On respiratory impairment in cancer cells. pdf

These findings suggest that IACS is a better choice for clinical application. H19 and numerous ribosomal protein genes are upregulated but MAPK pathway and cell cycle-associated genes are downregulated upon IACS treatment. In RTS patients, impaired RECQL4 function leads to an increase of mitochondrial respiratory complex I gene expression and function, and thereby induces premalignant phenotypes.

S5D Fig. These findings suggest that induction of senescence, but not ROS production and apoptosis, is one of the pharmacological mechanisms involved in IACSinduced RTS osteoblast growth inhibition. In summary, our systematic transcriptome analyses revealed multiple potential pharmacologic mechanisms for IACSmediated cell growth inhibition in RTS osteoblasts.

The advantage of the iPSC platform lies in its ability to establish highly flexible pluripotent human cell lines from an established unique genetic alteration and proven background.

In this case, our approach allowed us to dissect the impact of RECQL4 pathogenic variants on RTS-associated pathological consequences such as defective osteogenesis and osteosarcomagenesis. With appropriate differentiation protocols, these models can be used to study other clinical phenotypes of RTS, such as cataracts, poikiloderma, and abnormal dentition, that affect other tissues and organ systems.

Accumulating studies of energy metabolism in leukemias, lymphomas, pancreatic ductal adenocarcinoma, melanoma, and endometrial carcinoma reveal the essential role of OXPHOS in contributing to tumor formation and progression [ 10 ]. Mutant RECQL4 particularly translocates from nucleus to mitochondria and then interacts with mitochondrial replication helicase PEO1, which leads to elevated mtDNA synthesis and mitochondrial dysfunction [ 35 ]. Our study added a new finding to link mitochondrial dysfunction to RTS pathology and uncovered the upregulated mitochondrial respiratory complex I gene expression and activities in RTS osteoblasts.

Our thorough transcriptional and biochemical studies conclude that elevated mitochondrial respiratory complex I function in RTS osteoblasts is a potential therapeutic target to treat RTS osteosarcoma. H19 has also been shown to function as a tumor suppressor to promote osteogenesis and inhibit osteosarcomagenesis in LFS osteoblasts and osteosarcoma [ 17 ], implying that IACS may shift cells from a tumorigenic and undifferentiated profile towards normal osteoblast differentiation.

Homeostasis of ribosomal biogenesis may be an essential process to maintain survival of RTS osteoblasts. The upregulation of oxidative metabolism in RTS is a druggable pathway, and our preclinical studies using IACS suggest favorable, clinically relevant changes in RTS osteoblasts treated with this drug.

Overall, our study suggests strong clinical potential for therapies targeting mitochondrial respiratory complex I in RTS patients with osteosarcoma. Written formal consent for participation in this IRB-approved protocol was obtained by Dr. Lisa L. Wang P. RTS individuals and their parents provided informed consent to participate in an institutional review board-approved study at Baylor College of Medicine Houston, TX.

Teratoma formation assay was performed as described previously [ 41 ]. After 25 days in culture, cells at the edge of differentiated cell clusters became spindle-shaped.

The medium was changed daily. Osteogenic differentiation was carried out based on previously described protocols [ 17 , 18 , 40 ]. The medium was changed every three days. Stained osteoblasts were imaged under a Leica DMi8 microscope. In vitro AIG assay was described previously [ 17 ]. The cell suspensions were then plated in well plates containing solidified 0. Osteoblasts were maintained in osteoblast differentiation medium for 1.

Immunofluorescence staining and immunoblotting was described previously [ 41 — 43 ]. Differential gene expression was analyzed by DESeq2 [ 44 ]. The quantitative measure of viability was read by absorbance at nm. Trim Galore! Version 0. Single nucleotide variants were detected using MuTect2 [ 49 ], while indels were not interrogated given the high rates of false-positive calls.

Additional filters were applied to eliminate false-positive somatic variant calls: 1 read depth lower than 25th percentile of the sequencing coverage [ 50 ], 2 read depth higher than 75th percentile of the sequencing coverage [ 51 ], 3 present in dbSNP [ 52 ].

Briefly, cell lysis was incubated with ATPlite solution containing luciferase and D-Luciferin firefly. The ATP concentration is proportional to the emitted luminescence. The samples were incubated at room temperature in the dark for 10 minutes. Results were compared to the supplied ATP standard. Electron transport chain ETC enzymatic activity and citrate synthase CS activity assays were performed as previously described [ 55 , 56 ].

The total protein content of osteoblast lysates was quantified by Bradford protein assay Bio-Rad, and used for normalization. A Seahorse assay plate was prepared by incubating in water overnight and replacing with calibration medium for 4 h prior to performing the assay. Assay chemicals were dissolved in the assay medium without BSA. Assay measurements were made at baseline and every 6 min over 18 min 3 cycles each entailing a 3-min mix and 3-min measurement.

Next, IACS was injected from port A over 30 min and measurements were made at time 0 and at 6-min intervals over 30 min 5 cycles each of 3-min mix and 3-min measurement. Statistical analysis was performed in Prism 8. Left Representative phase-contrast microscope images show the area covered by RTS and FC osteoblasts at 72 hours after wounding.

Right The cell migration rate is determined by the rate of cells moving towards the scratched area upon time measured. The number of enriched genes in each GO is displayed as node size, with closer distance between nodes representing increased overlap between genes in ontologies.

Enriched gene sets in osteosarcoma are displayed in red and enriched gene sets in bone tissues and osteoblasts in blue. Right, representative enriched gene sets ATP synthesis coupled electron transport and respiration electron transport chain involved in mitochondrial ATP production are shown.

The authors gratefully acknowledge John F. Hancock, Jeffrey T. If a document is eliminated, the results of the literature have changed significantly, and the reasons for the significant impact of the literature on the overall results can be further analyzed.

This article included a total of 9 studies, including three studies from China, three studies from the United States, one study from Denmark, one study from Japan, and one study from Mexico. A total of people were enrolled in 9 studies, including patients with lung function impairment and controls.

According to the NOS scale, the quality of the included literature was scored, and the average score of the included literature was about 5. A total of 9 articles were included in this meta-analysis, with a total of research subjects.

Due to the large heterogeneity of this meta-analysis, subgroup analysis is needed to find the source of heterogeneity. The included literature was divided into several groups for subgroup analysis according to study race, number of included cases, literature quality, and so on.

The specific results are summarized as follows: 1 Subgroup analysis is performed according to different research races. The heterogeneity of the studies conducted in Europe and America is relatively low, and the results of the two groups are statistically significant, as shown in Figure 3. The results showed that this heterogeneity mainly comes from studies with more cases. The heterogeneity of studies with fewer cases included is relatively low, and the results of the two groups are statistically significant, as shown in Figure 4.

The high-quality studies have relatively low heterogeneity, and the results of the two groups are statistically significant, as shown in Figure 5. The random-effects model was used for sensitivity analysis after the included studies were eliminated one by one. The specific results are shown in Figure 6. After reading the full text again, the analysis may be due to the fact that the selected case treatment methods in this study are different from those of other studies.

Esophageal carcinoma is a common cancer [ 10 ]. Surgery is the first choice for treatment [ 13 ]. Though respiratory failure is difficult to predict and control, if it cannot be effectively controlled after surgical treatment, it is likely to endanger the lives of patients. Several studies have shown that lung function damage is one of the important indicators of postoperative respiratory failure in patients with esophageal cancer.

Yoshida et al. Other scholars pointed out that preoperative pneumonia, tuberculosis, acute respiratory distress syndrome ARDS , and other diseases in patients with esophageal cancer could make them more prone to respiratory failure [ 18 — 20 ]. The results of this meta-analysis initially show that esophageal cancer patients with preoperative lung function impairment are more likely to suffer from respiratory failure after surgical treatment, and lung function impairment may be a risk factor for respiratory failure.

This meta-analysis conducted a literature search in Pubmed, ScienceDirect, and CNKI based on a preestablished search strategy and finally included 9 related articles. According to the NOS scale for literature quality scoring, the average score 5. This meta-analysis was divided into several subgroups according to race, number of included cases, and literature quality sources.

Although the results of each subgroup analysis are not completely consistent, all show that lung function impairment is related to the risk of respiratory failure after esophageal cancer surgery. The subgroup showed that lung function impairment has a significant impact on the risk of esophageal cancer. This meta-analysis has several advantages: firstly, this study includes studies not only from developed countries but also from developing countries.

Although this study strictly formulated the literature retrieval strategy and inclusion and exclusion criteria and carried out a more systematic and comprehensive literature retrieval and literature screening, it also has certain limitations. Only one author conducted retrieval, screening, and quality assessment of the literature. When the data were combined, other factors for postoperative respiratory failure for esophageal cancer were not considered.

The number of documents included in this article was small 9 , and the included studies had high heterogeneity, and the heterogeneity in the overall analysis and subgroup analysis was relatively high. Therefore, the literature included in this article is not enough to directly prove the research.

More high-quality studies are required to further validate the results. The simulation experiment data used to support the findings of this study are available from the corresponding author upon request. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.

Read the winning articles. Journal overview. Special Issues. Academic Editor: Kalidoss Rajakani. Received 30 Sep Revised 27 Oct Accepted 30 Oct Adv Exp Med Biol — FEBS Lett — Small J Flux control coefficients determined by inhibitor titration: the design and analysis of experiments to minimize errors.

Biochem J — Cooper CE, Davies NA, Psychoulis M et al Nitric oxide and peroxynitrite cause irreversible increases in the Km for oxygen of mitochondrial cytochrome oxidase: in vitro and in vivo studies.

Biochim Biophys Acta — Lab Investig — Proteome Sci Mol Neurobiol — Cell Physiol Biochem — Birsoy K, Wang T, Chen WW et al An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Mol Cell — Gaude E, Frezza C Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival.

Nat Commun Download references. Erika Rodrigues-Silva, Edilene S. Siqueira-Santos, Juliana S. Ruas, Tiago R. You can also search for this author in PubMed Google Scholar. National Center for Biotechnology Information , U.

Journal List J Healthc Eng v. J Healthc Eng. Published online Nov Yanming Sun and Ying Zhu. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Yanming Sun: moc. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Associated Data Data Availability Statement The simulation experiment data used to support the findings of this study are available from the corresponding author upon request. Abstract Objective To study lung function impairment by meta-analysis to increase the risk of postoperative respiratory failure in patients with esophageal carcinoma.

Results Finally, 9 related articles and research subjects were included, and the average score of literature quality was 5. Conclusion The results of the study show that lung function impairment has a positive relationship with postoperative respiratory failure in patients with esophageal cancer.

Introduction According to relevant statistics, about , people die from esophageal cancer each year, which has become a gastrointestinal malignant tumor with a high incidence rate in the world, and China is a typical high-incidence area [ 1 ]. Materials and Methods 2. Meta-Analysis Steps The problem that the meta-analysis wants to solve is concisely and clearly put forward According to the purpose of this meta-analysis, the criteria for inclusion and exclusion of the literature are determined Appropriate search strategies are developed to collect relevant research The retrieved documents are deduplicated and screened The NOS scale is used to evaluate the literature quality of the selected literature Relevant data are extracted from the included literature according to the premade tables Review Manager and other statistical software are used to perform statistical analysis on the data extracted from the included literature The result is obtained through statistical analysis, and the result is explained in detail The database is searched again in the same way to maintain and update the literature.

Table 1 Search strategy. Open in a separate window. Inclusion and Exclusion Criteria 2. Inclusion Criteria 1 The English literature published since the establishment of the literature database; 2 the main confounding factors were controlled in the research; 3 the research design was reasonable; 4 there was clear information on lung function damage; and 5 patients with respiratory failure after esophageal cancer confirmed pathologically [ 6 — 8 ].

Exclusion Criteria 1 Articles in languages other than English; 2 documents with repeated reports; 3 articles with poor research design and substandard quality; 4 studies with incomplete data required; 5 reviews and systematic evaluative literature; 6 literature with few subjects included; and 7 studies without a control group [ 9 — 11 ]. Selection of Studies for This Systematic Review We import the documents retrieved from the database according to the preestablished search strategy into the EndNote software for deduplication.

Extraction of Data After carefully reading the full text of the included literature, we extracted the data according to the predesigned table. Assessment of Quality We carefully read the full text of the included literature.

Statistical Analysis 2. Choice of Effect Model The choice of random-effects model or fixed-effects model is determined based on I 2. Treatment of Heterogeneity Subgroup Analysis Subgroup analysis is to divide the included literature into multiple subgroups for analysis based on multiple characteristics.

The nine articles included in this study were divided into multiple subgroups based on the following characteristics to conduct subgroup analysis to find the source of heterogeneity: According to the research race, they are classified into Asians and Europeans and Americans Classification according to the number of cases included in the study Classification according to the quality of the literature. Heterogeneity Treatment Sensitivity Analysis Sensitivity analysis means that according to the characteristics or types of each study included in the meta-analysis, by excluding certain studies, the impact on the meta-analysis is explored.

Results 3. Figure 1. Data Extraction and Quality Evaluation This article included a total of 9 studies, including three studies from China, three studies from the United States, one study from Denmark, one study from Japan, and one study from Mexico. Table 2 Features of included studies and quality assessment results. Meta-Analysis Results 3. The Relationship between Lung Function Damage and the Risk of Respiratory Failure after Esophageal Cancer Surgery A total of 9 articles were included in this meta-analysis, with a total of research subjects.

Figure 2. Results of Subgroup Analysis Due to the large heterogeneity of this meta-analysis, subgroup analysis is needed to find the source of heterogeneity. The specific results are summarized as follows: Subgroup analysis is performed according to different research races.

Figure 3. Figure 4. Figure 5. Sensitivity Analysis Results The random-effects model was used for sensitivity analysis after the included studies were eliminated one by one. Figure 6. Discussion Esophageal carcinoma is a common cancer [ 10 ]. Data Availability The simulation experiment data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest The authors declare no conflicts of interest regarding the publication of this paper. References 1. Adrianne K.