a single-center randomized controlled trial and randomly assigned to MIE that included either 3-FL or 2-FL at a 1:1 ratio (n = 38 patients each). The survival outcomes and recurrence patterns were compared between the two groups. RESULTS: The 3-year cumulative overall survival (OS) probability was 68.2 % (95 % confidence interval [CI], 52.72-83.68 %) for the 3-FL group and 68.6 % (95 % CI, 53.12-84.08 %) for the 2-FL group. The 3-year cumulative probability of disease-free survival (DFS) was 66.3 % (95 % CI, 50.03-82.57 %) for the 3-FL group and 67.1 % (95 % CI, 51.03-83.17 %) for the 2-FL group.. The OS and DFS differences in the two groups were comparable. The overall recurrence rate did not differ significantly between the two groups (P = 0.737). The incidence of cervical lymphatic recurrence in the 2-FL group was higher than in the 3-FL group (P = 0.051). CONCLUSIONS: Compared with 2-FL in MIE, 3-FL tended to prevent cervical lymphatic recurrence. However, it was not found to add survival benefit for the patients with thoracic esophageal cancer.

Identification and experimental verification of an anoikis and immune related signature in prognosis for lung adenocarcinoma.

Background: Both metastasis and immune resistance are huge obstacle in lung adenocarcinoma (LUAD) treatment. Multiple studies have shown that the ability of tumor cells to resist anoikis is closely related to the metastasis of tumor cells. Methods: In this study, the risk prognosis signature related to anoikis and immune related genes (AIRGs) was constructed by cluster analysis and the least absolute shrinkage and selection operator (LASSO) regression by using The Cancer Genome Atlas (TCGA) Program and the Gene Expression Omnibus (GEO) database. Kaplan-Meier (K-M) curve described the prognosis in the different groups. Receiver operating characteristic (ROC) was applied to evaluate the sensitivity of this signature. Principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), independent prognostic analysis, and nomogram were utilized to assess the validity of the signature. In addition, we used multiple bioinformatic tools to analyze the function between different groups. Finally, mRNA levels were analyzed by quantitative real-time PCR (qRT-PCR). Results: The K-M curve showed a worse prognosis for the high-risk group compared to that for the low-risk group. ROC, PCA, t-SNE, independent prognostic analysis and nomogram showed well predictive capabilities. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that differential genes were mainly enriched in immunity, metabolism, and cell cycle. In addition, multiple immune cells and targeted drugs differed in the two risk groups. Finally, we found that the mRNA levels of AIRGs were remarkably different in normal versus cancer cells. Conclusions: In short, we established a new model about anoikis and immune, which can well predict prognosis and immune response.

Pulmonary mucoepidermoid carcinoma in the Chinese population: A clinical characteristic and prognostic analysis.

Background: Mucoepidermoid carcinoma is dominant in salivary glands and rarely occurs in the lung. Primary pulmonary mucoepidermoid carcinoma is a type of non-small-cell lung cancer, but the prognostic factors in Chinese patients remain controversial. This investigation aimed to review cases of pulmonary mucoepidermoid carcinoma, analyse the prognosis of this disease. Methods: Patients with pathologically proven pulmonary mucoepidermoid carcinoma were screened at the Department of Respiratory and Critical Care Medicine at the Peking University Third Hospital, Beijing Friendship Hospital Affiliated to Capital Medical University, and Peking University Cancer Hospital for inclusion in this retrospective study. Demographic data, including age, sex, clinical symptoms, smoking, alcohol consumption, allergies, family history, imaging findings, fibrobronchoscopy findings, surgical procedures, tumour location and pathologic stage, were collected. Telephone follow-up was conducted for all patients not lost to follow-up. The associations of sex, age, smoking, tumour differentiation, tumour size, lymph node metastasis, pathologic stage, and patient survival were retrospectively analysed. Kaplan-Meier, univariate and multivariate analysis curves were used to analyse patient prognosis and prognostic factors. Results: Thirty-one patients, comprising 23 males and 8 females, were enrolled in the analysis. The mean age was 60.77 ± 11.44 years. The first symptom was nonspecific, with cough being the most common (21/31, 67.77%); smokers accounted for 16 of the 31 patients, and ten patients had a history of alcohol consumption. Overall, the tumours could occur in either lobe of the lungs; tumours occurred in the right lung in 19/31 patients, and tumours occurred in the left lung in 12/31 patients. Regarding TNM stage, 10 patients had stage I (5 with stage 1a, 5 with stage 1b), 5 had stage II (1 with stage 2a, 4 with stage 2b), 3 had stage III (1 with stage 3a, 2 with stage 3b), and 13 had stage IV (10 with stage 4a, 3 with stage 4b). In our Cox univariate survival analysis of patients with pulmonary mucoepidermoid carcinoma, we found that TNM stage IV, degree of differentiation and lymph node metastasis were risk factors for pulmonary mucoepidermoid carcinoma and that degree of differentiation was an independent risk factor. Conclusion: The clinical, radiographical and pathological features of pulmonary mucoepidermoid carcinoma were systemically analysed and summarized, and the degree of differentiation and lymph node metastasis, as well as prognostic factors in addition to clinical stage, were confirmed.

Short-term outcomes of neoadjuvant sintilimab with chemotherapy in stage III non-small cell lung cancer: a case series.

Background: Neoadjuvant chemoimmunotherapy seems to be a promising treatment option for stage III non-small cell lung cancer (NSCLC). Sintilimab, as a programmed death receptor-1 inhibitor, has exhibited a fine performance in treating NSCLC. However, the efficiency of sintilimab combined with chemotherapy for stage IIIA/IIIB NSCLC remains inconclusive. The purpose of this study was to share our experience on sintilimab in neoadjuvant chemoimmunotherapy for stage III NSCLC. Methods: This study retrospectively reviewed patients who received surgical resection following 1-3 cycles of neoadjuvant sintilimab (200 mg) with chemotherapy for stage III NSCLC between June 2020 and March 2022 in our center. Patients characteristics, surgical factors, surgery-related complications 30 days postoperatively, and treatment-related adverse events (TRAEs) before surgery were recorded through reviewing medical record data and telephone follow-up. Results: A total of eight patients were enrolled, including six cases of squamous cell carcinoma and two cases of adenocarcinoma. All of the patients received 1-3 cycles of neoadjuvant therapy. There were no treatment-related surgical delays. All patients underwent lobectomy, among which two underwent sleeve lobectomy and one received bronchoplasty. Five patients underwent open thoracotomy. Fibrosis of the primary tumor and lymph nodes was observed in all the cases. There were no surgery-related complications > grade 2 at 30 days postoperatively. According to the radiographic findings, one patient had stable disease and all of the others achieved a partial response. The median of maximum standardized uptake value change from baseline was a 52.75% reduction (range, 37.2-68.8%). Five patients achieved a major pathological response. R0 resection was achieved in all eight cases. One grade 4 event was observed. Neutropenia was the most common TRAE > grade 2 (3/8). There were no cases of treatment discontinuation or dose reduction due to TRAEs. Conclusions: The current study found that neoadjuvant sintilimab plus chemotherapy bring a high rate of major pathological response and acceptable TRAEs. Even though it increased the difficulties of surgery, there is still no evidence suggesting that it will brings additional surgical death. We believe that neoadjuvant sintilimab plus chemotherapy might be feasible for stage III NSCLC.

Case Report: Miles Surgery Ameliorates High Blood Pressure in a Rectal Carcinoma Patient With Essential Hypertension.

Hypertension is one of the major causes of public health problems. Multiple factors affecting gastrointestinal tract function are involved in hypertension. Emerging studies have manifested that gut intervention may play significant roles in regulating blood pressure but the underlying mechanisms are complex and not fully clear. Here, we report a case of 66 years old male who had a long history of hypertension and received Miles surgery for rectal carcinoma. The blood pressure of this patient was returned to normal levels after the operation. The possible reasons could be the modulation of sympathetic tone and the gut microbiota-brain axis. This report provides evidence about the relevance between hypertension and gut intervention particularly in the colorectal sites and gives hints for investigating the possible mechanisms of hypertension and the novel strategy for blood pressure control.

Three-Field Lymphadenectomy in Minimally Invasive Esophagectomy for Squamous Cell Carcinoma.

BACKGROUND: Minimally invasive esophagectomy (MIE) has been used widely for the treatment of esophageal cancer. However, there is still a lack of consensus on the extent of lymphadenectomy in MIE. The objective of this study was to investigate the safety and efficacy of three-field lymphadenectomy (3-FL) in MIE, compared with the standard two-field lymphadenectomy (2-FL). METHODS: A single-center randomized controlled trial was conducted, enrolling patients with resectable thoracic esophageal cancer (cT1-3,N0-3,M0) between June 2016 and May 2019. Eligible patients were randomized into two groups to receive either 3-FL or 2-FL during MIE procedures. Perioperative outcomes of the two groups were compared. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-INR-16007957). RESULTS: Seventy-six eligible patients were randomly assigned to the 3-FL group (n = 38) and the 2-FL group (n = 38). Compared with patients in the 2-FL group, patients in the 3-FL group had more lymph nodes harvested (54.7 ± 16.5vs 30.9 ± 9.6, P < .001) and more metastatic lymph nodes identified (3.5 ± 4.5 vs 1.7 ± 2.0, P = .027). Patients in the 3-FL group were diagnosed with a more advanced final pathologic TNM stage than patients in the 2-FL group. There was no significant difference between the two groups in blood loss, major postoperative complications, or duration of hospital stay, except that the operation time was longer in the 3-FL group than in the 2-FL group (270.5 ± 45.4 minutes vs 236.7 ± 47.0 minutes, P = .002). CONCLUSIONS: Three-field lymphadenectomy allowed harvesting of more lymph nodes and more accurate staging without increased surgical risks compared with 2-FL MIE for esophageal cancer.

Salvage surgery for advanced non-small cell lung cancer after targeted therapy: A case series.

BACKGROUND: Tumor recurrence or residual tumor after targeted therapy is common in patients with advanced non-small cell lung cancer (NSCLC). There is a lack of high-level evidence on which type of treatment should be employed for these patients and the role of salvage surgery has not been well reported in the literature. METHODS: A retrospective analysis of patients who underwent salvage surgery in our center between January 2016 and June 2019 for advanced NSCLC after targeted therapy was performed. RESULTS: A total number of nine patients were identified, including five males and four females, with a median age of 56 years (range, 40-65 years), all diagnosed with lung adenocarcinoma stage IIIa-IVb. All patients had received targeted therapy according to individual positive mutation of driver gene(s). Salvage surgery was performed for tumor recurrence or residual tumor after a duration of 2-46 months of targeted therapy. A negative surgical margin was achieved in all cases. Postoperative complication rate was 11.1% (1/9). All patients were alive at the time of this analysis and two patients had disease progression. After a median follow-up of 17 months (range: 5-44 months), the median event-free survival and postoperative survival was 14 months (range: 2-44 months) and 17 months (range: 5-44 months) respectively. CONCLUSIONS: Salvage surgery may be a feasible and promising therapeutic option for tumor recurrence or residual tumor in advanced NSCLC in selective patients after targeted therapy. KEY POINTS: Salvage surgery is feasible in selected patients with advanced NSCLC and provides promising survival outcomes after targeted therapy failure. Salvage surgery provides precise molecular and pathological information which is most important for subsequent therapy.

Anisodamine Ameliorates Hyperkalemia during Crush Syndrome through Estradiol-Induced Enhancement of Insulin Sensitivity.

Hyperkalemia is a major cause of on-site death in crush syndrome (CS), which is more severe and common in male victims. Anisodamine is a belladonna alkaloid and widely used in China for treatment of shock through activation of α7 nicotinic acetylcholine receptor (α7nAChR). The present work was designed to study the protective effect of anisodamine in CS and the possible role of estradiol involved. Male and ovariectomized female CS mice exhibited lower serum estradiol and insulin sensitivity, and higher potassium compared to the relative female controls at 6 h after decompression. There was no gender difference in on-site mortality in CS mice within 24 h after decompression. Serum estradiol increased with similar values in CS mice of both gender compared to that in normal mice. Anisodamine decreased serum potassium and increased serum estradiol and insulin sensitivity in CS mice, and methyllycaconitine, selective antagonist of α7nAChR, counteracted such effects of anisodamine. Treatment with anisodamine or estradiol increased serum estradiol and insulin sensitivity, decreased serum potassium and on-site mortality, and eliminated the difference in these parameters between CS mice received ovariectomy or its sham operation. Anisodamine could also increase blood pressure in CS rats within 3.5 h after decompression, which could also be attenuated by methyllycaconitine, without influences on heart rate. These results suggest that activation of α7nAChR with anisodamine could decrease serum potassium and on-site mortality in CS through estradiol-induced enhancement of insulin sensitivity.

Diurnal Variation of the Peripheral Cholinergic Antiinflammatory Function in Mice.

AIMS: Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock. METHODS: Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine. RESULTS: Both levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA. CONCLUSION: Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.

Sodium Sulfide, a Hydrogen Sulfide-Releasing Molecule, Attenuates Acute Cerebral Ischemia in Rats.

AIMS: Acute cerebral ischemia may lead to ischemic stroke, which is a major cause of death and disability worldwide. Hydrogen sulfide (H2 S) functions importantly in mammalian systems. The present work was designed to study the effect of sodium sulfide, a donor of H2 S, on acute cerebral ischemia. METHODS: Acute cerebral focal ischemia was produced by middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. Bilateral vertebral arteries and common carotid arteries were blocked to establish cerebral global ischemia in SD rats. Acute cerebral anoxia was produced by hypobaric anoxia in C57BL/6 mice and hypoxic anoxia in SD rats. Nimodipine and aspirin were set as positive control separately. RESULTS: Infarct size after MCAO was decreased by sodium sulfide. Sodium sulfide improved cerebral energy metabolism after cerebral global ischemia and prolonged survival time of animals with acute cerebral anoxia. In addition, increased cerebral blood flow and decreased cerebrovascular resistance, blood viscosity, and thrombogenesis were observed in animals treated with sodium sulfide. In cultured neurons, sodium sulfide increased cell viability and decreased cell apoptosis induced by oxygen-glucose deprivation. CONCLUSION: Sodium sulfide, a H2 S donor, presents protective effect on acute cerebral ischemia, and might be a promising therapeutic drug.

Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway.

On-site mortality in crush syndrome remains high due to lack of effective drugs based on definite diagnosis. Anisodamine (Ani) is widely used in China for treatment of shock, and activation of α7 nicotinic acetylcholine receptor (α7nAChR) mediates such antishock effect. The present work was designed to test whether activation of α7nAChR with Ani decreased mortality in crush syndrome shortly after decompression. Sprague-Dawley rats and C57BL/6 mice with crush syndrome were injected with Ani (20 mg/kg and 28 mg/kg respectively, i.p.) 30 min before decompression. Survival time, serum potassium, insulin, and glucose levels were observed shortly after decompression. Involvement of α7nAChR was verified with methyllycaconitine (selective α7nAChR antagonist) and PNU282987 (selective α7nAChR agonist), or in α7nAChR knockout mice. Effect of Ani was also appraised in C2C12 myotubes. Ani reduced mortality and serum potassium and enhanced insulin sensitivity shortly after decompression in animals with crush syndrome, and PNU282987 exerted similar effects. Such effects were counteracted by methyllycaconitine or in α7nAChR knockout mice. Mortality and serum potassium in rats with hyperkalemia were also reduced by Ani. Phosphorylation of Na/K-ATPase was enhanced by Ani in C2C12 myotubes. Inhibition of tyrosine kinase on insulin receptor, phosphoinositide 3-kinase, mammalian target of rapamycin, signal transducer and activator of transcription 3, and Na/K-ATPase counteracted the effect of Ani on extracellular potassium. These findings demonstrated that activation of α7nAChR could decrease on-site mortality in crush syndrome, at least in part based on the decline of serum potassium through insulin signaling-Na/K-ATPase pathway.