Hypoxic State Research Articles

Mechanisms Behind Hypoxia-Driven Resistance to Immunotherapy in the Tumor Microenvironment

Tumor formation requires rapid proliferation of malignant cells which consume large amounts of oxygen from the microenvironment to meet metabolic demands. The resulting tumor microenvironment (TME) is usually low in oxygen compared to healthy tissue and left in a hypoxic state. Immune cells in the tissue rely on oxygen for energy production, therefore immune function is often inhibited in the TME. Novel immunotherapy treatments aim to reinvigorate the immune system, thus making hypoxia a concrete barrier against immunotherapeutics targeting solid tumors. Furthermore, oxygen levels are highly variable dependent on the tissue, raising the question of the influence of physoxia on immune cell survival in hypoxic counterparts. This review aims to provide insight into the mechanisms that influence this question, using an in-silico approach, in order to understand how the field can improve immunotherapy treatments for patients.

Cancer Metabolism and Ischemia-Reperfusion Injury: Two Sides of the Same Coin.

Cancer cells are characterized by the reprogramming of certain cell metabolisms via activation of definite pathways and regulation of gene signaling. Ischemia-reperfusion injury (IRI) is characterized by tissue damage and death following a lack of perfusion and oxygenation. It is most commonly seen in the setting of organ transplantation. Interestingly, the microenvironments seen in cancer and ischemic tissues are quite similar, especially due to the hypoxic state that occurs in both. As a consequence, there is genetic signaling involved in response to IRI that has common pathways with cancer. Some of these changes are seen across the board with many cancer cells and are known as Hallmarks of Cancer, among which are aerobic glycolysis and the induction of angiogenesis. This literature review aims to compare the metabolic pathways that are altered in cancer tissues and in normal tissues subjected to IRI in order to find common adaptive processes and to identify key pathways that could represent a therapeutic target in both pathologies. By increasing our understanding of this relationship, clinical correlations can be made and applied practically to improve outcomes of transplanted organs, given the known association with acute rejection, delayed graft function, and poor graft survival. The following metabolic pathways are discussed in our review, both in the setting of cancer and IRI: apoptosis, glycolysis, and angiogenesis. The role of the immune system in both pathologies as well as mitochondrial function and the production of reactive oxygen species (ROS) are reviewed.

Identification of m6A modification patterns and development of m6A-hypoxia prognostic signature to characterize tumor microenvironment in triple-negative breast cancer.

BackgroundN6-methylation (m6A) modification of RNA has been found to have essential effects on aspects of the tumor microenvironment (TME) including hypoxia status and mobilization of immune cells. However, there are no studies to explore the combined effect of m6A modification and hypoxia on molecular heterogeneity and TME of triple-negative breast cancer (TNBC).MethodsWe collected The Cancer Genome Atlas (TCGA-TNBC, N=139), the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC-TNBC, N=297), the GSE103091, GSE21653, and GSE135565 series from the Gene Expression Omnibus (GEO-TNBC, N=247), and FUSCCTNBC (N=245) for our study. The non-negative matrix factorization algorithm was used to cluster TNBC samples. Immune cell infiltration was analyzed by the CIBERSORT algorithm. The enrichment scores were calculated by single-sample gene set enrichment analysis(ssGSEA) to characterize TME in TNBC samples. Immunohistochemistry (IHC) and qRT-PCR were performed to detect the gene expression.ResultsBased on the expression of m6A-related genes, we identified three distinct m6A clusters (denoted A, B, and C) in TNBC samples. Comparing the TME characteristics among the three clusters, we observed that cluster C was strongly related to hypoxia status and immune suppression, whereas clusters A and B displayed more immune cell infiltration. Therefore, we combine m6A and hypoxia related genes to classify two m6A-hypoxia clusters of TNBC and screened six prognostic genes by LASSO-Cox regression to construct a m6A-hypoxia signature(MHPS), which divided TNBC samples into high- and low-risk groups. We identified different TME features, immune cell infiltration between the two groups, and a better immunotherapy response was observed in the low-risk group. A nomogram was constructed with tumor size, lymph node, and risk score to improve clinical application of MHPS.ConclusionWe identified distinct TME characteristics of TNBC based on three different m6A modification patterns. Then, we constructed a specific m6A–hypoxia signature for TNBC to evaluate risk and predict immunotherapy response of patients, to enable more accurate treatment in the future.

Sirolimus increases the anti-cancer effect of Huai Er by regulating hypoxia inducible factor-1α-mediated glycolysis in hepatocellular carcinoma.

BACKGROUNDGlycolysis caused by hypoxia-induced abnormal activation of hypoxia inducible factor-1α (HIF-1α) in the immune microenvironment promotes the progression of hepatocellular carcinoma (HCC), leading to enhanced drug resistance in cancer cells. Therefore, altering the immunosuppressive microenvironment by imp-roving the hypoxic state is a new goal in improving cancer treatment.AIMTo analyse the role of HIF-1α, which is closely related to tumour proliferation, invasion, metastasis, and angiogenesis, in the proliferation and invasion of liver cancer, and to explore the HIF-1α pathway-mediated anti-cancer mechanism of sirolimus (SRL) combined with Huai Er.METHODSPrevious studies on HCC tissues identified the importance of HIF-1α, glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) expression. In this study, HepG2 and Huh7 cell lines were treated, under hypoxic and normoxic conditions, with a combination of SRL and Huai Er. The effects on proliferation, invasion, cell cycle, and apoptosis were analysed. Proteomics and genomics techniques were used to analyze the HIF-1α-related signalling pathway during SRL combined with Huai Er treatment and its inhibition of the proliferation of HCC cells.RESULTSHigh levels of HIF-1α, LDHA, and GLUT-1 were found in poorly differentiated HCC, with lower patient survival rates. Hypoxia promoted the proliferation of HepG2 and Huh7 cells and weakened the apoptosis and cell cycle blocking effects of the SRL/Huai Er treatment. This was achieved by activation of HIF-1α and glycolysis in HCC, leading to the upregulation of LDHA, GLUT-1, Akt/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and Forkhead box P3 and downregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p27. The hypoxia-induced activation of HIF-1α showed the greatest attenuation in the SRL/Huai Er (S50 + H8) group compared to the drug treatments alone (P < 0.001). The S50 + H8 treatment significantly downregulated the expression of mTOR and HIF-1α, and significantly reduced the expression of VEGF mRNA. Meanwhile, the combined blocking of mTOR and HIF-1α enhanced the downregulation of Akt/mTOR, HIF-1α, LDHA, and GLUT-1 mRNA and resulted in the downregulation of PTEN, p27, and VEGF mRNA (P < 0.001).CONCLUSIONSRL increases the anti-cancer effect of Huai Er, which reduces the promotion of hypoxia-induced HIF-1α on the Warburg effect by inhibition of the PI3K/Akt/mTOR-HIF-1α and HIF-1α-PTEN signalling pathways in HCC.

Recent Advances and Therapeutic Strategies Using CRISPR Genome Editing Technique for the Treatment of Cancer.

CRISPR genome editing technique has the potential to target cancer cells in a precise manner. The latest advancements have helped to address one of the prominent concerns about this strategy which is the off-target integrations observed with dsDNA and have resulted in more studies being carried out for potentially safer and more targeted gene therapy, so as to make it available for the clinical trials in order to effectively treat cancer. CRISPR screens offer great potential for the high throughput investigation of the gene functionality in various tumors. It extends its capability to identify the tumor growth essential genes, therapeutic resistant genes, and immunotherapeutic responses. CRISPR screens are mostly performed in in vitro models, but latest advancements focus on developing in vivo models to view cancer progression in animal models. It also allows the detection of factors responsible for tumorigenesis. In CRISPR screens key parameters are optimized in order to meet proficient gene targeting efficiencies. It also detects various molecular effectors required for gene regulation in different cancers, essential pathways which modulate cytotoxicity to immunotherapy in cancer cells, important genes which contribute to cancer cell survival in hypoxic states and modulate cancer long non-coding RNAs. The current review focuses on the recent developments in the therapeutic application of CRISPR technology for cancer therapy. Furthermore, the associated challenges and safety concerns along with the various strategies that can be implemented to overcome these drawbacks has been discussed.

Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness.

Simple SummaryGiven the rising mortality rate caused by GBM, current therapies do not appear to be effective in counteracting tumor progression. The role of adenosine and its interaction with specific receptor subtypes in various physiological functions has been studied for years. Only recently, adenosine has been defined as a tumor-protective target because of its accumulation in the tumor microenvironment. Current knowledge of the adenosine pathway and its involvement in brain tumors would support research in the development of adenosine receptor antagonists that could represent alternative treatments for glioblastoma, used either alone and/or in combination with chemotherapy, immunotherapy, or both.Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.

Effects of dietary iron levels on growth performance, iron metabolism and antioxidant status in spotted seabass (Lateolabrax maculatus) reared at two temperatures

The increased ambient temperature is often accompanied by the enhanced metabolic rate and oxygen consumption of fish, which affects their nutritional requirements. Currently, no information compares the iron requirements of fish species under moderate and high temperatures. This study investigated the effects of dietary iron levels on growth performance, iron metabolism, and antioxidant status in spotted seabass (Lateolabrax maculatus) reared at two temperatures. Six diets were formulated to contain 63, 120, 188, 316, 425, and 554 mg/kg iron, each of which was fed to two groups of juveniles reared at 27°C (MT) and 33°C (HT) for 56 days. The results showed that the satisfied iron requirement for spotted seabass improved growth, feed utilization, and antioxidant capacity. Furthermore, fish fed with high‑iron diets prevented iron overload by repressing intestinal iron-regulatory proteins and inducing liver hepcidin production. Iron deficiency depressed erythropoiesis and worsened HT-induced hypoxic status. Moreover, the HT compromised fish growth, feed utilization and liver hepcidin expression, while inducing lipid deposition. Compared to 27°C, the iron demand of spotted seabass was increased at 33°C as more blood erythrocyte and tissue iron deposition were required. Based on the broken-line regression analysis of weight gain, the optimum dietary iron levels for spotted seabass reared at 27°C and 33°C were 178.5 and 209.0 mg/kg, respectively.

Serum HIF-1α Levels, miR-210 Expressions, and Reactive Oxygen Species Levels in Early Abortion and Normal Pregnancy

Background: The blastocyst implants in a relatively hypoxic state. Hypoxic state triggers hypoxia-inducible factor-1α (HIF-1ɑ) production, upregulates the transcription factor miR-210, and stimulates reactive oxygen species (ROS) production by trophoblast cells. HIF-1α also increases the expression of miR-210. High expression of micro-RNA 210 (miR-210) suppresses mitochondrial respiration, increasing ROS production. High level of ROS may result in DNA damage or cell disfunction, thereby impaired trophoblast invasion, leading to early abortion. This study aims to determine the differences of serum HIF-1ɑ levels, miR-210 expressions, and ROS levels between early abortion and normal pregnancy.&#x0D; Method: This cross-sectional comparative study was conducted in Dr. M. Djamil Hospital Padang, Andalas University Hospital, and 5 Public Health Centers in Padang. Fifty-patients with gestational age less than 12 weeks (25 early abortions and 25 normal pregnancies) were included in this study. All samples were tested for HIF-1ɑ and ROS level using enzyme-linked immunosorbent assay (ELISA) method, and miR-210 expression using real-time polymerase chain reaction (PCR) technique. Spearman correlation and Mann Whitney test. was used in this study.&#x0D; Results: Both study groups were equivalent in terms of age, gestational age, and gravidity (p = 0.51, 0.453 and 1.00). The median of HIF-1ɑ level, miR-210 expression, and ROS level were higher in early abortions than normal pregnancies i.e (3.73 vs 3.42) ng/mL (p = 0.016), (43.55 vs 17.85) copies/ng (p = 0.027), and (1.36 vs 1.20) ng/mL (p = 0.003). The coefficient correlations were 0.16 between HIF-1ɑ level and miR-210 expression (p=0.267), 0.46 between HIF-1ɑ level and ROS level (p=0.001), and 0.18 between miR-210 expression and ROS level (p=0.207).&#x0D; Conclusion: HIF-1ɑ level, miR-210 expression, and ROS level were associated with early abortion. HIF-1ɑ level has a correlation with ROS level.

Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC

BackgroundEmerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide,...

HIF-2α Inhibits Ameloblast Differentiation via Hey2 in Tooth Development

Enamel is the highly mineralized outer layer of teeth; the cells responsible for enamel formation are ameloblasts. Local hypoxia and hypoxia inducible factor (HIF) in embryonic tissues are important to promote normal organogenesis. However, hypoxic state in tooth germs and the roles of HIF in ameloblast differentiation have not been understood. The aim of this study is to clarify the role of HIF in ameloblast differentiation during tooth germ development. We found that tooth germs were under hypoxia and HIF-1α and HIF-2α were expressed in tooth germs in embryonic mice. Then, we used HIF inhibitors to evaluate the function of HIF during tooth germ development. The HIF-2α inhibitor significantly decreased the size of tooth germs in organ culture, while the HIF-1α inhibitor did not apparently affect the size of tooth germs. The HIF-2α inhibitor enhanced the expression of amelogenin, a marker of ameloblast differentiation, in the tooth germs in organ culture and rat dental epithelial SF2 cells. Moreover, we found that the HIF-2α inhibitor-stimulating amelogenin expression was regulated by hes-related family basic helix-loop-helix transcription factor with YRPW motif 2(Hey2) in SF2 cells. These findings suggest that the HIF-2α–Hey2 axis plays an important role in ameloblast differentiation during tooth germ development.

The role of oxygen and the Goldilocks range in the development of cataracts induced by space radiation in US astronauts

This article explores the role that oxygen levels in US spacecraft from 1961 to 1998 have on the development of cataracts induced by space radiation in astronauts and whether oxygen levels are well accounted for in experimental studies examining cataractogenesis. The first epidemiological report in 2001 linked an increased risk of the primary types of cataracts, and nuclear cataract alone, for astronauts with higher lens doses. However, later studies of US astronauts in 2009 and 2012 reported a higher risk of cortical cataract and posterior subcapsular cataract, but not for nuclear cataract. Firstly, it is postulated that the high oxygen level atmospheres of spacecraft employed before 1976 were a factor in promoting nuclear cataract. The high oxygen levels of hyperbaric oxygen therapy are reportedly associated with nuclear cataract, and the low intraocular oxygen levels of diabetic patients are possibly linked to their higher risk of posterior subcapsular cataract and cortical cataract. Secondly, it is hypothesized that the normal hypoxic environment of the lens and lens epithelial cells (LECs), and all stem/progenitor cells in general, have an optimal Goldilocks range of oxygen levels. Too high a lenticular oxygen level increases oxidative stress and radiosensitivity due to the oxygen effect. Whereas too low an oxygen tension also increases oxidative stress and disrupts LEC differentiation. Even so, a focused literature search of the PubMed database of in vitro experiments with LECs shows that studies rarely account for the hypoxic state of the normal lens, whether ionizing radiation is a factor or not. It is therefore recommended that ocular physioxic levels should therefore be considered when designing in vitro studies to better understand the progression of cataractogenesis on long-duration missions to the Moon and Mars.

Hypoxia-Immune-Related Gene SLC19A1 Serves as a Potential Biomarker for Prognosis in Multiple Myeloma.

BackgroundMultiple myeloma (MM) remains an incurable malignant tumor of plasma cells. Increasing evidence has reported that hypoxia and immune status contribute to the progression of MM. In this research, the prognostic value of the hypoxia–immune-related gene SLC19A1 in MM was evaluated by bioinformatics analysis.MethodRNA-sequencing (RNA-seq) data along with clinical information on MM were downloaded from the Gene Expression Omnibus (GEO) database. Consistent clustering analysis and ESTIMATE algorithms were performed to establish the MM sample subgroups related to hypoxia and immune status, respectively, based on the GSE24080 dataset. The differentially expressed analysis was performed to identify the hypoxia–immune-related genes. Subsequently, a hypoxia–immune-gene risk signature for MM patients was constructed by univariate and multivariate Cox regression analyses, which was also verified in the GSE4581 dataset. Furthermore, the mRNA expression of SLC19A1 was determined using qRT-PCR in 19 MM patients, and the correlations between the genetic expression of SLC19A1 and clinical features were further analyzed.ResultA total of 47 genes were identified as hypoxia–immune-related genes for MM. Among these genes, SLC19A1 was screened to construct a risk score model that had better predictive power for MM. The constructed prognostic signature based on SLC19A1 was verified in the GSE4581 dataset. All independent prognostic factors (age, β2-microglobulin, LDH, albumin, MRI, and gene risk score) were used to develop a nomogram that showed a better performance for predicting the survival probability of MM patients for 1–5 years. Furthermore, SLC19A1 was highly expressed in newly diagnosed and relapsed MM patients, and high expression of SLC19A1 is correlated with higher bone marrow aspiration plasma cells and β2-microglobulin levels in MM patients.ConclusionIn conclusion, our results suggest that SLC19A1 is aberrantly expressed in MM and highly expressed SLC19A1 might be a biomarker correlated with inferior prognosis. More importantly, we identified SLC19A1 as a hypoxia–immune-related gene in MM. Future functional and mechanistic studies will further clarify the roles of SLC19A1 in MM.

Development and Validation of a 6-Gene Hypoxia-Related Prognostic Signature For Cholangiocarcinoma.

Cholangiocarcinoma (CHOL) is highly malignant and has a poor prognosis. This study is committed to creating a new prognostic model based on hypoxia related genes. Here, we established a novel tumor hypoxia-related prognostic model consisting of 6 hypoxia-related genes by univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) algorithm to predict CHOL prognosis and then the risk score for each patient was calculated. The results showed that the patients with high-risk scores had poor prognosis compared with those with low-risk scores, which was verified as an independent predictor by multivariate analysis. The hypoxia-related prognostic model was validated in both TCGA and GEO cohorts and exhibited excellent performance in predicting overall survival in CHOL. The PPI results suggested that hypoxia-related genes involved in the model may play a central role in regulating the hypoxic state. In addition, the presence of IDH1 mutations in the high-risk group was high, and GSEA results showed that some metabolic pathways were upregulated, but immune response processes were generally downregulated. These factors may be potential reasons for the high-risk group with worse prognosis. The analysis of different immune regulation-related processes in the high- and low-risk groups revealed that the expression of genes related to immune checkpoints would show differences between these two groups. We further verified the expression of the oncogene PPFIA4 in the model, and found that compared with normal samples, CHOL patients were generally highly expressed, and the patients with high-expression of PPFIA4 had a poor prognosis. In summary, the present study may provide a valid prognostic model for bile duct cancer to inform better clinical management of patients.

Heparanase is a prognostic biomarker independent of tumor purity and hypoxia based on bioinformatics and immunohistochemistry analysis of esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive tract with a poor prognosis. The tumor microenvironment (TME) is mainly composed of tumor cells, stromal cells, and immune cells and plays an important role in ESCC development. There are substantial differences in tumor purity among different parts of ESCC tissues, consisting of distinct immune and stromal cells and variations in the status of hypoxia. Thus, prognostic models of ESCC based on bioinformatic analysis of tumor tissues are unreliable.MethodDifferentially expressed genes (DEGs) independent of tumor purity and hypoxia were screened by Spearman correlation analysis of public ESCC cohorts. Subsequently, the DEGs were subjected to Cox regression analysis. Then, we constructed a protein–protein interaction (PPI) network of the DEGs using Cytoscape. Intersection analysis of the univariate Cox and PPI results indicated that heparanase (HPSE), an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains, was a predictive factor. Gene set enrichment analysis (GSEA) was used to reveal the potential function of HPSE, and single-cell sequencing data were analyzed to evaluate the distribution of HPSE in immune cells. Furthermore, a human ESCC tissue microarray was used to validate the expression and prognostic value of HPSE.ResultWe found that HPSE was downregulated in ESCC tissues and was not correlated with tumor purity or hypoxia status. HPSE is involved in multiple biological processes. ESCC patients with low HPSE expression in cancerous tissues exhibited poor prognosis.ConclusionsThese results indicate that low HPSE expression in cancerous tissues correlates with poor prognosis in patients with ESCC. HPSE is a novel prognostic biomarker independent of tumor purity and hypoxia status in ESCC.

Recent Advances on the Role of ATGL in Cancer.

The hypoxic state of the tumor microenvironment leads to reprogramming lipid metabolism in tumor cells. Adipose triglyceride lipase, also known as patatin-like phospholipase= domain-containing protein 2 and Adipose triglyceride lipase (ATGL), as an essential lipid metabolism-regulating enzyme in cells, is regulated accordingly under hypoxia induction. However, studies revealed that ATGL exhibits both tumor-promoting and tumor-suppressing effects, which depend on the cancer cell type and the site of tumorigenesis. For example, elevated ATGL expression in breast cancer is accompanied by enhanced fatty acid oxidation (FAO), enhancing cancer cells’ metastatic ability. In prostate cancer, on the other hand, tumor activity tends to be negatively correlated with ATGL expression. This review outlined the regulation of ATGL-mediated lipid metabolism pathways in tumor cells, emphasizing the Hypoxia-inducible factors 1 (HIF-1)/Hypoxia-inducible lipid droplet-associated (HIG-2)/ATGL axis, peroxisome proliferator-activated receptor (PPAR)/G0/G1 switch gene 2 (G0S2)/ATGL axis, and fat-specific protein 27 (FSP-27)/Early growth response protein 1 (EGR-1)/ATGL axis. In the light of recent research on different cancer types, the role of ATGL on tumorigenesis, tumor proliferation, and tumor metastasis was systemically reviewed.

HIF‑1α and MBP1 are associated with the progression of breast cancer cells by repressing β‑catenin transcription.

Breast cancer (BC) is a common type of tumor. Numerous patients are diagnosed and treated in the early stages of the disease; however, the recurrence rate remains high. Therefore, identifying sensitive and specific tumor markers to prevent and treat BC is essential. c-Myc promoter binding protein 1 (MBP1) is a regulatory molecule located in the cell nucleus. It targets and regulates the expression of various cell proliferation-, apoptosis- and tumor-associated genes. MBP1 expression in BC tissues was detected using immunohistochemistry and further validated in BC and normal human cell lines using RT-qPCR and western blot analysis. Low MBP1 expression, in clinical samples of BC, was associated with a poor prognosis of BC (n=50). MBP1 overexpression effectively inhibited the growth and metastasis of xenograft tumors in vivo. Cell counting kit-8 assays confirmed that the proliferation of the BC cell lines was significantly increased following knockdown of MBP1 expression, while overexpression of MBP1 could significantly inhibit the proliferation of the BC cell lines. Mechanistically, a dual-luciferase assay was used to confirm that MBP1 was the key transcriptional regulator of β-catenin. In addition, MBP1 transcription and hypoxia-inducible factor (HIF-1α) induction were associated. By regulating the hypoxic microenvironmental state in the MDA231 and MCF7 cell lines, it was demonstrated that MBP1 served as a hypoxia-responsive factor and could be a new target for tumor therapy. Taken together, these results suggested that MBP1, as a potential tumor marker associated with prognosis of BC and may serve as a therapeutic target for BC. Moreover, MBP1 plays a critical role in inhibiting the growth and progression of BC cell lines.

Effectiveness of Noninvasive Positive Pressure Ventilation Combined with Enteral Nutrition in the Treatment of Patients with Combined Respiratory Failure after Lung Cancer Surgery and Its Effect on Blood Gas Indexes.

Purpose To investigate the effect of noninvasive positive pressure ventilation (NIPPV) combined with enteral nutrition support in the treatment of patients with combined respiratory failure after lung cancer surgery and its effect on blood gas indexes. Methods A total of 82 patients with combined respiratory failure after lung cancer surgery who were treated in our hospital from March 2016∼September 2021 were selected as the research subjects, and according to the random number table method, they were equally divided into the parenteral nutrition group (n = 41) with NIPPV + parenteral nutrition support treatment and the enteral nutrition group (n = 41) with NIPPV + enteral nutrition support treatment. The curative effects of two groups after treatment were compared, and the pulmonary function indexes (maximum expiratory pressure (PEmax), maximum midexpiratory flow rate (MMF), and maximum ventilation volume (MVV)), blood gas indexes (blood oxygen partial pressure (PaO2) and partial pressure of carbon dioxide (PaCO2)), oxygen metabolism indicators [mixed venous oxygen tension (PvO2) and central venous oxygen saturation (ScvO2)], nutritional status indicators (hemoglobin (HGB), serum albumin (ALB), and total protein (TP)), and nutritional score before and after treatment in two groups were detected, and the 6-month follow-up of the two groups was recorded. Results After treatment, the total effective rate of the enteral nutrition group 95.12% (39/41) was higher than that of the parenteral nutrition group 80.49% (33/41) (P < 0.05). At 3, 12, 24, and 48 hours after the operation, the levels of PEmax, MMF, and MVV in two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group at the same time point (P < 0.05). At 3, 12, 24, and 48 hours after the operation, the PaO2 levels in two groups were higher than those before treatment, and the PaCO2 levels were lower than those before treatment. The PaO2 levels in the enteral nutrition group were higher than those in the parenteral nutrition group at the same time point, and the PaCO2 levels were lower than those in the parenteral nutrition group at the same time point (P < 0.05). At 3, 12, 24, and 48 hours after the operation, the levels of PvO2 and ScvO2 in two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group at the same time point (P < 0.05). After treatment, the levels of HGB, ALB, and TP in two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group (P < 0.05). After treatment, the nutritional scores of the two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group (P < 0.05). At 6-month postoperative follow-up, the incidence of death in the enteral nutrition group 2.44% (1/41) was lower than that of the parenteral nutrition group 17.07% (7/41) (P < 0.05). Conclusions The efficacy of NIPPV combined with enteral nutrition support in treating patients with combined respiratory failure after lung cancer surgery is remarkable. It can improve patients' pulmonary function and blood gas index, correct patients' hypoxia status and the patients' nutritional level was significantly improved, which helped to reduce the mortality rate and improve the prognosis.

Chronic Intermittent Hypoxia Increases Cell Proliferation in Hepatocellular Carcinoma.

Obstructive sleep apnea (OSA) syndrome is characterized by chronic intermittent hypoxia and is associated with an increased risk of all-cause mortality, including cancer mortality. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, characterized by increasing incidence and high mortality. However, the link between HCC and OSA-related chronic intermittent hypoxia remains unclear. Herein, we used a diethylnitrosamine (DEN)-induced HCC model to investigate whether OSA-related chronic intermittent hypoxia has an impact on HCC progression. To elucidate the associated mechanisms, we first evaluated the hypoxia status in the DEN-induced HCC model. Next, to simulate OSA-related intermittent hypoxia, we exposed cirrhotic rats with HCC to intermittent hypoxia during six weeks. We performed histopathological, immunohistochemical, RT-qPCR, and RNA-seq analysis. Chronic DEN injections strongly promoted cell proliferation, fibrosis, disorganized vasculature, and hypoxia in liver tissue, which mimics the usual events observed during human HCC development. Intermittent hypoxia further increased cell proliferation in DEN-induced HCC, which may contribute to an increased risk of HCC progression. In conclusion, our observations suggest that chronic intermittent hypoxia may be a factor worsening the prognosis of HCC.

Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches.

Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.

Comparison of multiple gene expression platforms for measuring a bladder cancer hypoxia signature.

Tumour hypoxia status provides prognostic information and predicts response to hypoxia‑modifying treatments. A previous study by our group derived a 24‑gene signature to assess hypoxia in bladder cancer. The objectives of the present study were to compare platforms for generating signature scores, identify cut‑off values for prospective studies, assess intra‑tumour heterogeneity and confirm hypoxia relevance. Briefly, RNA was extracted from prospectively collected diagnostic biopsies of muscle invasive bladder cancer (51patients), and gene expression was measured using customised Taqman Low Density Array (TLDA) cards, NanoString and Clariom S arrays. Cross‑platform transferability of the gene signature was assessed using regression and concordance analysis. The cut‑off values were the cohort median expression values. Intra‑ and inter‑tumour variability were determined in a retrospective patient cohort (n=51) with multiple blocks(2‑18) from the same tumour. To demonstrate relevance, bladder cancer cell lines were exposed to hypoxia (0.1% oxygen, 24h), and extracted RNA was run on custom TLDA cards. Hypoxia scores(HS) values showed good agreement between platforms: ClariomS vs. TLDA (r=0.72, P<0.0001; concordance73%); ClariomS vs. NanoString (r=0.84, P<0.0001; 78%); TLDA vs. NanoString (r=0.80, P<0.0001;78%). Cut‑off values were 0.047 (TLDA), 7.328 (NanoString) and 6.667 (ClariomS). Intra‑tumour heterogeneity in gene expression and HS (coefficient of variation3.9%) was less than inter‑tumour (7.9%) variability. HS values were higher in bladder cancer cells exposed to hypoxia compared with normoxia (P<0.02). In conclusion, the present study revealed that application of the 24‑gene bladder cancer hypoxia signature was platform agnostic, cut‑off values determined prospectively can be used in a clinical trial, intra‑tumour heterogeneity was low and the signature was sensitive to changes in oxygen levels invitro.