A review of obstructive sleep apnea and lung cancer: epidemiology, pathogenesis, and therapeutic options.

Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleep-breathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology.

Role of oxygen reserve index monitoring in patients undergoing robot-assisted radical prostatectomy: a retrospective study.

PURPOSE: Robot-assisted radical prostatectomy (RARP) is a common surgical procedure for the treatment of prostate cancer. Although beneficial, it can lead to intraoperative hypoxia due to high-pressure pneumoperitoneum and Trendelenburg position. This study explored the use of oxygen reserve index (ORi) to monitor and predict hypoxia during RARP. METHODS: A retrospective analysis was conducted on 329 patients who underwent RARP at the Seoul National University Bundang Hospital between July 2021 and March 2023. Various pre- and intraoperative variables were collected, including ORi values. The relationship between ORi values and hypoxia occurrence was assessed using receiver operating characteristic curves and logistic regression analysis. RESULTS: Intraoperative hypoxia occurred in 18.8% of the patients. The receiver operating characteristic curve showed a satisfactory area under the curve of 0.762, with the ideal ORi cut-off value for predicting hypoxia set at 0.16. Sensitivity and specificity were 64.5% and 75.7%, respectively. An ORi value of < 0.16 and a higher body mass index were identified as independent risk factors of hypoxia during RARP. CONCLUSIONS: ORi monitoring provides a non-invasive approach to predict intraoperative hypoxia during RARP, enabling early management. Additionally, the significant relationship between a higher body mass index and hypoxia underscores the importance of individualized patient assessment.

The role and mechanism of PDZ binding kinase in hypobaric and hypoxic acute lung injury.

Background: Acute lung injury (ALI) caused by hypobaric hypoxia (HH) is frequently observed in high-altitude areas, and it is one of the leading causes of death in high-altitude-related diseases due to its rapid onset and progression. However, the pathogenesis of HH-related ALI (HHALI) remains unclear, and effective treatment approaches are currently lacking. Methods: A new mouse model of HHALI developed by our laboratory was used as the study subject (Chinese patent No. ZL 2021 1 1517241 X). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the messenger RNA (mRNA) expression levels of PDZ-binding kinase (PBK), sirtuin 1 (SIRT1), and PTEN-induced kinase 1 (PINK1) in mouse lung tissue. Hematoxylin and eosin staining was used to observe the main types of damage and damaged cells in lung tissue, and the lung injury score was used for quantification. The wet-dry (W/D) ratio was used to measure lung water content. Enzyme-linked immunosorbent assay was used to detect changes in inflammatory factors and oxidative stress markers in the lungs. Western blotting verified the expression of various mitochondrial autophagy-related proteins. The 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) method was used determined the health status of mitochondria based on changes in mitochondrial membrane potential. Transmission electron microscopy was used to directly observe the morphology of mitochondria. Multicolor immunofluorescence was used to observe the levels of mitochondrial autophagy markers. Other signaling pathways and molecular mechanisms that may play a role in epithelial cells were analyzed via through RNA sequencing. Results: Low pressure and hypoxia caused pathological changes in mouse lung tissue, mainly ALI, leading to increased levels of inflammatory factors and intensified oxidative stress response in the lungs. Overexpression of PBK was found to alleviate HHALI, and activation of the p53 protein was shown to abrogate this therapeutic effect, while activation of SIRT1 protein reactivated this therapeutic effect. The therapeutic effect of PBK on HHALI is achieved via the activation of mitochondrial autophagy. Finally, RNA sequencing demonstrated that besides mitochondrial autophagy, PBK also exerts other functions in HHALI. Conclusions: Overexpression of PBK inhibits the expression of p53 and activates SIRT1-PINK1 axis mediated mitochondrial autophagy to alleviate HHALI.

Folic Acid Functionalized AQ4N/Gd@PDA Nanoplatform with Real-Time Monitoring of Hypoxia Relief and Enhanced Synergistic Chemo/Photothermal Therapy in Glioma.

Purpose: Hypoxia is often associated with glioma chemoresistance, and alleviating hypoxia is also crucial for improving treatment efficacy. However, although there are already some methods that can improve efficacy by alleviating hypoxia, real-time monitoring that can truly achieve hypoxia relief and efficacy feedback still needs to be explored. Methods: AQ4N/Gd@PDA-FA nanoparticles (AGPF NPs) were synthesized using a one-pot method and were characterized. The effects of AGPF NPs on cell viability, cellular uptake, and apoptosis were investigated using the U87 cell line. Moreover, the effectiveness of AGPF NPs in alleviating hypoxia was explored in tumor-bearing mice through photoacoustic imaging. In addition, the diagnosis and treatment effect of AGPF NPs were evaluated by magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) on orthotopic glioma mice respectively. Results: In vitro experiments showed that AGPF NPs had good dispersion, stability, and controlled release. AGPF NPs were internalized by cells through endocytosis, and could significantly reduce the survival rate of U87 cells and increase apoptosis under irradiation. In addition, we monitored blood oxygen saturation at the tumor site in real-time through photoacoustic imaging (PAI), and the results showed that synergistic mild-photothermal therapy/chemotherapy effectively alleviated tumor hypoxia. Finally, in vivo anti-tumor experiments have shown that synergistic therapy can effectively alleviate hypoxia and inhibit the growth of orthotopic gliomas. Conclusion: This work not only provides an effective means for real-time monitoring of the dynamic feedback between tumor hypoxia relief and therapeutic efficacy, but also offers a potential approach for the clinical treatment of gliomas.

The Application of Drugs and Nano-Therapies Targeting Immune Cells in Hypoxic Inflammation.

Immune cells are pivotal in the dynamic interplay between hypoxia and inflammation. During hypoxic conditions, HIF-1α, a crucial transcription factor, facilitates the adaptation of immune cells to the hypoxic micro-environment. This adaptation includes regulating immune cell metabolism, significantly impacting inflammation development. Strategies for anti-inflammatory and hypoxic relief have been proposed, aiming to disrupt the hypoxia-inflammation nexus. Research extensively focuses on anti-inflammatory agents and materials that target immune cells. These primarily mitigate hypoxic inflammation by encouraging M2-macrophage polarization, restraining neutrophil proliferation and infiltration, and maintaining Treg/TH17 balance. Additionally, oxygen-releasing nano-materials play a significant role. By alleviating hypoxia and clearing reactive oxygen species (ROS), these nano-materials indirectly influence immune cell functions. This paper delves into the response of immune cells under hypoxic conditions and the resultant effects on inflammation. It provides a comprehensive overview of various therapies targeting specific immune cells for anti-inflammatory purposes and explores nano-materials that either carry or generate oxygen to alleviate anoxic micro-environments.

Plant Quiescence Strategy and Seed Dormancy under Hypoxia.

Plant quiescence and seed dormancy can be triggered by reduced oxygen availability. Under water, oxygen depletion caused by flooding can culminate in a quiescent state, which is a plant strategy for energy preservation and survival. In adult plants, a quiescent state can be activated by sugar starvation, culminating in metabolic depression. In seeds, secondary dormancy can be activated by reduced oxygen availability, which creates an unfavourable state for germination. The physical dormancy of some seeds and buds includes barriers to external conditions, which indirectly results in hypoxia. The molecular processes that support seed dormancy and plant survival through quiescence under hypoxia include the N-degron pathway, which enables the modulation of ethylene responsive factors of group VII and downstream targets. This oxygen- and nitric oxide-dependent mechanism interacts with phytohormone-related pathways to control growth.

Neural processing without O2 and glucose delivery: from the pond to the clinic.

Neuronal activity requires a large amount of ATP, leading to a rapid collapse of brain function when aerobic respiration fails. Here, we summarize how rhythmic motor circuits in the brainstem of adult frogs, which normally have high metabolic demands, transform to produce proper output during severe hypoxia associated with emergence from hibernation. We suggest that general principles underlying plasticity in brain bioenergetics may be uncovered by studying non-mammalian models that face extreme environments, yielding new insights to combat neurological disorders involving dysfunctional energy metabolism.

CAR-T cell expansion platforms yield distinct T cell differentiation states.

With investigators looking to expand engineered T cell therapies such as CAR-T to new tumor targets and patient populations, a variety of cell manufacturing platforms have been developed to scale manufacturing capacity using closed and/or automated systems. Such platforms are particularly useful for solid tumor targets, which typically require higher CAR-T cell doses. Although T cell phenotype and function are key attributes that often correlate with therapeutic efficacy, how manufacturing platforms influence the final CAR-T cell product is currently unknown. We compared 4 commonly used T cell manufacturing platforms (CliniMACS Prodigy, Xuri W25 rocking platform, G-Rex gas-permeable bioreactor, static bag culture) using identical media, stimulation, culture length, and donor starting material. Selected CD4+CD8+ cells were transduced with lentiviral vector incorporating a CAR targeting FGFR4, a promising target for pediatric sarcoma. We observed significant differences in overall expansion over the 14-day culture; bag cultures had the highest capacity for expansion while the Prodigy had the lowest (481-fold versus 84-fold, respectively). Strikingly, we also observed considerable differences in the phenotype of the final product, with the Prodigy significantly enriched for CCR7+CD45RA+ naïve/stem central memory (Tn/scm)-like cells at 46% compared to bag and G-Rex with 16% and 13%, respectively. Gene expression analysis also showed that Prodigy CAR-Ts are more naïve, less cytotoxic and less exhausted than bag, G-Rex, and Xuri CAR-Ts, and pointed to differences in cell metabolism that were confirmed via metabolic assays. We hypothesized that dissolved oxygen level, which decreased substantially during the final 3 days of the Prodigy culture, may contribute to the observed differences in T cell phenotype. By culturing bag and G-Rex cultures in 1% O2 from day 5 onward, we could generate >60% Tn/scm-like cells, with longer time in hypoxia correlating with a higher percentage of Tn/scm-like cells. Intriguingly, our results suggest that oxygenation is responsible, at least in part, for observed differences in T cell phenotype among bioreactors and suggest hypoxic culture as a potential strategy prevent T cell differentiation during expansion. Ultimately, our study demonstrates that selection of bioreactor system may have profound effects not only on the capacity for expansion, but also on the differentiation state of the resulting CAR-T cells.

Existing wetland conservation programs miss nutrient reduction targets.

Restoring wetlands will reduce nitrogen contamination from excess fertilization but estimates of the efficacy of the strategy vary widely. The intervention is often described as effective for reducing nitrogen export from watersheds to mediate bottom-level hypoxia threatening marine ecosystems. Other research points to the necessity of applying a suite of interventions, including wetland restoration to mitigate meaningful quantities of nitrogen export. Here, we use process-based physical modeling to evaluate the effects of two hypothetical, but plausible large-scale wetland restoration programs intended to reduce nutrient export to the Gulf of Mexico. We show that full adoption of the two programs currently in place can meet as little as 10% to as much as 60% of nutrient reduction targets to reduce the Gulf of Mexico dead zone. These reductions are lower than prior estimates for three reasons. First, net storage of leachate in the subsurface precludes interception and thereby dampens the percent decline in nitrogen export caused by the policy. Unlike previous studies, we first constrained riverine fluxes to match observed fluxes throughout the basin. Second, the locations of many restorable lands are geographically disconnected from heavily fertilized croplands, limiting interception of runoff. Third, daily resolution of the model simulations captured the seasonal and stormflow dynamics that inhibit wetland nutrient removal because peak wetland effectiveness does not coincide with the timing of nutrient inputs. To improve the health of the Gulf of Mexico efforts to eliminate excess nutrient, loading should be implemented beyond the field-margin wetland strategies investigated here.

Early heart and skeletal muscle mitochondrial response to a moderate hypobaric hypoxia environment.

In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post-MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High-Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post-exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin-related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro-fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. KEY POINTS: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia. Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart. Skeletal muscle shows an early mitochondrial pro-fission response following exposure to moderate hypobaric hypoxia.

HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.

Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

Hypoxia-associated markers in the prognosis of oral canine melanoma.

Canine oral malignant melanoma (COMM) is the most common neoplasm in the oral cavity characterized by local invasiveness and high metastatic potential. Hypoxia represents a crucial feature of the solid tumor microenvironment promoting cancer progression and drug resistance. Hypoxia-inducible factor-1α (HIF-1α) and its downstream effectors, vascular endothelial growth factor A (VEGF-A), glucose transporter isoform 1 (GLUT1), C-X-C chemokine receptor type 4 (CXCR4), and carbonic anhydrase IX (CAIX), are the main regulators of the adaptive response to low oxygen availability. The prognostic value of these markers was evaluated in 36 COMMs using immunohistochemistry. In addition, the effects of cobalt chloride-mediated hypoxia were evaluated in 1 primary COMM cell line. HIF-1α expression was observed in the nucleus, and this localization correlated with the presence or enhanced expression of HIF-1α-regulated genes at the protein level. Multivariate analysis revealed that in dogs given chondroitin sulfate proteoglycan-4 (CSPG4) DNA vaccine, COMMs expressing HIF-1α, VEGF-A, and CXCR4 were associated with shorter disease-free intervals (DFI) compared with tumors that were negative for these markers (P = .03), suggesting hypoxia can influence immunotherapy response. Western blotting showed that, under chemically induced hypoxia, COMM cells accumulate HIF-1α and smaller amounts of CAIX. HIF-1α induction and stabilization triggered by hypoxia was corroborated by immunofluorescence, showing its nuclear translocation. These findings reinforce the role of an hypoxic microenvironment in tumor progression and patient outcome in COMM, as previously established in several human and canine cancers. In addition, hypoxic markers may represent promising prognostic markers, highlighting opportunities for their use in therapeutic strategies for COMMs.

Effects of acute exposure to hypoxia on sleep structure in healthy adults: A systematic review.

The sleep quality of lowlanders in hypoxic environments has become increasingly important with an increase in highland and alpine activities. This study aimed to identify the effects of acute exposure to hypoxia on the sleep structure of lowlanders and to analyze the changes in sleep indicators at varying levels of hypoxia. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-three studies were screened and included in the quantitative analysis. The results showed that acute exposure to hypoxia reduced sleep quality in lowlanders. Post-sleep arousal events and the percentage of N1 were significantly increased, whereas total sleep time, sleep efficiency, and the percentage of N3 and rapid eye movement sleep were significantly decreased in hypoxic environments. Acute exposure to hypoxia had the greatest negative impact on wakefulness after sleep onset (WASO). In addition, a larger decrease in sleep efficiency and higher increase in the percentages of N1 and WASO were observed when lowlanders were exposed to higher levels of hypoxia. This study clarifies the quantitative effects of acute hypoxic exposure on sleep in lowlanders based on original studies and explains the sleep disorders faced by lowlanders in hypoxic environments.

Maternal levels of care during pregnancy influence labor and delivery outcomes - present practices and future priorities.

Neonatal encephalopathy (NE) is a diagnosis that is usually unexpected. Though there are many risk factors for the condition and multiple theories as to its genesis, the majority of cases cannot be predicted prior to the occurrence of the clinical syndrome. Indeed, it is common for a pregnant person to have multiple risk factors and a completely healthy child. Conversely, people with seemingly no risk factors may go on to have a profoundly affected child. In this synopsis we review risk factors, potential mechanisms for encephalopathy, the complicated issue of choosing which morbidity to take on and how the maternal level of care may influence outcomes. The reader should be able to better understand the limitations of current testing and the profound levels of maternal intervention that have been undertaken to prevent or mitigate the rare, but devastating occurrence of NE. Further, we suggest candidate future approaches to prevent the occurrence, and decrease the severity of NE. Any future improvements in the NE syndrome cannot be achieved via obstetric intervention and management alone or conversely, by improvements in treatments offered post-birth. Multidisciplinary approaches that encompass prepregnancy health, pregnancy care, intrapartum management and postpartum care will be necessary.

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.

Rel Family Transcription Factor NFAT5 Upregulates COX2 via HIF-1α Activity in Ishikawa and HEC1a Cells.

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.

Effect of Dimethyloxalylglycine on Stem Cells Osteogenic Differentiation and Bone Tissue Regeneration-A Systematic Review.

Dimethyloxalylglycine (DMOG) has been found to stimulate osteogenesis and angiogenesis of stem cells, promoting neo-angiogenesis in bone tissue regeneration. In this review, we conducted a comprehensive search of the literature to investigate the effects of DMOG on osteogenesis and bone regeneration. We screened the studies based on specific inclusion criteria and extracted relevant information from both in vitro and in vivo experiments. The risk of bias in animal studies was evaluated using the SYRCLE tool. Out of the 174 studies retrieved, 34 studies met the inclusion criteria (34 studies were analyzed in vitro and 20 studies were analyzed in vivo). The findings of the included studies revealed that DMOG stimulated stem cells' differentiation toward osteogenic, angiogenic, and chondrogenic lineages, leading to vascularized bone and cartilage regeneration. Addtionally, DMOG demonstrated therapeutic effects on bone loss caused by bone-related diseases. However, the culture environment in vitro is notably distinct from that in vivo, and the animal models used in vivo experiments differ significantly from humans. In summary, DMOG has the ability to enhance the osteogenic and angiogenic differentiation potential of stem cells, thereby improving bone regeneration in cases of bone defects. This highlights DMOG as a potential focus for research in the field of bone tissue regeneration engineering.

Estrogen α and ß Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model.

Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors (ERs) which play an important role in the development and progression of many cancers, and whose expression levels are often correlated with patient survival. This study utilized two research models: an in vitro model employing the U87 cell line and a second model involving tumors resected from patients (including tumor core, enhancing tumor region, and peritumoral area). ER expression was assessed at both gene and protein levels, with the results validated using confocal microscopy and immunohistochemistry. Under hypoxic conditions, the U87 line displayed a decrease in ERß mRNA expression and an increase in ERα mRNA expression. In patient samples, ERß mRNA expression was lower in the tumor core compared to the enhancing tumor region (only in males when the study group was divided by sex). In addition, ERß protein expression was lower in the tumor core than in the peritumoral area (only in women when the study group was divided by sex). Immunohistochemical analysis indicated the highest ERß protein expression in the enhancing tumor area, followed by the peritumoral area, and the lowest in the tumor core. The findings suggest that ER expression may significantly influence the development of GBM, exhibiting variability under the influence of conditions present in different tumor areas.

Pathway-based stratification of gliomas uncovers four subtypes with different TME characteristics and prognosis.

Increasing evidences have found that the interactions between hypoxia, immune response and metabolism status in tumour microenvironment (TME) have clinical importance of predicting clinical outcomes and therapeutic efficacy. This study aimed to develop a reliable molecular stratification based on these key components of TME. The TCGA data set (training cohort) and two independent cohorts from CGGA database (validation cohort) were enrolled in this study. First, the enrichment score of 277 TME-related signalling pathways was calculated by gene set variation analysis (GSVA). Then, consensus clustering identified four stable and reproducible subtypes (AFM, CSS, HIS and GLU) based on TME-related signalling pathways, which were characterized by differences in hypoxia and immune responses, metabolism status, somatic alterations and clinical outcomes. Among the four subtypes, HIS subtype had features of immunosuppression, oxygen deprivation and active energy metabolism, resulting in a worst prognosis. Thus, for better clinical application of this acquired stratification, we constructed a risk signature by using the LASSO regression model to identify patients in HIS subtype accurately. We found that the risk signature could accurately screen out the patients in HIS subtype and had important reference value for individualized treatment of glioma patients. In brief, the definition of the TME-related subtypes was a valuable tool for risk stratification in gliomas. It might serve as a reliable prognostic classifier and provide rational design of individualized treatment, and follow-up scheduling for patients with gliomas.

Long-term developments in seasonal hypoxia and response to climate change: A three-decade modeling study in the Ariake Sea, Japan.

Hypoxia in the Ariake Sea, Japan, is steadily increasing in both duration and spatial coverage. Hypoxia, defined as dissolved oxygen (DO) below 3 mg/L, is strongly associated with the amplified frequency of extreme rainfall events driven by climate change, which poses a mounting threat to marine ecosystems on a global scale. In this study, we employed a general three-dimensional (3-D) hydrodynamic coastal model and a phytoplankton-based ecosystem model to identify the potential cause of seasonal hypoxic events over three decades. The results indicated a substantial decrease in bottom DO levels from 1992 to 2021, with the rate of increase in hypoxic area being 8 km2/yr (95 % CI: -0.38, 16.2) and the anoxic area increasing from almost non-existent to 100 km2. Notably, among various environmental drivers, increased river discharge was identified as a pivotal factor in the occurrence of hypoxia. Large-scale river discharge events can potentially increase water stratification, leading to the formation of hypoxia. River discharge volume and the duration of bottom hypoxia in the Ariake Sea were correlated. The duration of hypoxia was strongly associated with river discharge magnitude, with correlation coefficients ranging from 0.56 to 0.82 across six observational stations. Furthermore, analysis of varied simulated environmental factors over multiple years revealed diverse responses to climate change, indicating that the Ariake Sea is prone to experiencing a decline in its physical and water quality conditions.