Levels Of Hypoxia Research Articles

WITHDRAWN: Detection and impact of hypoxic regions in multicellular tumor spheroid cultures formed by head and neck squamous cell carcinoma cells lines

In solid tumors like head and neck cancer (HNC), chronic and acute hypoxia have serious adverse clinical consequences including poorer overall patient prognosis, enhanced metastasis, increased genomic instability, and resistance to radiation-, chemo-, or immuno-therapies. However, cells in the two-dimensional monolayer cultures typically used for cancer drug discovery experience 20%-21% O2 levels (normoxic) which are 4-fold higher than O2 levels in normal tissues and ≥10-fold higher than in the hypoxic regions of solid tumors. The oxygen electrodes, exogenous bio-reductive markers, and increased expression of endogenous hypoxia-regulated proteins like HIF-1α generally used to mark hypoxic regions in solid tumors are impractical in large sample numbers and longitudinal studies. We used a novel homogeneous live-cell permeant HypoxiTRAK™ (HPTK) molecular probe compatible with high content imaging detection, analysis, and throughput to identify and quantify hypoxia levels in live HNC multicellular tumor spheroid (MCTS) cultures over time. Accumulation of fluorescence HPTK metabolite in live normoxic HNC MCTS cultures correlated with hypoxia detection by both pimonidazole and HIF-1α staining. In HNC MCTSs, hypoxic cytotoxicity ratios for the hypoxia activated prodrugs (HAP) evofosfamide and tirapazamine were much smaller than have been reported for uniformly hypoxic 2D monolayers in gas chambers, and many viable cells remained after HAP exposure. Cells in solid tumors and MCTSs experience three distinct O2 microenvironments dictated by their distances from blood vessels or MCTS surfaces, respectively; oxic, hypoxic, or intermediate levels of hypoxia. These studies support the application of more physiologically relevant in vitro 3D models that recapitulate the heterogeneous microenvironments of solid tumors for preclinical cancer drug discovery.

Aerobic Exercise Training Under Normobaric Hypoxic Conditions to Improve Glucose and Lipid Metabolism in Overweight and Obese Individuals: A Systematic Review and Meta-Analysis.

Guo, Hai, Linjie Cheng, Dilihumaier Duolikun, and Qiaoling Yao. Aerobic exercise training under normobaric hypoxic conditions to improve glucose and lipid metabolism in overweight and obese individuals: a systematic review and meta-analysis. High Alt Med Biol. 24:312-320, 2023. Background: Obesity is a critical public health issue around the world, reaching epidemic proportions in some countries. However, only a few studies have examined the effects of hypoxic training on metabolic parameters in an obese population. This systematic review and meta-analysis aimed to determine the effects of aerobic exercise training under normobaric hypoxic conditions versus normoxic training in improving glucose and lipid metabolism in obese individuals. Methods: A systematic search of PubMed, EMBASE, Web of Science, and Wan Fang databases (up to August 2021) was performed to identify randomized controlled trials (RCTs) of overweight or obese human subjects eligible for inclusion. Main study endpoints were changes in body mass index (BMI), waist/hip (W/H) ratio, leptin, blood glucose and insulin levels, as well as blood lipids between hypoxic and normoxic conditioning. Results: Fourteen RCTs with a total of 413 subjects qualified for inclusion. Pooled analyses revealed that BMI (d = 0.38), W/H ratio (d = 0), blood glucose (d = 0.01), and triglyceride (d = -2.27) were not significantly different between aerobic exercise training under hypoxic and normoxic conditions. However, significant differences were found in heart rate at rest (d = -4.50) between aerobic exercise training under hypoxic versus normoxic conditions. Conclusions: In conclusion, no significant benefits were noted in aerobic exercise training under hypoxic conditions over normoxic conditions in overweight or obese individuals. However, the maximum training heart rate mm was significantly higher under hypoxic conditions than under normoxic conditions. Future studies with larger samples controlling for exercise-related parameters, and addressing the potential modifying effects of level of hypoxia, sex, or age on the role of hypoxic exercise training are warranted. PROSPERO registration number: CRD42020221680.

Hypoxia-induced PLOD2 promotes clear cell renal cell carcinoma progression via modulating EGFR-dependent AKT pathway activation

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that is both common and aggressive, with a rising incidence in recent decades. Hypoxia is a key factor that plays a vital role in the tumorigenesis and metastasis of malignancy. However, the precise mechanisms of hypoxia driving ccRCC progression were not totally uncovered. Our study found that hypoxia level was elevated in ccRCC and might be an independent risk factor of prognosis in ccRCC patients. We identified a key protein PLOD2 was induced under hypoxic conditions and strongly associated with poor prognosis in ccRCC patients. When PLOD2 was depleted, the proliferation and migration of ccRCC cells were reduced in vitro and in vivo, while overexpression of PLOD2 had the opposite effect. Mechanically, the study further revealed that PLOD2 was transcriptionally activated by HIF1A, which binds to a specific promoter region of the PLOD2 gene. PLOD2 was also shown to interact with EGFR, leading to the phosphorylation of the receptor. Furthermore, PLOD2 was responsible for binding to the extracellular domain of EGFR, which ultimately activated the AKT signaling pathway, thus promoting the malignant progression of ccRCC. Treatment with the PLOD2 inhibitor Minoxidil significantly suppressed ccRCC progression by inactivating the EGFR/AKT signaling axis. In summary, the findings of this study shed light on the molecular mechanisms behind PLOD2 expression in ccRCC and suggest that it may serve as a potential predictor and therapeutic target for the clinical prognosis and treatment of ccRCC.

Identification of hypoxia-related gene signatures based on multi-omics analysis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer and one of the malignancies with the highest incidence rate and mortality worldwide. Hypoxia is a typical feature of tumour microenvironment (TME), which affects the progression of LUAD from multiple molecular levels. However, the underlying molecular mechanisms behind LUAD hypoxia are not fully understood. In this study, we estimated the level of hypoxia by calculating a score based on 15 hypoxia genes. The hypoxia scores were relatively high in LUAD patients with poor prognosis and were bound up with tumour node metastasis (TNM) stage, tumour size, lymph node, age and gender. By comparison of high hypoxia score group and low hypoxia score group, 1820 differentially expressed genes were identified, among which up-regulated genes were mainly about cell division and proliferation while down-regulated genes were primarily involved in cilium-related biological processes. Besides, LUAD patients with high hypoxia scores had higher frequencies of gene mutations, among which TP53, TTN and MUC16 had the highest mutation rates. As for DNA methylation, 1015 differentially methylated probes-related genes were found and may play potential roles in tumour-related neurobiological processes and cell signal transduction. Finally, a prognostic model with 25 multi-omics features was constructed and showed good predictive performance. The area under curve (AUC) values of 1-, 3- and 5-year survival reached 0.863, 0.826 and 0.846, respectively. Above all, our findings are helpful in understanding the impact and molecular mechanisms of hypoxia in LUAD.

Amorphous 2D Mn-doped CoMo-layered double hydroxide nanosheets for magnetic resonance imaging-guided sonodynamic cancer therapy

Sonodynamic therapy (SDT) has attracted increasing attention owing to its superior tissue penetration compared with other therapies. However, the development of multifunctional sonosensitizers with imaging capability and high production efficiency of reactive oxygen species (ROS) is still a challenge for current sonodynamic cancer therapy. Herein, we report the design and preparation of amorphous 2D Mn-doped CoMo-layered double hydroxide (a-Mn-CoMo-LDH) nanosheets (NSs) through acid etching-induced crystalline-to-amorphous phase transformation as a highly active nano-agent for magnetic resonance imaging (MRI)-guided SDT. The a-Mn-CoMo-LDH NSs exhibit superior ROS production capacity compared with amorphous CoMo-LDH NSs (∼1.3 times) and crystalline Mn-CoMo-LDH NSs (∼3.9 times) under ultrasound (US) irradiation, which is ∼ 9.9 times of the previously reported TiO2 sonosensitizer. The doped Mn4+ in the a-Mn-CoMo-LDH NSs can not only decompose H2O2 into O2 to alleviate the hypoxia level in tumor microenvironment (TME), but also consume glutathione (GSH) to reduce its clearance of ROS, promoting the SDT performance synergistically. Importantly, the GSH consumption can partially reduce the Mn4+ to Mn2+ within the tumors, which can serve as an agent for T1-weighted MRI, thus endowing the a-Mn-CoMo-LDH NSs with excellent MRI capability. Therefore, the as-prepared a-Mn-CoMo-LDH NSs with polyethylene glycol modification can be used as an efficient nano-agent for MRI-guided SDT, which can effectively achieve apoptosis of cancer cells in vitro and eradication of tumors in vivo under US irradiation.

Sports despite masks: no negative effects of FFP2 face masks on cardiopulmonary exercise capacity in children

Face masks were recognized as one of the most effective ways to prevent the spread of the COVID-19 virus in adults. These benefits were extended to children and adolescents. However, the fear of negative consequences from wearing a face mask during physical exercise led to cancellations of physical education lessons. This further decreased the amount of physical activity available to children and adolescents during the pandemic. However, there is little published data on the potential adverse effects of wearing the most effective and partially mandatory FFP2/N95 face masks during PE or physical activity (PA) in this age. Even though the pandemic has been declared as passed by the WHO, the rise of a new pandemic and thus the use of face masks for limiting its spread is inevitable, so we need to be better prepared for alternative options to lockdown and limitation of PA in such a scenario. Twenty healthy children aged 8–10 years performed two identical cardiopulmonary exercise tests as an incremental step test on a treadmill within an interval of 2 weeks, one time without wearing a protective mask and one time wearing an FFP2 mask. The cardiopulmonary exercise parameter and especially the end-expiratory gas exchange for oxygen and carbon dioxide (petO2 and petCO2) were documented for each step, at rest and 1 min after reaching physical exhaustion. Twelve boys (mean age 8.5 ± 1.4 years) and 8 girls (mean age 8.8 ± 1.4 years) showed no adverse events until maximal exertion. The mean parameters measured at peak exercise did not differ significantly between both examinations (mean peak VO2 = 42.7 ± 9.5 vs 47.8 ± 12.9 ml/min/kg, p = 0.097, mean O2pulse 7.84 ± 1.9 ml/min vs. 6.89 ± 1.8, p = 0.064, mean VE/VCO2slope 33.4 ± 5.9 vs. 34.0 ± 5.3, p = 0.689). The only significant difference was the respiratory exchange rate (RER, 1.01 ± 0.08 vs 0.95 ± 0.08, p = 0.004). The measured respiratory gases (end-tidal O2 and CO2) decreased and respectively increased significantly in almost every step when wearing an FFP2 mask. However, these levels were well below hypercapnia and above hypoxia.Conclusion: In this study, no significant differences in the cardiorespiratory function at peak exercise could be discerned when wearing an FFP2/N95 face mask. While the end-tidal values for CO2 increased significantly and the end-tidal values for O2 decreased significantly, these values did never reach levels of hypercapnia or hypoxia. Furthermore, the children terminated the exercise at a lower RER and heart rate (HR) suggesting a subconscious awareness of the higher strain. Since the detrimental effects of limiting sports during the pandemic are well documented, stopping PE lessons altogether because of the minor physiological effects of wearing these masks instead of simply stopping pushing children to perform at their best seems premature and should be reconsidered in the future.What is Known:• Wearing a face mask has an influence on psychological, social, and physiological functions in adults.• Because of the observed effects of wearing face masks in adults, physical activity in children was limited during the pandemic.What is New:• Wearing an FFP2/N95 mask during physical activity did not lead to hypercapnia or hypoxia in children in this study.• Even though end-tidal CO2 values were significantly higher and end-tidal O2 values significantly lower when wearing an FFP2/N95 face mask, no pathological values were reached.

A large-pore mesoporous Au@Pt@Rh trimetallic nanostructure with hyperthermia-enhanced enzyme-mimic activities for immunomodulation-improved tumor catalytic therapy

Catalytic therapy based on the nanozymes is an emerging strategy for tumor therapy. However, its therapeutic outcomes are considerably limited by many characters in tumor microenvironment (TME), such as hypoxia, immunosuppression, and insufficient endogenous hydrogen peroxide (H2O2) level. Herein, a new layer-by-layer trimetallic nanozyme (Au@Pt@Rh) with large mesopores is developed for immunoregulation enhanced tumor nanocatalytic therapy. Such outside-in porous Au@Pt@Rh nanozyme exhibits both intrinsic peroxidase (POD)- and catalase (CAT)-like activities under acidic TME, which can catalyze H2O2 into hydroxyl radicals (·OH) and oxygen (O2), respectively. Meanwhile, Au@Pt@Rh-enabled photothermal hyperthermia improves the POD- and CAT-mimic activities. With the assistance of homologous tumor cell membrane (CM), the TGF-β inhibitor (LY2157299, LY) is successfully loaded and retained in the large mesopores of Au@Pt@Rh-CM. LY-Au@Pt@Rh-CM nanocomposites can improve tumor immunosuppressive microenvironment through polarizing the macrophages from M2 to M1, and thus induce the regeneration of H2O2 to promote the catalytic activities. Both in vitro and in vivo results demonstrate that LY-Au@Pt@Rh-CM is able to effectively reprogram immunosuppressive TME, relief the tumor hypoxia, produce highly toxic ·OH, and therefore yield increased therapeutic efficiency upon laser irradiation of tumors. Therefore, this study provides a promising strategy for immunomodulatory enhanced tumor catalytic therapy based on polymetallic nanozymes.

Bioresponsive and immunotherapeutic nanomaterials to remodel tumor microenvironment for enhanced immune checkpoint blockade

Immune checkpoint blockade (ICB) therapy is a revolutionary approach to treat cancers, but still have limited clinical applications. Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment (TME) as one major obstacle. The TME, characterized by acidity, hypoxia and elevated ROS levels, exerts its detrimental effects on infiltrating anti-tumor immune cells. Here, we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles (termed as CAT@CaCO3 NPs) as the simple yet versatile multi-modulator for TME remodeling. CaCO3 NPs can consume protons in the acidic TME to normalize the TME pH. CAT catalyzed the decomposition of ROS and thus generated O2. The released Ca2+ led to Ca2+ overload in the tumor cells which then triggered the release of damage-associated molecular patterns (DAMP) signals to initiate anti-tumor immune responses, including tumor antigen presentation by dendritic cells. Meanwhile, CAT@CaCO3 NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype, further enhancing tumor antigen presentation. Consequently, T cell-mediated anti-tumor responses were activated, the efficacy of which was further boosted by aPD-1 immune checkpoint blockade. Our study demonstrated that local treatment of CAT@CaCO3 NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses, inhibiting the growth of treated tumors and distant diseases.

THE EFFECTS OF VARIOUS MODES OF INTERVAL HYPOXIC TRAINING IN EXPERIMENTAL MODELS OF ANXIETY AND DEPRESSION IN RATS

The development of non-drug methods for correcting stress-induced disorders and improving adaptation to stressful factors remains an urgent task of physiology, which has a great translational potential. Previously, we proposed effective methods of hypoxic hypobaric preconditioning and distant ischemic conditioning in this regard. The purpose of this work was to transfer the principles of preconditioning to the approaches of normobaric intermittent hypoxic training (IHT). The effects of five new IHT regimens (3 five-minute sessions of hypoxia of 16% O2 per day, 3 sessions of 12% O2, 7 sessions of 12% O2, 15 sessions of 12% O2, 3 sessions of 9% O2) were studied in experimental models of depression and post-traumatic stress disorder in rats. The preconditioning regime of high intensity 3x9%O2 had the most pronounced antidepressant and anxiolytic effect in models of both pathologies. With a decrease in the level of hypoxia to 12% O2, IHT regimens partially retained their effectiveness with an increase in the number of sessions. The training regime of the longest duration – 15 × 12%O2, was effective in correcting the formation of experimental depression. The intermediate regime – 7 × 12%O2, had an anxiolytic effect, while the preconditioning regime of medium intensity – 3 × 12%O2, demonstrated both an antidepressant and anxiolytic effect. The results indicate that the intensity of hypoxic exposure had the greatest impact on the effectiveness. At the same time, a decrease in the intensity to 16% O2 led to a weakening or loss of stress-protective properties. With regard to the 3 × 9%O2 regime as the most promising, it is advisable to conduct further studies to identify the molecular mechanisms that implement its stress-protective and anxiolytic effects.

Hypoxia-induced Long Non-coding RNA LSAMP-AS1 Regulates ceRNA Network to Predict Prognosis for Pancreatic Cancer.

The limited efficacy of chemotherapy and immunotherapy for pancreatic cancer is thought to be largely influenced by the surrounding cancer microenvironment. The hypoxic microenvironment caused by insufficient local blood supply is very important. However, the method to assess the level of hypoxia in the microenvironment of pancreatic cancer (PC) remains unclear. In our research, we downloaded transcriptomic and clinicopathological data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A prognostic model was developed using univariate and multivariate Cox regression. The ConsensuClusterPlus R package was used to consistently cluster PC samples through unsupervised clustering. Gene set variation analysis (GSVA) was performed to identify the different functional phenotypes. The CIBERSORT evaluated the infiltration status of immune cells. qRT-PCR was performed to detect the expression of genes in PC cells and tissues. A preliminary risk model was developed to reflect the hypoxic environment of pancreatic cancer. We found that a high hypoxia risk score indicated poor long-term survival and the presence of an immunosuppressive microenvironment. In addition, based on prognostic hypoxia-related genes, 177 PC samples were divided into two subtypes. Compared with cluster 2, cluster 1 was defined as the "hypoxic subgroup". The infiltration of CD8 T cells, activated memory CD4 T cells, naive B cells, memory B cells, plasma cells, and neutrophils were lower in cluster 1, suggesting that there was significant immunosuppression in cluster 1. Beyond that, we constructed a ceRNA regulatory network composed of differentially expressed lncRNA, miRNA, and mRNA. LSAMP-AS1/hsa-miR-129-5p/S100A2 has been identified as a key ceRNA network that regulates the hypoxic environment and the prognosis of PC. Notably, in our study, qRT-PCR revealed the relative expression of LSAMP-AS1 and S100A2 was significantly upregulated in PC cells and tissue. The hypoxia-related prognostic risk model and core ceRNA network established in our study will provide a new perspective for exploring the carcinogenic mechanism and potential therapeutic targets of pancreatic cancer.

To what extent do physiological tolerances determine elevational range limits of mammals?

A key question in biology concerns the extent to which distributional range limits of species are determined by intrinsic limits of physiological tolerance. Here, we use common-garden data for wild rodents to assess whether species with higher elevational range limits typically have higher thermogenic capacities in comparison to closely related lowland species. Among South American leaf-eared mice (genus Phyllotis), mean thermogenic performance is higher in species with higher elevational range limits, but there is little among-species variation in the magnitude of plasticity in this trait. In the North American rodent genus Peromyscus, highland deer mice (Peromyscus maniculatus) have greater thermogenic maximal oxygen uptake ( ) than lowland white-footed mice (Peromyscus leucopus) at a level of hypoxia that matches the upper elevational range limit of the former species. In highland deer mice, the enhanced thermogenic in hypoxia is attributable to a combination of evolved and plastic changes in physiological pathways that govern the transport and utilization of O2 and metabolic substrates. Experiments with Peromyscus mice also demonstrate that exposure to hypoxia during different stages of development elicits plastic changes in cardiorespiratory traits that improve thermogenic via distinct physiological mechanisms. Evolved differences in thermogenic capacity provide clues about why some species are able to persist in higher-elevation habitats that lie slightly beyond the tolerable limits of other species. Such differences in environmental tolerance also suggest why some species might be more vulnerable to climate change than others.

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial.

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2 -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 μg.kg-1 .h-1 ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.

Glucose transporter 1 deficiency, AMP-activated protein kinase activation and immune dysregulation in autism spectrum disorder: Novel biomarker sources for clinical diagnosis

The neurophysiological basis of autism spectrum disorder (ASD) is still uncertain. Nevertheless, studies support the hypotheses that oxidative stress, neuroinflammation, immune dysregulation, and metabolic stress are contributors. In this study, the serum levels of 3-nitrotyrosine (3-NT), hypoxia-inducible factor 1 α (HIF-1 α), heat shock protein 70 (HSP-70), interleukin-17A (IL-17A), IL-35, vitamin D3 (VITD), glucose transporter-1 (GUT1), and AMP-activated protein kinase (AMPK) were estimated in Saudi ASD children versus age-matched neurotypical controls, aiming to investigate whether these parameters have potential roles in the pathophysiologic mechanisms of ASD and hoping to find a reliable marker for early ASD diagnosis. This study included 25 ASD children and 25 typically developing children (3–11 years old). The diagnosis of ASD cases was made based on the Autism Diagnostic Observation Schedule (ADOS) and the Statistical Manual of Mental Disorders (DSM-5). ASD subjects were commonly male and revealed an intelligence quotient (IQ) < 70.The results detected that ASD children have remarkable greater serum levels of nitrosative stress (3-NT), hypoxia (HIF-1 α), inflammatory (HSP-70, IL-17A, and AMPK) biomarkers and lower serum levels of anti-inflammatory (IL-35 and VITD) and metabolic stress (GUT-1) biomarkers versus age-matched controls (P ≤ 0.0001). Pearson's correlation study revealed that 3-NT was positively associated with HIF-1 α and HSP-70. HIF-1 α was also positively correlated with HSP-70. AMPK was positively associated with GUT-1, however, IL-17A was negatively correlated with IL-35 and VITD.Limitation:No specific therapeuticdrugs were administered in this study, and further studies are required to confirm the role of the selected biomarkers in ASD managements. ConclusionChanges in concentrations of different biomarkers indicate that they are involved in oxidative stress, metabolic stress, immune dysregulation and ASD pathogenesis. Hence, these parameters can prove to be promising biomarkers as well as therapeutic targets for the timely diagnosis and treatment of ASD patients.

Biodegradable nanotherapeutic with simultaneously GSH depletion and H2O2 supplying for enhanced synergistic chemotherapy/chemodynamic therapy

Chemodynamic therapy (CDT) has been exploited as an emerging therapeutic modality for cancer treatment. However, insufficient intracellular H2O2 levels and ultrahigh glutathione (GSH) in the tumor microenvironment (TME) severely restrict CDT efficacy. To address these concerns, in this work, a self-reinforcing biodegradable nanotherapeutic was developed to modulate the TME to amplify CDT. The nanotherapeutic (GOD-FeCaP@TPZ, abbreviated GFCT) was fabricated through a mild one-step biomineralization process using the enzyme catalyst glucose oxidase (GOD) as a template to form biodegradable iron-doped calcium phosphate nanoparticles, followed by the loading of the prodrug tirapazamine (TPZ). When GFCT decomposes and releases Fe3+ in the acidic TME, the delivered GOD can effectively catalyze the oxidization of glucose to enhance the subsequent Fenton-like reaction by promoting intracellular acidity (via the production of gluconic acid) and improving the generation of H2O2. Moreover, the released iron constantly depletes GSH by self-cyclic valence alterations in Fe(III) and Fe(II) and then triggers H2O2 to produce •OH through an Fe(II)-mediated Fenton-like reaction. Moreover, the elevated level of hypoxia induced by GOD-mediated glucose oxidization can activate the prodrug TPZ for effective chemotherapy, thus achieving remarkable synergistic therapeutic outcomes. This work provides another paradigm to augment antitumor efficacy via modulation of the TME.

Comparing Sleep Patterns and Clinical Features between Preschool and School-Age Children with OSA.

This study aimed to evaluate sleep patterns and investigate differences in clinical features among young individuals with snoring and obstructive sleep apnea (OSA). Data from 213 children and adolescents who underwent polysomnography (PSG) for primary snoring or OSA were collected between July 2017 and December 2021. To analyze differences in sleep architecture, hypoxia levels, and other clinical features, the participants were divided into two age groups: a preschool group and a school-age group. The school-age group had significantly higher apnea-hypopnea index, obstructive apnea index, oxygen desaturation index, and body mass index than the preschool group. Both the lowest and average oxygen saturation levels were lower in the school-age group. Adenoid hypertrophy was more prevalent in the preschool group. The rate of overweight or obesity was 35.6% in the preschool group and even 94.2% in the school-age group. There were higher percentages of N1 and N2 sleep stages, and lower percentages of N3 and REM sleep stages in the school-age group. The groups exhibiting moderate to severe OSA demonstrated significant alterations in the difference between sleeping and waking diastolic blood pressure. There is a higher frequency of respiratory events among school-age children compared with their preschool peers. Moreover, alterations in sleep structure are more prominent in the school-age group. Adenoid hypertrophy may serve as the primary instigator of OSA in preschool children, whereas the predominant causes in school-age children may be obesity or excessive weight. Retrospective chart review, 3 Laryngoscope, 134:1472-1478, 2024.

Peroxide-Simulating and GSH-Depleting Nanozyme for Enhanced Chemodynamic/Photodynamic Therapy via Induction of Multisource ROS.

Reactive oxygen species (ROS) generation, using photodynamic therapy (PDT) and chemodynamic therapy (CDT), is a promising strategy for cancer treatment. However, the production of ROS in tumor cells is often limited by hypoxia, insufficient substrates, and high level of ROS scavengers in a tumor microenvironment, which seriously affects the efficacy of ROS-related tumor therapies. Herein, we report a lipid-supported manganese oxide nanozyme, MLP@DHA&Ce6, by decorating a MnO2 nano-shell on the liposome loaded with dihydroartemisinin (DHA) and photosensitizer Ce6 for generating multisource ROS to enhance cancer therapy. MLP@DHA&Ce6 can be accumulated in tumors and can release active components, Mn2+ ions, and O2. The conjugate generates ROS via nanozyme-catalyzed CDT using DHA as a substrate, PDT through Ce6, and the Fenton reaction catalyzed by Mn2+ ions. The production of O2 from MnO2 enhanced Ce6-mediated PDT under near-infrared light irradiation. Meanwhile, MLP@DHA&Ce6 showed prominent glutathione depletion, which allowed ROS to retain high activity in tumor cells. In addition, the release of Mn2+ ions and DHA in tumor cells induced ferroptosis. This multisource ROS generation and ferroptosis effect of MLP@DHA&Ce6 led to enhanced therapeutic effects in vivo.

Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis

The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12+PDGFRα+ mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12+ MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3 and Csf1. Genetic depletion of ADAM12+ cells restored a functional tumor vasculature, reduced hypoxia and acidosis and normalized CAFs, inducing infiltration of effector T cells and growth inhibition of melanomas and pancreatic neuroendocrine cancer, in a process dependent on TGF-β. In human cancer, ADAM12 stratifies patients with high levels of hypoxia and innate resistance mechanisms, as well as factors associated with a poor prognosis and drug resistance such as AXL. Altogether, our data show that depletion of tumor-induced slow-cycling PDGFRα+ MSCs through ADAM12 restores antitumor immunity.

Maternal high-fat diet changes breathing pattern and causes excessive sympathetic discharge in juvenile offspring rat.

Early life over-nutrition, as experienced in maternal obesity, is a risk factor for developing cardiorespiratory and metabolic diseases. Here we investigated the effects of high-fat diet (HFD) consumption on the breathing pattern and sympathetic discharge to blood vessels in juvenile offspring from dams fed with HFD (O-HFD). Adult female Holtzman rats were given a standard diet (SD) or HFD from 6 wk before gestation to weaning. At weaning (P21), the male offspring from SD dams (O-SD) and O-HFD received SD until the experimental day (P28-P45). Nerve recordings performed in decerebrated in situ preparations demonstrated that O-HFD animals presented abdominal expiratory hyperactivity under resting conditions and higher vasoconstrictor sympathetic activity levels. The latter was associated with blunted respiratory-related oscillations in sympathetic activity, especially in control animals. When exposed to elevated hypercapnia or hypoxia levels, the O-HFD animals mounted similar ventilatory and respiratory motor responses as the control animals. Hypercapnia and hypoxia exposure also increased sympathetic activity in both groups but did not reinstate the respiratory-sympathetic coupling in the O-HFD rats. In freely behaving conditions, O-HFD animals exhibited higher resting pulmonary ventilation and larger variability of arterial pressure levels than the O-SD animals due to augmented sympathetic modulation of blood vessel diameter. Maternal obesity modified the functioning of cardiorespiratory systems in offspring at a young age, inducing active expiration and sympathetic overactivity under resting conditions. These observations represent new evidence about pregnancy-related complications that lead to the development of respiratory distress and hypertension in children of obese mothers.NEW & NOTEWORTHY Maternal obesity is a risk factor for developing cardiorespiratory and metabolic diseases. This study highlights the changes on the breathing pattern and sympathetic discharge to blood vessels in juvenile offspring from dams fed with HFD. Maternal obesity modified the functioning of cardiorespiratory systems in offspring, inducing active expiration and sympathetic overactivity. These observations represent new evidence about pregnancy-related complications that lead to the development of respiratory distress and hypertension in children of obese mothers.

Perivascular nanocarrier aggregation as a drug reservoir augments tumor drug delivery and treatment efficacy

Anticancer nanomedicines must overcome a series of physiological and pathological barriers to reach the site of action, and this often leads to low overall therapeutic efficiency. Herein, we present tumor acidity regulated rapid aggregation of nanocarriers around tumor blood vessels to construct drug reservoirs for on-demand drug delivery. We designed two nanocarriers, one that protonates extremely quickly to expose click reactive groups on its surface and that subsequently reacted with the other noncarrier via click chemistry to rapidly form agglomerates as drug reservoirs. In proof-of-concept experiments, vascular disrupting agent combretastatin A4 (CA4) and hypoxia-activated prodrug PR-104A were loaded into the two nanocarriers, respectively. CA4 was enriched near blood vessels while PR-104A diffused deep into tumors and was activated by profound hypoxia levels induced by CA4. This combination produced effective adaptive therapy for tumors with different hypoxia levels.

Oxygen Imaging of a Rabbit Tumor Using a Human-Sized Pulse Electron Paramagnetic Resonance Imager.

Spatial heterogeneity in tumor hypoxia is one of the most important factors regulating tumor growth, development, aggressiveness, metastasis, and affecting treatment outcome. Most solid tumors are known to have hypoxia or low oxygen levels (pO2 ≤10 torr). Electron paramagnetic resonance oxygen imaging (EPROI) is an emerging oxygen mapping technology. EPROI utilizes the linear relationship between the relaxation rates of the injectable OX071 trityl spin probe and the partial oxygen pressure (pO2). However, most of the EPROI studies have been limited to mouse models of solid tumors because of the instrument-size limitations. The purpose of this work was to develop a human-sized 9-mT (250 MHz resonance frequency, 60 cm bore size) pulse EPROI instrument and evaluate its performance with rabbit VX-2 tumor oxygen imaging. A New Zealand white rabbit with a 3.2-cm VX-2 tumor in the calf muscle was imaged using the human-sized EPROI instrument and a 2.25-in. ID volume coil. The animal received a ~8-min intravenous injection of OX071 (5.2 mL total volume at 72 mM concentration) and, after 75 min, an intratumoral injection (120 μL total at 5 mM OX071 concentration) and underwent EPROI. At the end of the experiments, MRI was performed using a preclinical 9.4-T MRI system to outline the tumor boundaries. For the first time, a human-sized pulse EPROI instrument with a 60-cm bore size/250-MHz frequency was built and evaluated using rabbit tumor oxygen imaging. For the first time, the systemic IV injection of the oxygen-sensitive trityl OX071 spin probe was used for an animal of this size. The resulting EPROI image from the IV injection showed complete tumor coverage. The image obtained after intratumoral injection showed localized coverage in the upper lobe of the tumor, demonstrating the need for improved intratumoral injection protocol. This study demonstrates the performance of the world's first human-sized pulse EPROI instrument. It also demonstrates that the EPROI of larger animals can be performed using the systemic injection of a manageable amount of the spin probe. This brings EPROI one step closer to clinical applications in cancer therapies. Oxygen imaging is a platform technology, and the instrument and techniques developed here will also be useful for other clinical applications.