Hypoxic State Research Articles

A Novel Instantaneous Self-Assembled Hollow MOF-Derived Nanodrug for Microwave Thermo-Chemotherapy in Triple-Negative Breast Cancer.

Hollow materials derived from metal-organic frameworks (MOFs) have emerged in the biomedical field due to their unique properties, and different synthesis methods have been proposed. However, so far, the large-scale use of hollow MOFs is mostly limited by the timeliness of synthesis methods. Herein, we propose a new ultrasonic aerosol flow strategy for the instantaneous synthesis of a Zr-MOF-derived hollow sphere complex (ZC-HSC) in only one step. Through rapid transient heating, the coordination between metal salts and organic ligands occurs along with prompt evaporation of the solvent. The whole process lasts for only about 21 s, compared with several steps that take hours or even days for conventional synthesis methods. Based on the ZC-HSC, we designed a nanodrug with the functions of manipulating the tumor microenvironment, which can reshape the tumor microenvironment by improving tumor hypoxia and inflammatory microenvironment and promoting antiangiogenic therapy. Combined with microwave thermo-chemotherapy, the nanodrugs effectively treat triple-negative breast cancer (the tumor cell survival rate was only 34.76 and 31.05% in normoxic and hypoxic states, respectively, and the tumor inhibition rate reached 87.9% at the animal level), providing a new theoretical basis for the treatment of triple-negative breast cancer. This rapid, one-step, and continuous ultrasonic aerosol flow strategy has bright prospects in the synthesis of MOF-derived hollow materials and promotes the further development of large-scale applications of biological nanomaterials.

Abstract 302: Esophageal Saturation Monitoring More Accurately Detects Severe Tissue Hypoxia Than Near-infrared Spectroscopy

Introduction: Balance between oxygen delivery and demand is typically assessed based on venous oxyhemoglobin saturation (SvO2), which requires repeated blood sampling from a central location. Alternative, non-invasive methods such as near-infrared spectroscopy (NIRS) demonstrate poor sensitivity to tissue hypoxia. Methods: We explored the possibility of measuring regional tissue oxyhemoglobin saturation in the esophagus (EsSO2) using a new, linear probe using resonance Raman spectroscopy (RRS, 420 nm excitatory light, A) to quantify the fraction of oxyhemoglobin. The RRS probe was passed from the mouth into the mid-esophagus in Yorkshire swine (n=7, weight 11.2-13.4 kg). Cerebral (cNIRS) and splanchnic NIRS (sNIRS, Somanetics) were continuously recorded. Swine underwent complete asphyxia by endotracheal tube occlusion for 12 minutes, during which time they were resuscitated using CPR and drugs. EsSO2, cNIRS, sNIRS were compared with SO2 based on arterial blood gas co-oximetry (SaO2). For the purpose of analysis, SaO2 was considered functionally equivalent to SvO2 due to the obligate intrapulmonary (veno-arterial) shunting in this physiology. Results: During asphyxia, SO2 rapidly declined to nearly 0%. This was reflected in EsSO2, but cNIRS and sNIRS decreased to a lesser extent (B). EsSO2 exhibited a strong correlation with SO2 (r 2 =0.63, p<0.001) compared to sNIRS (r 2 =0.53, p<0.001) and cNIRS (r 2 =0.06, p=0.106, C). Defining SO2 <30% as the presence of critical hypoxia, EsSO2 had a higher sensitivity than both the sNIRS and cNIRS (D). EsSO2 was <30 in 100% (33/33) of timepoints in which critical hypoxia was present, significantly more sensitive than rSO2 based on cNIRS (which was <30 in 58% (19/33) of timepoints) and sNIRS (<30 in 24% (8/33) of timepoints). Conclusion: EsSO2 accurately detects critical hypoxic states, more so than cNIRS or sNIRS, and may represent an alternative, continuous, less invasive approach to central venous monitoring.

Reirradiation Options for Previously Irradiated Prostate cancer (RO-PIP): Feasibility study investigating toxicity outcomes following reirradiation with stereotactic body radiotherapy (SBRT) versus high-dose-rate brachytherapy (HDR-BT)

IntroductionRadiotherapy is the most common curative treatment for non-metastatic prostate cancer; however, up to 13% of patients will develop local recurrence within 10 years. Patients can undergo further and potentially...

Experimental Modeling of Damaging and Protective Hypoxia of the Mammalian Brain.

Currently, there is a new surge of interest in the problem of hypoxia, almost lost in recent decades. Due to the fact that the circle of competent specialists in this field has significantly narrowed, it is necessary to carry out an intensive exchange of knowledge. In order to inform a wide range of interested researchers and doctors, this review summarizes the current understanding of hypoxia, its pathogenic and adaptogenic consequences, as well as key physiological and molecular mechanisms that implement the response to hypoxia at various levels-from cellular to organismic. The review presents a modern classification of forms of hypoxia, the understanding of which is necessary for the formation of a scientifically based approach to experimental modeling of hypoxic states. An analysis of the literature covering the history and current level of hypoxia modeling in mammals and human experiments, including methods for creating moderate hypoxia used to increase the resistance of the nervous system to severe forms of hypoxia and other extreme factors, is carried out. Special attention is paid to the discussion of the features and limitations of various approaches to the creation of hypoxia, as well as the disclosure of the potential for the practical application of moderate hypoxic effects in medicine.

In vitro and in vivo Evidence on Intra-tumor Injection of Allogeneic Serum for Immunotherapy in a Mouse Model of Colon Cancer.

It is believed that preformed antibodies are responsible for blood transfusion reactions and transplant rejections. In order to remove a tumor, the tissue must be rejected. On the basis of transfusion reaction and transplantation immunology, we hypothesized that allogeneic serum can inhibit tumor growth when injected intra-tumor. Initially, an in vitro cytotoxicity test was conducted using the C57BL/6 serum (intact or decomplemented) in combination with the BALB/c-originating CT26 cell line. The CT26 cell line was used to establish a mouse model of colon cancer. When the tumor was palpable, C57BL/6 serum was injected intra-tumor. In addition to tumor size, hypoxia, metastatic capacity, angiogenesis, and metabolic and inflammatory status, we evaluated matrix metalloproteinase-2 (MMP)-2 and 9, vascular endothelial growth factor (VEGF)-A, Cluster of Designation (CD) 31, CD38 and interleukine (IL)-10. An in vitro experiment showed that heat-inactivated C57BL/6 serum had significantly lower cytotoxic effects on BALB/c-derived CT26 cells than intact C57BL/6 serum or BALB/c serum. In vivo experiments revealed that tumor size, HIF-1α, MMP-2, and MMP-9 levels were significantly lower in the experimental group than in the control group. In contrast to control animals, allogeneic serum treatment led to marked reductions in CD31, VEGF-1, CD38, and IL-10 levels. A new approach to serum or plasma therapy and allogeneic vaccines for cancer is intra-tumor injection of allogeneic serum. In light of the ease and availability of allogeneic immunotherapies, allogeneic serum and plasma therapy could potentially be used as an alternative monotherapy or in combination with other therapies.

Tumor Volume Predicts for Baseline Hypoxia Status in HPV Related Oropharyngeal Carcinomas (OPC) that Underwent Major Radiation De-escalation: The 30 Reduction in Oropharyngeal Cancer Trial

<h3>Purpose/Objective(s)</h3> The 30 ROC Trial utilizes functional imaging, specifically pre-treatment (Tx) and intra-Tx fluorine-18-labeled fluoromisonidazole positron emission tomography (18F-FMISO PET) to select appropriate human papillomavirus positive (HPV+) OPC patients for major de-escalation to 30 Gy. In this trial, patients also underwent pre-Tx and weekly multiparametric magnetic resonance imaging (MRI) scans to correlate with hypoxia status. The aim of the present study was to assess the value of MRI tumor volume to predict baseline hypoxia status in HPV+OPC patients who underwent major dose de-escalation. <h3>Materials/Methods</h3> A total (N = 158) patients with cT0-2,N1-2b (AJCC 7^th ed.) p16+ OPC were enrolled. All patients had pre-Tx 18F-FMISO PET scans to assess baseline hypoxia status, and only those with baseline hypoxia underwent a repeat intra-Tx scan. Pre-Tx and weekly intra-Tx MRI scans were acquired on technology company's 3T MRI scanner using a neurovascular phased array coil. Radiation oncologists delineated gross nodal disease as regions of interest on T₂w images. Tumor volume (cm³) was calculated in ITK SNAP for each patient using the segmentation software. All standard statistical analyses were performed on RStudio 2021.09.2. <h3>Results</h3> Of the 158 patients, N=95 patients had analyzable pre-Tx and weekly on-Tx MRI scans. Based on pre-Tx 18F-FMISO PET results, increased tumor volume was associated with baseline nodal hypoxia (N=69, median 18.55 cm³, range: 3.15- 60.62) compared to initially non-hypoxic tumors (N= 26, median 6.44 cm³, range: 0.48 – 47.74, p<0.001). After the intra-Tx 18F-FMISO PET result, patients were further stratified into converted negative (N= 57), persistently hypoxic (N=12), and never hypoxic (N=26). We found that the median pre-Tx nodal volume for the persistently hypoxic (median 17.75 cm³, range 5.54- 42.93, p=0.006) and converted negative (median 18.55 cm³, range 3.15 – 60.62, p<0.001) groups was significantly (P= <0.05) increased compared to the initially hypoxia negative patients (6.44 cm³, range 0.48 – 47.74). We performed further assessment of this pattern with intra-Tx MRIs (weeks 1-4) and found that this correlation of groups with baseline hypoxia (converted negative and persistently hypoxic) continued to exhibit larger nodal volume compared to the never hypoxic group. <h3>Conclusion</h3> Pre-Tx nodal volume on MRI correlates with pre-Tx hypoxia status where the larger the volume, the higher the likelihood of hypoxia. This correlation continued throughout radiation Tx as evidenced by the weekly MRI scans.

Identification of Immune and Hypoxia Risk Classifier to Estimate Immune Microenvironment and Prognosis in Cervical Cancer.

Purpose Cervical cancer (CC) is one of the most common gynecologic neoplasms. Hypoxia is an essential trigger for activating immunosuppressive activity and initiating malignant tumors. However, the determination of the role of immunity and hypoxia on the clinical outcome of CC patients remains unclear. Methods The CC independent cohort were collected from TCGA database. Consensus cluster analysis was employed to determine a molecular subtype based on immune and hypoxia gene sets. Cox relevant analyses were utilized to set up a risk classifier for prognosis assessment. The underlying pathways of classifier genes were detected by GSEA. Moreover, we conducted CIBERSORT algorithm to mirror the immune status of CC samples. Results We observed two cluster related to immune and hypoxia status and found the significant difference in outcome of patients between the two clusters. A total of 251 candidate genes were extracted from the two clusters and enrolled into Cox relevant analyses. Then, seven hub genes (CCL20, CXCL2, ITGA5, PLOD2, PTGS2, TGFBI, and VEGFA) were selected to create an immune and hypoxia-based risk classifier (IHBRC). The IHBRC can precisely distinguish patient risk and estimate clinical outcomes. In addition, IHBRC was closely bound up with tumor associated pathways such as hypoxia, P53 signaling and TGF β signaling. IHBRC was also tightly associated with numerous types of immunocytes. Conclusion This academic research revealed that IHBRC can be served as predictor for prognosis assessment and cancer treatment estimation in CC.

Fipronil impairs the GABAergic brain responses of Nile Tilapia during the transition from normoxia to acute hypoxia.

γ-aminobutyric acid (GABA) is one of the main neurotransmitters involved in the adaptation processes against the damage that hypoxia can cause to the brain. Due to its antagonist action on GABA receptors, the insecticide fipronil can turn the fish more susceptible to the negative effects of hypoxia. This study aimed to understand better if fipronil affects these GABAergic responses of Tilapia ahead to hypoxia. Oreochromis Niloticus (Nile Tilapia) were exposed for 3 and 8 h to fipronil (0.0, 0.1, and 0.5 µg.L-1 ) under normoxia (dissolved O2 > 6 mg.L-1 ) and moderate hypoxia (dissolved O2 < 2 mg.L-1 ) conditions. Briefly, hypoxia caused opposite effects on the gene transcription of the evaluated ionotropic and metabotropic GABA receptors. Unexpectedly, we obtained reduced HIF1A mRNA and brain GABA levels, mostly in the first 3 h of the experiment, for the hypoxic group compared with the normoxia one. Besides that, we also demonstrated that the insecticide fipronil impairs the brain GABAergic signaling of a hypoxia-tolerant fish during the transition from a normoxic to an acute hypoxic state. Thus, these results predict the relevant impact on the brain metabolic adaptations of fishes exposed to such stressful conditions in an aquatic environment, as well as the effects of fipronil in the GABAergic responses to hypoxia, which in turn may have ecological and physiological significance to hypoxia-tolerant fishes exposed to this insecticide.

Real-time optical imaging of the hypoxic status in hemangioma endothelial cells during propranolol therapy.

Infantile hemangioma (IH) is the most common microvascular tumor of infancy involving the area of head and neck. One of the most important independent risk factors of IH is the hypoxia microenvironment. Fluorescent chemosensor provides a noninvasive intervention, high spatiotemporal resolution, ultrasensitive response, and real-time feedback approach to reveal the hypoxic status of cells. Our research group developed an ultrasensitive fluorescent chemosensor, HNT-NTR, and investigated the potential ability of imaging the hypoxic status of hemangioma-derived endothelial cells (HemECs). In this study, we successfully visualized the propranolol (PRN) treatment in HemECs using NHT-NTR with “Turn-off” sensing method. This chemosensor exhibited high sensitivity and selectivity for optical imaging of hypoxic status with fast responsiveness, real-time feedback and durable photostability of the fluorescent signal. It was also confirmed that HNT-NTR could monitor nitroreductase in vivo. Paramountly, we expected this chemosensor to offer an available optical method for imaging of the hypoxic status and visualizing the therapeutic status of PRN therapy in IH with the hypoxia-imaging capability.

FORMATION OF DEEP INFANTILE HEMANGIOMA AGAINST THE BACKGROUND OF CONGENITAL HERPES VIRUS INFECTION

The aim is to describe the main forms and etiology of deep infantile hemangioma. On a clinical example, to show the erroneous diagnosis of sialadenitis in a child with deep infantile hemangioma against the background of congenital herpesvirus infection, hospitalized in the Department of Maxillofacial Surgery of the Moscow City Clinical Hospital. In 75% of cases of observation in children, tumors of the outer integument are represented by hemangiomas. Sialoadenitis develops against the background of acute (bacterial, viral) infections. Primary care specialists — pediatricians, pediatric surgeons and dentists in the presence of a mother’s history of placental insufficiency, hypoxic state of the fetus, the threat of termination of pregnancy and the use of hormonal and vascular drugs, the presence of a persistent infection, must include the child in the risk group for developing a vascular tumor.

Self-reinforcement hydrogel with sustainable oxygen-supply for enhanced cell ingrowth and potential tissue regeneration.

Hydrogels composed of natural biopolymers are attractive for tissue regeneration applications owing to their advantages such as biocompatibility and ease of administration, etc.. Yet, the low oxygen level and the crosslinked network inside bulk hydrogels, as well as the hypoxic status in defect areas, hamper cell viability, function, and eventual tissue repair. Herein, based on Ca2+-crosslinked alginate hydrogel, oxygen-generating calcium peroxide (CaO2) was introduced, which could provide a dynamic crosslinking alongside the CaO2 decomposition. Compared to the CaCl2-crosslinked alginate hydrogel, bone marrow mesenchymal stromal cells cultured with CaO2-contained system displayed remarkably improved biological behaviors. Furthermore, in vivo evaluations were carried out on a subcutaneous implantation in rats, and the results demonstrated the importance of the local oxygen availability in a series of crucial events for tissue regeneration, such as activating cell viability, migration, angiogenesis, and osteogenesis. In summary, the obtained Ca2+-crosslinked alginate hydrogel achieved a better microenvironment for cell ingrowth and potential tissue regeneration as the CaCl2 crosslinker being replaced by oxygen-generating CaO2 nanoparticles, due to its contribution in remedying the local hypoxic condition, promisingly, the release of Ca2+ makes the hydrogel to be a possible candidate scaffold for bone tissue engineering.

S3065 Ischemic Hepatitis Associated With Influenza A Infection

Introduction: Ischemic hepatitis is one of the few differential diagnoses to consider in cases of severely elevated serum aminotransferases 20 times the upper limit of normal. Given the inherently robust nature of the liver despite ischemic states, ischemic hepatitis usually presents in patients requiring advanced care in an intensive care unit, and often carries a high rate of in-hospital mortality. Moreover, most cases occur in patients with underlying heart failure. Here we report a case of ischemia hepatitis in a patient not requiring intensive care and without apparent heart failure, who was successfully treated for COPD exacerbation in the setting of an influenza A infection. Case Description/Methods: A 56-year-old female with COPD presented with 3 days of dyspnea with SpO2 as low as 79% on room air. She tested positive for influenza A. She was incidentally found to have elevated aminotransferases, which peaked within 12 hours of admission, with AST of 1226 IU/L and ALT of 943 U/L, and LDH of 1300 U/L. She had unremarkable INR, bilirubin, albumin, ALP, and GGT. Hepatitis panel, acetaminophen, ethanol, alpha-1 antitrypsin, antinuclear antibody, anti-smooth muscle antibody, antimitochondrial antibody, and ceruloplasmin were also all unremarkable. CT and ultrasound of the abdomen did not suggest underlying liver disease, and echocardiogram did not suggest any heart dysfunction. She denied any recent changes to her medications but did take marijuana gummy supplements. Her aminotransferases drastically fell with standard treatment of COPD exacerbation. Oxygen supplementation was limited to nasal cannula only, and she never required intensive care. At discharge, the patient's AST was 63 IU/L and ALT was 211 U/L. Discussion: Although ischemic hepatitis is a rare diagnosis primarily diagnosed in the intensive care setting, it can be infrequently seen in the hospital ward when patients demonstrate serum aminotransferases 20 times the upper limit of normal. In the setting of infections by viruses not traditionally considered as hepatotropic, ischemic hepatitis serves as a potential mechanism for severe serum aminotransferase elevations due to a hypoxic state. Furthermore, recent research suggests that an immune-mediated response to viral infection, and not hypoxia, is what primarily drives the aminotransferase elevation.

Unravelling Contributions of Astrocytic Connexin 43 to the Functional Activity of Brain Neuron-Glial Networks under Hypoxic State In Vitro.

Brain hypoxia remains an Achilles’ heel for public health that must be urgently addressed. Hypoxic damage affects both neurons and glial cells, particularly astrocytes, which are in close dynamic bi-directional communication, and are organized in plastic and tightly regulated networks. However, astroglial networks have received limited attention regarding their influence on the adaptive functional rearrangements of neural networks to oxygen deficiency. Herein, against the background of astrocytic Cx43 gap junction blockade by the selective blocker Gap19, we evaluated the features of spontaneous calcium activity and network characteristics of cells in primary cultures of the cerebral cortex, as well as the expression levels of metabotropic glutamate receptors 2 (mGluR2) and 5 (mGluR5) in the early and late periods after simulated hypoxia in vitro. We showed that, under normoxic conditions, blockade of Cx43 leads to an increase in the expression of metabotropic glutamate receptors mGluR2 and mGluR5 and long-term modulation of spontaneous calcium activity in primary cortical cultures, primarily expressed in the restructuring of the functional architectonics of neuron–glial networks through reducing the level of correlation between cells in the network and the percentage of existing correlated connections between cells. Blocking Cx43 during hypoxic injury has a pronounced neuroprotective effect. Together with the increased expression of mGluR5 receptors, a decrease in mGluR2 expression to the physiological level was found, which suggests the triggering of alternative molecular mechanisms of cell adaptation to hypoxia. Importantly, the blockade of Cx43 in hypoxic damage contributed to the maintenance of both the main parameters of the spontaneous calcium activity of primary cortical cultures and the functional architectonics of neuron–glial networks while maintaining the profile of calcium oscillations and calcium signal communications between cells at a highly correlated level. Our results demonstrate the crucial importance of astrocytic networks in functional brain adaptation to hypoxic damage and could be a promising target for the development of rational anti-hypoxic therapy.

Mechanism investigation of Shi-Xiao-San in treating blood stasis syndrome based on network pharmacology, molecular docking and in vitro/vivo pharmacological validation

Ethnopharmacological relevanceShixiao San (SXS) is a traditional Chinese formula that has been widely used in clinical practice to treat blood stasis syndromes, such as hyperlipidemia, atherosclerotic, thrombosis and coronary heart disease. However, the effectiveness and mechanism of SXS have not been studied in detail yet. Aim of the studyCurrent study aimed to identify the compounds in SXS, evaluate the formula efficacies using network pharmacology, molecular docking, and verify the pharmacological effects by in vivo and in vitro experiments. Materials and methodsThe compounds in SXS were analyzed using UPLC-QTOF-MS. Potential target genes for identified compounds were obtained from three databases. DAVID database was used to perform GO and KEGG pathway enrichment analyses. PPI network was constructed to screen core targets. Molecular docking was used to examine interactions between active compounds and potential targets. The mechanism was also verified by model of acute blood stasis rats and human umbilical vein cells. ResultsIn total, 45 compounds were identified from SXS. Among the detected phytochemicals, quercetin, isorhamnetin, kaempferol, D-catechin, naringenin and amentoflavone were identified as the active constituents. SXS is primarily involved in the modulation of hypoxic state, vascular regulation, and inflammation response, according to GO and KGG pathway enrichment analysis. A network of protein-protein interactions (PPIs) was constructed and five core targets were identified as VEGFA, AKT1, EGFR, PTGS2, and MMP9. Molecular docking simulation revealed good binding affinity of the five putative targets with the corresponding compounds. SXS reduced HIF-1α and COX-2 levels and increased the eNOS expression levels in hypoxic HUVECs. SXS can reduce the whole blood viscosity in adrenaline induced acute blood stasis rats and relieve blood stasis. ConclusionsSXS removes blood stasis might through VEGFA/AKT/eNOS/COX-2 pathway and flavonoids are the main active components in the formula.

Oxygen tank for synergistic hypoxia relief to enhance mitochondria-targeted photodynamic therapy

BackgroundMitochondria play an essential role in cellular redox homeostasis maintenance and meanwhile serve as an important target for organelle targeted therapy. Photodynamic therapy (PDT) is a promising strategy for organelle targeted therapy with noninvasive nature and highly spatiotemporal selectivity. However, the efficacy of PDT is not fully achieved due to tumor hypoxia. Moreover, aerobic respiration constantly consumes oxygen and leads to a lower oxygen concentration in mitochondria, which continuously limited the therapeutic effects of PDT. The lack of organelle specific oxygen delivery method remains a main challenge.MethodsHerein, an Oxygen Tank is developed to achieve the organelle targeted synergistic hypoxia reversal strategy, which not only act as an oxygen storage tank to open sources and reduce expenditure, but also coated with red blood cell membrane like the tank with stealth coating. Within the oxygen tank, a mitochondrion targeted photosensitizer (IR780) and a mitochondria respiration inhibitor (atovaquone, ATO) are co-loaded in the RBC membrane (RBCm) coated perfluorocarbon (PFC) liposome core.ResultsInside these bio-mimic nanoparticles, ATO effectively inhibits mitochondrial respiration and economized endogenous oxygen consumption, while PFC supplied high-capacity exogenous oxygen. These Oxygen modulators reverse the hypoxia status in vitro and in vivo, and exhibited a superior anti-tumor activity by mitochondria targeted PDT via IR780. Ultimately, the anti-tumor effects towards gastric cancer and colon cancer are elicited in vivo.ConclusionsThis oxygen tank both increases exogeneous oxygen supply and decreases endogenous oxygen consumption, may offer a novel solution for organelle targeted therapies.

Inattention and hyperactivity in children and adolescents with repaired D-transposition of the great arteries: Prevalence, perioperative risk factors, and clinical outcomes.

ObjectiveThe present study objectives were to determine the prevalence of attention-deficit/hyperactivity disorder symptoms (ADHD-like symptoms) in children and adolescent with d-transposition of great artery (D-TGA) after arterial switch operation (ASO) and examine associated risk factors and adverse personal, family dysfunctions.MethodsThis cohort study included 103 patients with D-TGA who underwent ASO in early infancy at Shanghai Children’s Medical Center between 2011 and 2016 and then follow-up. Data analysis was conducted from September 2020 to April 2022. A standardized Swanson, Nolan, and Pelham IV (SNAP-IV) questionnaire is used to evaluate inattention and hyperactivity symptoms. Demographic, preoperative, intraoperative, and postoperative factor were collected. Univariate and multivariable regression analyses were performed with odds ratios (OR) and 95% confidence intervals (CIs).ResultsPrevalence of ADHD-like symptoms was 27.18% (28/103). Attention-deficit (18/28, 64.29%) symptom was the predominant subphenotype. After underwent TGA surgery, 39% of patients with ADHD-like symptoms receive remedial special academic services. There is none had repeated grade. Univariate analysis showed that, positive inotropic drug score (P = 0.03) and delayed sternal closure (P = 0.02) were risk factors of ADHD-like symptoms; increased preoperative oxygen saturation (SpO2) (P = 0.01) and surgical height (P = 0.01) and TGA subtype (VSD) (P = 0.02) were protective factor of ADHD-like symptoms. Multivariable analysis showed that delayed sternal closure (DSC) (OR, 1.50; 95% CI, 1.02–2.18) is a risk factor for the occurrence of ADHD-like symptom while increased preoperative oxygen saturation [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.92–0.99] is a protective factor of ADHD-like symptom.ConclusionThe children and adolescents with D-TGA after ASO were at high risk of ADHD-like symptoms. Preoperative hypoxic status and postoperative DSC became predominant risk factors. Modification of the risk factors may be helpful to relieve ADHD-like symptoms for these patients.

Plumbagin Suppresses Breast Cancer Progression by Downregulating HIF-1α Expression via a PI3K/Akt/mTOR Independent Pathway under Hypoxic Condition.

Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional regulator that plays a crucial role in the hypoxic response of rapidly growing tumors. Overexpression of HIF-1α has been associated with breast cancer metastasis and poor clinical prognosis. Plumbagin, the main phytochemical from Plumbago indica, exerts anticancer effects via multiple mechanisms. However, its precise mechanisms on breast cancer cells under hypoxic conditions has never been investigated. This study aims to examine the anticancer effect of plumbagin on MCF-7 cell viability, transcriptional activity, and protein expression of HIF-1α under normoxia and hypoxia-mimicking conditions, as well as reveal the underlying signaling pathways. The results demonstrate that plumbagin decreased MCF-7 cell viability under normoxic conditions, and a greater extent of reduction was observed upon exposure to hypoxic conditions induced by cobalt chloride (CoCl2). Mechanistically, MCF-7 cells upregulated the expression of HIF-1α protein, mRNA, and the VEGF target gene under CoCl2-induced hypoxia, which were abolished by plumbagin treatment. In addition, inhibition of HIF-1α and its downstream targets did not affect the signaling transduction of the PI3K/Akt/mTOR pathway under hypoxic state. This study provides mechanistic insight into the anticancer activity of plumbagin in breast cancer cells under hypoxic conditions by abolishing HIF-1α at transcription and post-translational modifications.

Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC

BackgroundCurrent evidence suggests that the hypoxic tumor microenvironment further aggravates tumor progression, leading to poor therapeutic outcomes. There is as yet no biomarker capable of evaluating the hypoxic state of the tumor. The cytochrome c oxidase (COX) subunit is crucial to the mitochondrial respiratory chain.MethodsWe investigated the potential oncogenic role of COX subunit 4 isoform 2 gene (COX4I2) in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and COX regression analysis to examine whether COX4I2 overexpression can predict colorectal cancer (CRC) prognosis. The association of COX4I2 levels with clinical features and its biological actions were evaluated both in vitro and in vivo.ResultsOur analysis showed that elevated COX4I2 levels were correlated with poor clinical outcomes. We also observed that that COX4I2 may be involved in epithelial-mesenchymal transition, activation of cancer-related fibroblasts and angiogenesis in relation to fibroblast growth factor 1.ConclusionsThe COX4I2 level may be a predictor of outcome in CRC and may represent a novel target for treatment development.Graphical

P12.11.B The role of miRNAs in glioma in response to hypoxia

Abstract Background Hypoxia, low oxygen, is a microenvironment that promotes tumour progression, particularly in gliomas. The regulation of many biological processes are maintained by miRNAs. The hypoxia status of glioma cells effects the regulation of processes by affecting the expression of individual miRNAs.The aims of this study is identifying significant miRNAs that are either under or overexpressed in hypoxia compared to normoxia in glioma cells and further exploring the effect of hypoxia on miR-92a-3p and miR-149-5p in gliomas on the apoptotic and cellular senescence pathways. Material and Methods A range of glioma cells were used for screening including primary cell lines: GIN28 and GIN31; low-grade cell lines: LGG19 and LGG24; paediatric cell line: SF188 and commercially available glioblastoma cell line U87. These cells were culture at both 1% (hypoxia) and 20% (normoxia) oxygen levels. Screening of miRNAs was achieved by quantitative polymerase chain reaction (qPCR) using miRNA specific primers. Knockdowns/in were achieved by transfecting with miR-92a-3p and miR-149-5p mimics and inhibitors. Caspase-glo assay was used to assess the effect of hypoxia on apoptosis. Results miRNA 92a-3p and miR-149-5p were found to be downregulated and upregulated respectively in primary gliomas cells in hypoxia compared to normoxia. These particular miRNAs are also found to have multiple targets in apoptosis and cellular senescence. Conclusion The screening of 90 miRNAs among the different categories of gliomas highlighted multiple miRNAs that were significant in hypoxia compared to normoxia. Using primary cell lines have identified hypoxia-affected miRNAs in glioblastomas. This discovery will increase our knowledge and understanding of the hypoxia effect on miRNAs which may aid and direct targeted therapy to conquer hypoxia in glioblastomas.

Meteorin links the bone marrow hypoxic state to hematopoietic stem/progenitor cell mobilization.

Hematopoietic stem/progenitor cells (HSPCs) are supported and regulated by niche cells in the bone marrow with an important characterization of physiological hypoxia. However, how hypoxia regulates HSPCs is still unclear. Here, we find that meteorin (Metrn) from hypoxic macrophages restrains HSPC mobilization. Hypoxia-induced factor 1α and Yin Yang 1 induce the high expression of Metrn in macrophages, and macrophage-specific Metrn knockout increases HSPC mobilization through modulating HSPC proliferation and migration. Mechanistically, Metrn interacts with its receptor 5-hydroxytryptamine receptor 2b (Htr2b) to regulate the reactive oxygen species levels in HSPCs through targeting phospholipase C signaling. The reactive oxygen species levels are reduced in HSPCs of macrophage-specific Metrn knockout mice with activated phospholipase C signaling. Targeting the Metrn/Htr2b axis could therefore be a potential strategy to improve HSPC mobilization for stem cell-based therapy.