Comprehensive Analysis of Alteration Landscape and Its Clinical Significance of Mitochondrial Energy Metabolism Pathway-Related Genes in Lung Cancers.

Pancreatic cancer (PAAD) is one of the most malignant tumors with the worst prognosis. The abnormalities in the mitochondrial energy metabolism pathway are intimately correlated with the occurrence and progression of cancer. For the diagnosis and treatment of pancreatic cancer, abnormal genes in the mitochondrial energy metabolism system may offer new targets and biomarkers. In this study, we compared the dysregulated mitochondrial energy metabolism-associated pathways in PAAD based on pancreatic cancer samples in the Cancer Genome Atlas (TCGA) database and normal pancreas samples from the Genotype Tissue Expression project (GTEx) database. Then identified 32 core genes of mitochondrial energy metabolism pathway-related genes (MMRG) were based on the gene set enrichment analysis (GSEA). We found most of these genes were altered among different clinical characteristic groups, and showed significant prognostic value and association with immune infiltration, suggesting critical roles of MMRG involve tumor genesis of PAAD. Therefore, we constructed a four-gene (LDHA, ALDH3B1, ALDH3A1, and ADH6) prognostic biomarker after eliminating redundant factors, and confirming its efficiency and independence. Further analysis indicated the potential therapeutic compounds based on the mitochondrial energy metabolism-associated prognostic biomarker. All of the above analyses dissected the critical role of mitochondrial energy metabolism signaling in pancreatic cancer and gave a better understanding of the clinical intervention of PAAD.

Abnormalities in the mitochondrial energy metabolism pathways are closely related to the occurrence and development of many cancers. Furthermore, abnormal genes in mitochondrial energy metabolism pathways may be novel targets and biomarkers for the diagnosis and treatment of osteosarcoma. In this study, we aimed to establish a mitochondrial energy metabolism-related gene signature for osteosarcoma prognosis. We first obtained differentially expressed genes based on the metastatic status of 84 patients with osteosarcoma from the TARGET database. After Venn analysis of differentially expressed genes and mitochondrial energy metabolism pathway-related genes (MMRGs), 2 key genes were obtained using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Next, we used these 2 genes to establish a prognostic signature. Subsequent analyses elucidated the correlation between these 2 key genes with clinical features and 28 types of immune cells. Pathway changes in osteosarcoma pathogenesis under different metastatic states were clarified using gene set enrichment analysis (GSEA) of differentially expressed genes. A gene signature composed of 2 key prognosis-related genes (KCNJ5 and PFKFB2) was identified. A risk score was calculated based on the gene signature, which divided osteosarcoma patients into low- or high-risk groups that showed good and poor prognosis, respectively. High expression of these 2 key genes is associated with low-risk group in patients with osteosarcoma. We constructed an accurate nomogram to help clinicians assess the survival time of patients with osteosarcoma. The results of immune cell infiltration level showed that the high-risk group had lower levels of immune cell infiltration. GSEA revealed changes in immune regulation and hypoxia stress pathways in osteosarcoma under different metastatic states. Our study identified an excellent gene signature that could be helpful in improving the prognosis of patients with osteosarcoma.

Objective: To compare the clinical characteristics and outcomes of patients with lung cancer, gastrointestinal (GI) cancer and urologic cancer with venous thromboembolism (VTE). Methods: From January 2003 to January 2013, 192 lung cancer, GI cancer and urologic cancer patients with VTE were retrospectively evaluated for the clinical characteristics and outcomes. Results: Among 192 patients, 82 cases of lung cancer, 78 cases of GI cancer, 32 cases of urologic cancer were involved. The Eastern Cooperative oncology Group Performance Status score of GI cancer group was significantly higher than those of the lung cancer and urologic cancer groups[(2.4±1.1) vs (2.0±1.4), (1.8±1.0), both P<0.05]. The proportion of smoking patients in lung cancer group was significantly higher than that in GI cancer and urologic cancer groups (79.3% vs 30.8%, 53.1%, both P<0.05), while the proportion of operation was significantly lower than that in the latter two groups (35.4% vs 53.8%, 68.8%, both P<0.05). Pathological types of cancer were mostly adenocarcinoma, and the proportion of adenocarcinoma in lung cancer and GI cancer groups was significantly higher than that in urologic cancer group (76.9%, 73.8% vs 37.9%, both P<0.001). The proportion of moderately and/or poorly differentiated histodifferentiation in the first two groups was significantly higher than that of urologic cancer group (90.0%, 95.7% vs 40.0%, both P<0.001). The proportion of patients with TNM stage Ⅲ-Ⅳ in lung cancer group was significantly higher than that of the urological cancer group (87.0% vs 64.3%, P<0.05). The incidence of VTE in lung cancer group was significantly higher than those of GI cancer and urologic cancer groups within 6 months after tumor diagnosis, chemotherapy and operation (79.3% vs 60.3%, 46.9%; 76.5% vs 48.6%, 36.4%; 92.3% vs 57.9%, 59.1%; all P<0.05). The case fatality rate within one year in lung cancer and GI cancer groups was significantly higher than that in urologic cancer group (51.2%, 52.6% vs 18.8%, both P<0.01). The median survival time of the lung cancer and GI cancer groups was significantly shorter than that of the urological cancer group (P=0.001, 0.010, respectively). Conclusions: Adenocarcinoma, advanced cancer, and poor histodifferentiation are risk factors of VTE in cancer patients. Most events of VTE occur within 6 months after a diagnosis of cancer. The prognosis of lung cancer and GI cancer complicated with VTE is worse than that of urologic cancer with VTE.

To the Editor: Although the causes and mechanisms of lung cancer (LC) are still not clear, with the advances in science and technology and the progress in research methods, it has been shown that tumor cells aggregate with platelets (PLTs) and escape being recognized by the immune system. They adhere to distant vascular endothelial cells and continue to metastasize, invade and grow through the blood circulation.[1] Therefore, the hypercoagulable state and enhancement of PLT functions promote tumor growth, invasion, and metastasis.[2,3] Therefore, the effective reduction in PLT counts and their activities can help reduce the progression and prognosis of LC. We conducted this research to explore the effect of the tumor on circulating platelets in patients with LC. Forty patients with LC (LC group) hospitalized in the 96th Hospital of the People's Liberation Army of China were selected for the study. This study follows relevant ethical regulations and is approved by the Ethics Committee of the 96th Hospital of the People's Liberation Army of China (2016 Number 40, the Jinan Military Region General Hospital). All the patients provided written informed consent. The group included 28 men and 12 women (mean age: 58.08 ± 10.22 years). Among these patients, 12, 26 and 2 had squamous cell carcinoma, adenocarcinoma, and small cell carcinoma, respectively. During the same period, 50 healthy individuals formed the control group and included 32 men and 18 women (mean age: 58.52 ± 11.93 years). Fasting venous blood samples were collected in the morning from both the LC and control group subjects who were not given hemostasis and anticoagulant medication for up to two weeks prior to the blood sampling. Thromboelastograms were drawn using a thromboelastograph, and PLT counts were determined using an automatic blood analyzer. From the initial study sample, 30 NSCLC patients (17 men and 13 women, mean age: 61.27 ± 7.90 years) and 20 control individuals (11 men and nine women, mean age: 57.00 ± 10.08 years) were selected for determination of CD62P positivity. Peripheral blood samples (2 mL) were centrifuged at 2000 r/min for 10 min. Using a straw-type pipette 100 μL of the intermediate gray cloudy interfacial layer, containing PLT-rich plasma was removed (making sure not to recover other layers) and transferred into a flow tube. PLT-rich plasma (5 μL each) was taken into test tube A (negative control tube) and test tube B (study tube). While CD61-FITC + IgG1-PE antibody (5 μL) was added to tube A, CD61-FITC + CD62P-PE antibody (5 μL) was added to tube B and incubated in the dark at room temperature for 20 min. Cells were washed once with 5 volumes of phosphate-buffered saline (PBS) solution, centrifuged at 2000 r/min for 5 min, and discarded the supernatant. CD62P positive rate = (CD61 + CD62P + count/CD61 + count) × 100%. Compared with the control group, the LC group showed lower values of reaction time (R), K time (K), and PLT distribution width (PDW). However, values of angle, maximum amplitude (MA), coagulation composite index (CI), PLT, mean PLT volume (MPV) and FIB were higher in the LC group compared to the control group. Based on the 2017 version of clinical TNM staging, patients were divided into two groups: early stage (I/II) and late stage (III/IV). The differences in MA values were statistically significant between the two groups [Table 1].Table 1: Comparison of the parameters between patients with different TNM stage cancers.The PLT counts in the LC group was (250.60 ± 57.09) × 109/L, which was significantly higher than that in the control group (192.35 ± 43.37) ×109/L. At the same time, patients with LC also had a significantly higher rate (%) of CD62P positive expression (50.42 ± 15.42), compared to the control group (27.31 ± 18.16). LC patients were classified as stage I (nine cases), stage II (six cases), stage III (11 cases), and stage IV (four cases). Compared to the control group, while the PLT counts in stage I patients (193.44 ± 42.03)×109/L were not significantly different, those in stages II, III, and IV patients were significantly higher and also increased with the stage of the disease. Similarly, the rate of CD62P positivity in stage I, II, III, and IV patients was significantly higher compared to the control group, and increased with advancing stage. The CD62P expression in stage IV patients was significantly higher than that in stage I patients [Table 2].Table 2: Comparison of expression of CD62P on PLT surface with different TNM staging.High PLT numbers and expression of fibrinogen are often observed in NSCLC patients with local regional or distant metastasis.[4] In this study, evaluation of thromboelastography (TEG) plots showed an increase in the MA. A larger MA value reflects increased PLT aggregation. The series of changes are indicative of the abnormal changes in coagulation, fibrinolysis, and PLTs caused by the tumor. PLTs play an important and multifaceted role in cancer progression.[5] We analyzed findings of blood tests and found that PLT numbers and their morphology in patients with LC were significantly different from the control group. It has been reported that MA values in the group with later stage cancer were significantly increased, indicating a direct relationship between tumor stage and PLT function. TEG and PLT counts were, therefore, evaluated to assess if the patients are in a hypercoagulable state to determine the TNM stage and prognosis. Structural changes in PLTs have been shown to play an important role in their functional changes. The main functions of PLTs include adhesion and aggregation (white thrombosis), secretion and release (release of particulate matter), enhancement of coagulation factors and endothelial cell function, and deformation (morphological changes). Receptor activation results in a series of physiological and chemical changes, which constitute the pathophysiological basis of PLT-dependent thrombosis.[6] We first analyzed that, compared to the control group, PLT counts in stage I patients were not significantly different, while those in stages II, III, and IV patients were all comparable and significantly higher. Our findings suggest that the PLTs count does not change significantly in the early stages of LC, but increase as the stage of the disease advances. The PLT counts in phase IV were significantly higher than those in phase I. It can be seen that in the early stage, especially stage I, the PLT count does not clearly reflect the existence of LC. The longer the disease course and later the disease stage, the more pronounced is the increase in PLT counts,[7] which is consistent with our findings. We detected the viscoelasticity of coagulation clots during coagulation by TEG and found that the tumor causes an increase in the aggregation function of PLTs in peripheral blood. Flow cytometric analysis revealed that the rate of CD62P positivity on PLT membranes in the LC group (50.42 ± 15.42%) was significantly higher than in the control group (27.31 ± 18.16%). The rate of CD62P positivity in stages I, II, III, and IV was significantly higher than that in the control group. It is suggested that as the tumor size increases with increasing stage, the adhesion capacity of PLTs also increase. Treatment of early stage (I) patients for inhibition of PLT function should, therefore, be considered. In general, stage IV disease often has distant metastatic lesions which are difficult to be cured surgically. It is suggested that the rate of CD62P positivity in LC patients is significantly associated with the occurrence, development, and distant metastasis of LC. We also found that the rate of CD62P positivity in stage IV was significantly higher than that in stage I. More and more evidence show that compared with healthy control subjects, the PLT counts in LC patients are significantly increased, they are in an activated state, and their membrane glycoproteins are significantly altered and overexpressed, which are important factors in promoting thrombosis. This study confirmed that LC is an important factor in increasing the PLT counts and enhancing their adhesion and aggregation function, especially in patients with late-stage cancer and lymph node metastasis. With the increase of the stage, the PLT counts and their functional activation is increased, which promotes and metastasis of LC cells. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. They understand that the patient's name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Conflicts of interest None.

Objective The mitochondrial energy metabolic pathway (MEMP) is the primary energy metabolism of tumor cells, and its disruption may promote cancer emergence, spreading, and immune escape. However, there is a lack of studies to determine the relationship between relevant functional mechanisms and lung adenocarcinoma (LUAD) prognosis. Methods Gene set enrichment analysis (GSEA) was employed to determine MEMP pathway-related genes. Then, a prognostic model was created using the MEMP key genes that were found by LASSO-Cox regression analysis. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases provided the training and validation sets. Furthermore, the infiltration of immune cells was examined by ssGSEA. Finally, a screening of candidate therapeutic compounds for LUAD patients was performed using DrugBank, Protein Data Bank (PDB), and AutoDock Vina databases. Results First, 266 MEMP pathway-related genes that exhibited aberrant activity in tumors were identified. Then, 19 MEMP key genes were used to build a prognostic model, which can successfully predict the survival rates of LUAD patients after 1, 3, and 5 years, respectively. The Kaplan-Meier curve showed that patients in the high-risk group had considerably lower survival outcomes than those in the low-risk group. Furthermore, it was discovered that the high-risk group had the majority of activated T cells, while the low-risk group tended to have more other activated immune cells. The majority of immunological checkpoints expressed themselves more strongly in the high-risk group as well. Finally, 11 prospective medication small molecules were obtained from the projected potential therapeutic drugs, with DB0980 being regarded as the most promising of them for the treatment of LUAD. Conclusion This current study developed reliable prognostic signature, called MEMP score, which provides new guidance for prognostic assessment, immunotherapy, and drug development in LUAD. Thereby, DB0980 appears to be the most likely approach for the treatment of LUAD.

Mitochondria are the main sites of oxidative metabolism and energy release of sugars, fats and amino acids in the body. According to studies, malignant tumor occurrence and development have been linked to abnormal mitochondrial energy metabolism (MEM). However, the feasible role of abnormal MEM in colon adenocarcinoma (COAD) is poorly understood. In this work, we obtained COAD patient data from The Cancer Genome Atlas (TCGA) as the training set, and GSE103479 from Gene Expression Omnibus (GEO) as the validation set. Combined with the mitochondrial energy metabolic pathway (MEMP)-related genes in Kyoto Encyclopedia of Genes and Genomes (KEGG) database, a risk prognostic model was constructed by utilizing Cox regression analysis to identify 6 feature genes (CYP4A11, PGM2, PKLR, PPARGC1A, CPT2 and ACAT2) that were significantly associated with MEMP in COAD. By stratifying the samples based on riskscore, two distinct groups, namely the high- and low-risk groups, were identified. The model demonstrated accurate assessment of the prognosis risk in COAD patients and exhibited independent prognostic capability, as evidenced by the survival curve and receiver operating characteristic (ROC) curve analysis. A nomogram was plotted based on clinical information and riskscore. We proved it could predict the survival time of COAD patients effectively combined with the calibration curve of risk prediction. Subsequently, based on the immune evaluation and mutation frequency analysis performed on COAD patients, patients in high-risk group had observably higher immune scores, immune activity and PDCD1 expression level than low-risk group. In general, the prognostic model developed using MEMP-related genes served as a valuable biomarker for forecasting the prognosis of COAD patients, which offered a reference for the prognosis evaluation and clinical cure of COAD patients.

Deciphering the role of MitomiRs in cancer: A comprehensive review

NADH Ties One-Carbon Metabolism to Cellular Respiration

Diversity in mitochondrial metabolic pathways in parasitic protists Plasmodium and Cryptosporidium

Lung cancer remains a leading cause of cancer-related death globally, with high malignancy and poor prognosis. PANoptosis, a novel programmed cell death pathway combining apoptosis, pyroptosis, and necroptosis, has been increasingly implicated in disease pathogenesis, yet its role in lung cancer is poorly understood. This study integrated bulk and single-cell RNA-seq data from TCGA and GEO databases to identify and validate PANoptosis-related genes in lung cancer. We identified eight key genes (DAPK2, CAV1, PDK4, IL3RA, NOTCH1, CHMP4B, IRAK1, and SFN) that are significantly dysregulated in tumors and correlated with prognosis. Functional enrichment analysis implicated these genes in cell adhesion, cytokine signaling, necrotic pathways, and cell cycle regulation. Furthermore, immune infiltration analysis suggested roles for CHMP4B and IRAK1 in modulating the tumor immune microenvironment. Experimental validation via qPCR and IHC confirmed differential expression of these genes in cell lines and clinical samples. Drug sensitivity analysis also linked CHMP4B and PDK4 to response to targeted agents like Gefitinib. In conclusion, our results reveal the significance of PANoptosis-related genes in lung cancer pathogenesis and highlight their potential as prognostic biomarkers and therapeutic targets. Lung cancer is among the leading causes of cancer-related morbidity and mortality worldwide, characterized by high aggressiveness, early metastasis, and poor prognosis. PANoptosis, a recently recognized form of programmed cell death that integrates apoptosis, pyroptosis, and necroptosis, has been implicated in various diseases. However, comprehensive studies investigating PANoptosis-related genes in lung cancer remain limited, and their functional roles in tumorigenesis and progression are not fully understood. In this study, we integrated transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases with single-cell RNA sequencing analysis to identify PANoptosis-related genes involved in lung cancer. A combination of differential gene expression analysis, functional enrichment analysis, immune infiltration profiling, and drug sensitivity prediction was performed to explore the biological significance and therapeutic potential of these genes. Furthermore, we validated the expression patterns of key genes using quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in lung cancer cell lines and tissue specimens. Eight PANoptosis-related genes (DAPK2, CAV1, PDK4, IL3RA, NOTCH1, CHMP4B, IRAK1, and SFN) were identified as being significantly associated with lung cancer. Their expression levels were notably altered in tumor tissues compared to normal controls and were significantly correlated with patient prognosis. Functional enrichment analysis revealed these genes were mainly involved in cell adhesion, cytokine signaling, necrosis-related pathways, and cell cycle regulation. Notably, CHMP4B and IRAK1 showed distinct expression patterns in different immune cell populations, indicating their potential roles in shaping the tumor immune microenvironment. Importantly, qPCR and IHC analyses confirmed the differential expression of these genes across lung cancer cell lines and clinical specimens. Drug sensitivity analysis further suggested that genes such as CHMP4B and PDK4 were associated with the response to targeted therapies including Gefitinib. This study provides a comprehensive landscape of PANoptosis-related gene dysregulation in lung cancer and highlights their potential as prognostic biomarkers and therapeutic targets. The integrated bioinformatics analysis combined with experimental validation supports their functional relevance in lung cancer development and treatment.

The present study aimed to investigate the correlation of the of hemoglobin A1c (HbA1c), C-peptide and insulin-like growth factor-1 (IGF-1) levels with the development and progression of lung cancer. The serum HbA1c, C-peptide and IGF-1 levels were measured and compared between 80 lung cancer patients and 80 healthy controls; furthermore, their correlation with histopathological type and tumor stage was analyzed in the 80 lung cancer patients. Our results suggested that the levels of HbA1c, C-peptide and IGF-1 were significantly increased in patients with lung cancer compared to those in the control group (P<0.05). In addition, the levels of C-peptide and IGF-1 were significantly higher in the small-cell lung cancer group (n=18), the stage III-IV (n=55) group and the lung cancer with diabetes mellitus group (n=43) compared to those in the non-small-cell lung cancer group (n=62), the stage I-II lung cancer group (n=25) and the lung cancer without diabetes group (n=37), respectively (P<0.05). Thus, the present study suggests that the increased serum HbA1c, C-peptide and IGF-1 levels are significantly correlated with the development and progression of lung cancer.

MiR-125b-1-3p-mediated UQCRB inhibition facilitates mitochondrial metabolism disorders in a rat cellular senescencemodel

Lung cancer (LC) is a common malignant tumor with high morbidity and mortality. The development of new molecular markers and the early diagnosis of LC and the exploration of emerging targeted therapies are of great significance. Therefore, this study systematically evaluates the correlation between peripheral serum MIC-1 levels and LC. Search PubMed, Web of Science, Medline and other databases, the search time is from the establishment of the database to July 2021. The LC group included LC patients, the Non-cancer group included patients with benign lung diseases (BLD), and the control group included healthy people. The serum MIC-1 levels of LC group and control group, LC group and Non-cancer group were compared respectively, and the correlation between serum MIC-1 and clinical characteristics of LC patients was evaluated and analyzed, and the ROC curve of MIC-1 in prediction of LC. Finally, 5 articles were included, including 1179 patients with LC, 109 patients with BLD, and 1020 healthy people. Meta-analysis results: the level of MIC-1 in LC group was overtop that in healthy group, and the difference was obvious [SMD=1.97, 95%CI (1.35, 2.59), PC0.00001]. The level of MIC-1 in LC group was overtop that in Non-cancer group, and the difference was obvious [SMD=382.97,95%CI (313.74, 452.19), PC0.00001]. The descriptive evaluation analyzes the correlation between MIC-1 and the clinical characteristics of LC group, and the results show that MIC-1 has a certain correlation with the stage of LC group. The AUC of serum MIC-1 in the identification of LC group and the control group was greater than 0.5. The AUC value of MIC-1 in the diagnosis of LC was 0.851-0.906, and the best sensitivity range was 63.50%-99.00%. The best specificity is in the range of 70.4%-95.80%. The Meta-analysis indicated that the serum MIC-1 level in LC group is overtop that in BLD and healthy people, and has a obvious correlation with LC stage staging; and the ROC curve shows that it has important significance in the diagnosis and prognosis of LC.

Lung Cancer Associated with Rheumatoid Arthritis Does Not Shorten Life Expectancy

The expression of microRNA-340 and cyclin D1 and its relationship with the clinicopathological characteristics and prognosis of lung cancer