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Blais, Jaime D., Vasilisa Filipenko, Meixia Bi, Heather P. Harding, David Ron, Costas Koumenis, Bradly G. Wouters und John C. Bell. „Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress“. Molecular and Cellular Biology 24, Nr. 17 (01.09.2004): 7469–82. http://dx.doi.org/10.1128/mcb.24.17.7469-7482.2004.
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ABSTRACT Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2α at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2α was able to attenuate the phosphorylation of eIF2α and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2α-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.
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Sotiridis, Alexandros, Tadej Debevec, Adam C. McDonnell, Urša Ciuha, Ola Eiken und Igor B. Mekjavic. „Exercise cardiorespiratory and thermoregulatory responses in normoxic, hypoxic, and hot environment following 10-day continuous hypoxic exposure“. Journal of Applied Physiology 125, Nr. 4 (01.10.2018): 1284–95. http://dx.doi.org/10.1152/japplphysiol.01114.2017.
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We examined the effects of acclimatization to normobaric hypoxia on aerobic performance and exercise thermoregulatory responses under normoxic, hypoxic, and hot conditions. Twelve men performed tests of maximal oxygen uptake (V̇O2max) in normoxic (NOR), hypoxic [HYP; 13.5% fraction of inspired oxygen (FiO2)], and hot (HE; 35°C, 50% relative humidity) conditions in a randomized manner before and after a 10-day continuous normobaric hypoxic exposure [FiO2 = 13.65 (0.35)%, inspired partial pressure of oxygen = 87 (3) mmHg]. The acclimatization protocol included daily exercise [60 min at 50% hypoxia-specific peak power output (Wpeak)]. All maximal tests were preceded by a steady-state exercise (30 min at 40% Wpeak) to assess the sweating response. Hematological data were assessed from venous blood samples obtained before and after acclimatization. V̇o2max increased by 10.7% ( P = 0.002) and 7.9% ( P = 0.03) from pre-acclimatization to post acclimatization in NOR and HE, respectively, whereas no differences were found in HYP [pre: 39.9 (3.8) vs. post: 39.4 (5.1) ml·kg−1·min−1, P = 1.0]. However, the increase in V̇O2max did not translate into increased Wpeak in either NOR or HE. Maximal heart rate and ventilation remained unchanged following acclimatization. Νo differences were noted in the sweating gain and thresholds independent of the acclimatization or environmental conditions. Hypoxic acclimatization markedly increased hemoglobin ( P < 0.001), hematocrit ( P < 0.001), and extracellular HSP72 ( P = 0.01). These data suggest that 10 days of normobaric hypoxic acclimatization combined with moderate-intensity exercise training improves V̇o2max in NOR and HE, but does not seem to affect exercise performance or thermoregulatory responses in any of the tested environmental conditions. NEW & NOTEWORTHY The potential crossover effect of hypoxic acclimatization on performance in the heat remains unexplored. Here we show that 10-day continuous hypoxic acclimatization combined with moderate-intensity exercise training can increase maximal oxygen uptake in hot conditions.
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Blais, Jaime D., Christina L. Addison, Robert Edge, Theresa Falls, Huijun Zhao, Kishore Wary, Costas Koumenis et al. „Perk-Dependent Translational Regulation Promotes Tumor Cell Adaptation and Angiogenesis in Response to Hypoxic Stress“. Molecular and Cellular Biology 26, Nr. 24 (09.10.2006): 9517–32. http://dx.doi.org/10.1128/mcb.01145-06.
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ABSTRACT It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk−/− mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk+/+ and Perk−/− MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.
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Harper, Kelly, Anna Yatsyna, Martine Charbonneau, Karine Brochu-Gaudreau, Alexis Perreault, Claudio Jeldres, Patrick P. McDonald und Claire M. Dubois. „The Chicken Chorioallantoic Membrane Tumor Assay as a Relevant In Vivo Model to Study the Impact of Hypoxia on Tumor Progression and Metastasis“. Cancers 13, Nr. 5 (04.03.2021): 1093. http://dx.doi.org/10.3390/cancers13051093.
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Hypoxia in the tumor microenvironment is a negative prognostic factor associated with tumor progression and metastasis, and therefore represents an attractive therapeutic target for anti-tumor therapy. To test the effectiveness of novel hypoxia-targeting drugs, appropriate preclinical models that recreate tumor hypoxia are essential. The chicken ChorioAllantoic Membrane (CAM) assay is increasingly used as a rapid cost-effective in vivo drug-testing platform that recapitulates many aspects of human cancers. However, it remains to be determined whether this model recreates the hypoxic microenvironment of solid tumors. To detect hypoxia in the CAM model, the hypoxic marker pimonidazole was injected into the vasculature of tumor-bearing CAM, and hypoxia-dependent gene expression was analyzed. We observed that the CAM model effectively supports the development of hypoxic zones in a variety of human tumor cell line-derived and patient’s tumor fragment-derived xenografts. The treatment of both patient and cell line-derived CAM xenografts with modulators of angiogenesis significantly altered the formation of hypoxic zones within the xenografts. Furthermore, the changes in hypoxia translated into modulated levels of chick liver metastasis as measured by Alu-based assay. These findings demonstrate that the CAM xenograft model is a valuable in vivo platform for studying hypoxia that could facilitate the identification and testing of drugs targeting this tumor microenvironment.
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Patil, Deepak. „Does culture condition of reduced oxygen pressure helps in embryo quality? A prospective randomized study“. International Journal of Reproduction, Contraception, Obstetrics and Gynecology 10, Nr. 6 (27.05.2021): 2239. http://dx.doi.org/10.18203/2320-1770.ijrcog20212154.
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Background: Embryo quality is of paramount importance in an in vitro fertilization and embryo transfer (IVF-ET) cycle. A healthy embryo leads to a robust pregnancy. Incubation in an ideal atmosphere is essential requirement in an IVF-ET cycle.Methods: Traditionally carbon dioxide incubator with sensors for carbon dioxide levels and temperature has been used widely. We compared the quality of these embryos to incubation in hypoxic condition by addition of nitrogen. Oxygen levels were brought to 5% as compared to 21% in room air.Results: Ladies with high body mass index (BMI) and advanced age had more embryos available for transfer. More embryos reached day 3 and day 5, thus increasing availability for cryopreservation. The fragmentation rate and fertilization failure were less. Pregnancy rate was definitely improved as compared to traditional incubation.Conclusions: Hypoxic incubation condition leads to better embryo health. This translates into improved and efficient cycle outcome.
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Joyner-Matos, J., H. Richardson, T. Sammeli und L. J. Chapman. „A fingernail clam (Sphaerium sp.) shows higher reproductive success in hypoxic waters“. Canadian Journal of Zoology 89, Nr. 3 (März 2011): 161–68. http://dx.doi.org/10.1139/z10-106.
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Low dissolved O2, or hypoxia, is becoming increasingly prevalent in aquatic habitats and is considered to be stressful for aerobic organisms. However, hypoxia also can be beneficial by decreasing cellular stress, particularly that related to free radicals. Therefore, an animal’s ideal habitat may have the minimum O2 necessary to sustain aerobic metabolism, with excess O2 increasing the need to scavenge free radicals and repair free radical damage. Here we show that a natural population of small (<9 mm shell length) freshwater clams (genus Sphaerium Scopoli, 1777) lives along a dissolved O2 gradient from extreme hypoxia to moderate hypoxia. We tested the hypothesis that clams living in extreme hypoxia would have higher reproductive success than clams that live in moderate hypoxia. Clam abundance was highest in water with very low dissolved O2, conditions previously demonstrated to decrease cellular stress. The internally brooding clams reproduced year-round and had higher reproductive output in extreme hypoxia than in moderate hypoxia. The findings demonstrate that the apparent cellular-level benefits of hypoxia may translate into increased fitness, especially for small organisms.
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Burtscher, Johannes, Vittorio Maglione, Alba Di Pardo, Grégoire P. Millet, Christoph Schwarzer und Luca Zangrandi. „A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease“. International Journal of Molecular Sciences 22, Nr. 2 (08.01.2021): 582. http://dx.doi.org/10.3390/ijms22020582.
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Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.
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Burtscher, Johannes, Vittorio Maglione, Alba Di Pardo, Grégoire P. Millet, Christoph Schwarzer und Luca Zangrandi. „A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease“. International Journal of Molecular Sciences 22, Nr. 2 (08.01.2021): 582. http://dx.doi.org/10.3390/ijms22020582.
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Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.
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Sheehan, Jason, Christopher P. Cifarelli, Kasandra Dassoulas, Claire Olson, Jessica Rainey und Shaojie Han. „Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide“. Journal of Neurosurgery 113, Nr. 2 (August 2010): 234–39. http://dx.doi.org/10.3171/2009.11.jns091314.
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Object Glioblastoma (GB) tumors typically exhibit regions of hypoxia. Hypoxic areas within the tumor can make tumor cells less sensitive to chemotherapy and radiation therapy. Trans-sodium crocetinate (TSC) has been shown to transiently increase oxygen to hypoxic brain tumors. The authors examined whether this improvement in intratumor oxygenation translates to a therapeutic advantage when delivering standard adjuvant treatment to GBs. Methods The authors used C6 glioma cells to create a hypoxic GB model. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Fifteen days later, MR imaging was used to confirm the presence of a glioma. The animals were randomly assigned to 1 of 3 groups: 1) temozolomide alone (350 mg/m2/day for 5 days); 2) temozolomide and radiation therapy (8 Gy); or 3) TSC (100 μg/kg for 5 days), temozolomide, and radiation therapy. Animals were followed through survival studies, and tumor response was assessed on serial MR images obtained at 15-day intervals during a 2-month period. Results Mean survival (± SEM) of the temozolomide-alone and the temozolomide/radiotherapy groups was 23.2 ± 0.9 and 29.4 ± 4.4 days, respectively. Mean survival in the TSC/temozolomide/radiotherapy group was 39.8 ± 6 days, a statistically significant improvement compared with either of the other groups (p < 0.05). Although tumor size was statistically equivalent in all groups at the time of treatment initiation, the addition of TSC to temozolomide and radiotherapy resulted in a statistically significant reduction in the MR imaging–documented mean tumor size at 30 days after tumor implantation. The mean tumor size in the TSC/temozolomide/radiotherapy group was 18.9 ± 6.6 mm2 compared with 42.1 ± 2.7 mm2 in the temozolomide-alone group (p = 0.047) and 35.8 ± 5.1 mm2 in the temozolomide/radiation group (p = 0.004). Conclusions In a hypoxic GB model, TSC improves the radiological and clinical effectiveness of temozolomide and radiation therapy. Further investigation of this oxygen diffusion enhancer as a radiosensitizer for hypoxic brain tumors seems warranted.
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Yu, Jicheng, Yuqi Zhang, Yanqi Ye, Rocco DiSanto, Wujin Sun, Davis Ranson, Frances S. Ligler, John B. Buse und Zhen Gu. „Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery“. Proceedings of the National Academy of Sciences 112, Nr. 27 (22.06.2015): 8260–65. http://dx.doi.org/10.1073/pnas.1505405112.
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A glucose-responsive “closed-loop” insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (“smart insulin patch”) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
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White, Kevin, Lynn Loughlin, Zakia Maqbool, Margaret Nilsen, John McClure, Yvonne Dempsie, Andrew H. Baker und Margaret R. MacLean. „Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH“. Physiological Genomics 43, Nr. 8 (April 2011): 417–37. http://dx.doi.org/10.1152/physiolgenomics.00249.2010.
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Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBPβ, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBPβ, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBPβ, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBPβ, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17β-estradiol increased CEBPβ, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBPβ, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH.
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Burger, R., und A. C. Bryan. „Pulmonary hypertension after postlavage lung injury in rabbits: possible role of polymorphonuclear leukocytes“. Journal of Applied Physiology 71, Nr. 5 (01.11.1991): 1990–95. http://dx.doi.org/10.1152/jappl.1991.71.5.1990.
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Previous studies showed that repeated lung lavage leads to a severe lung injury with very poor gas exchange, a substantial protein leak into the alveoli with hyaline membrane formation, pulmonary hypertension, and migration of granulocytes (PMN) into the alveolar spaces. Depletion of PMN leads to a better gas exchange and a markedly decreased protein leak with only scanty hyaline membranes. In this study we show that there is sustained pulmonary hypertension after the lung lavage, but in PMN-depleted rabbits there is no postlavage increase in pulmonary arterial pressure. Changing the shunt fraction by manipulating mean airway pressure still leads to a hypoxic vasoconstriction with increase of pulmonary arterial pressure. Thus, after lung lavage, pulmonary reactivity to hypoxia is still preserved. Comparisons between high-frequency ventilation and conventional mechanical ventilation at the same mean airway pressures showed that equal mean airway pressure in these two very different modes of ventilation do not translate into the same mean functional lung volumes.
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Krawczyk, Malgorzata A., Michal Kunc, Malgorzata Styczewska, Anna Gabrych, Gabrielle Karpinsky, Ewa Izycka-Swieszewska und Ewa Bien. „High Expression of Solute Carrier Family 2 Member 1 (SLC2A1) in Cancer Cells Is an Independent Unfavorable Prognostic Factor in Pediatric Malignant Peripheral Nerve Sheath Tumor“. Diagnostics 11, Nr. 4 (26.03.2021): 598. http://dx.doi.org/10.3390/diagnostics11040598.
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Malignant peripheral nerve sheath tumor (MPNST) in children is a rare mesenchymal malignancy developing predominantly in the setting of neurofibromatosis type 1. The prognosis in advanced MPNST is poor therefore new prognostic markers are highly needed for optimal therapeutic decisions. In many solid tumors, the bidirectional interactions between hypoxia and inflammation in the tumor microenvironment via functions of tumor-associated cells, like neutrophils, lymphocytes and macrophages, have been investigated recently. There is no data whether in MPNST hypoxic microenvironment may translate into systemic inflammation, which is a well-established factor for worse prognosis in cancer patients. Therefore, we investigated the prognostic significance of markers of tumor hypoxia and systemic inflammation in 26 pediatric malignant peripheral nerve sheath tumors (MPNST). Tumor tissue microarrays were stained for hypoxia-inducible factor-1α (HIF1A), solute carrier family 2 member 1 (SLC2A1, also known as glucose transporter 1 (GLUT1)), carbonic anhydrase 9 (CA9), and vascular endothelial growth factor A (VEGFA) and classified into low- or high-expression groups. Baseline complete blood counts and C-reactive protein (CRP) levels were collected for all cases. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were calculated from age-adjusted complete blood count parameters. Both 10-year RFS and OS were significantly lower in patients with high NLR values (17% vs. 75%, p = 0.009, q = 0.018; and 31% vs. 100%, p = 0.0077, q = 0.014; respectively). Ten-year-OS was significantly lower in patients with high expression of SLC2A1 (20.00% vs. 94%, p < 0.001, log-rank), high expression of HIF1A (23% vs. 79%, p = 0.016, log-rank), and CRP higher than 31 mg/L (11% vs. 82%, p = 0.003, q = 0.009). Cox’s proportional hazard regression analysis revealed that high expression of SLC2A1 (HR = 3.31, 95% CI = 1.08–10.09, p = 0.036) and VEGFA (HR = 4.40, 95% CI = 0.95–20.34, p = 0.058) were the independent factors predicting relapse, whereas high SLC2A1 was identified as the independent risk factor for death (HR = 12.20, 95% CI = 2.55–58.33, p = 0.002). Patients with high expression of hypoxic markers and low or high NLR/CRP values had the highest events rate, patients with low hypoxic markers and high NLR/CRP had intermediate events rate, while patients with low hypoxic markers and low NLR/CRP had the lowest events rate. SLC2A1 and VEGFA are promising novel prognostic factors in pediatric MPNST. Correlations between hypoxic and systemic inflammatory markers suggest the interplay between local tumor hypoxia and systemic inflammation.
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Tan, Yixiong, Wei Nie, Cheng Chen, Xuesong He, Yuzhi Xu, Xiaoqian Ma, Juan Zhang, Mengqun Tan, Pengfei Rong und Wei Wang. „Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets“. Experimental Biology and Medicine 244, Nr. 9 (01.05.2019): 781–88. http://dx.doi.org/10.1177/1535370219844472.
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Islet transplantation is a promising treatment for selected patients with type 1 diabetes mellitus (T1DM). Hypoxia and oxidative stress are major causes of damage to transplanted islets. Mesenchymal stem cells (MSCs) have been shown to enhance cell survival mainly through paracrine secretion. However, mechanisms of action underlying the protective effects of MSCs on islets have not been fully elucidated. In this study, we investigated whether human umbilical cord-derived MSCs (huc-MSCs) could inhibit hypoxia and ROS-related cell death of neonatal porcine islet cell clusters (NICCs) and further determined the underlying molecular mechanisms. NICCs were cultured in vitro under normoxic and hypoxic (1% O2) conditions with or without MSC-conditioned medium (MSC-CM). Apoptosis of NICCs was evaluated by the AO/EB staining and Annexin V/PI flow cytometry analysis. Total and mitochondrial ROS production was detected by fluorometric assays. Western blot and the ERK pathway inhibitor, PD98059, were used to assess the possible pathways involved. The results showed that MSC-CM suppressed hypoxia-induced oxidative stress and cell death of NICCs. MSC-CM also activated several pro-survival pathways in NICCs under hypoxic conditions. Furthermore, MSC-secreted exosomes and IL-6 partially recapitulated the multifunctional benefits of MSC-CM. This study showed that huc-MSCs protected NICCs from hypoxia-induced cell death by regulating the cell redox state and cell signaling pathways. This increased understanding may enable MSCs to become a more promising adjuvant cell therapy for islet transplantation. Impact statement The utilization of mesenchymal stem cells (MSCs) is a promising approach to serve as adjuvant therapy for islet transplantation. But the inability to translate promising preclinical results into sound therapeutic effects in human subjects indicates a lack of key knowledge of MSC-islet interactions that warrant further research. Hypoxia and oxidative stress are critical factors which lead to a tremendous loss of islet grafts. However, previous studies mainly focused on other aspects of MSC protection such as inducing revascularization, enhancing insulin secretion, and reducing islet apoptosis. In this study, we aim to investigate whether MSC can protect islet cells from hypoxic damage by inhibiting ROS production and the potential underlying pathways involved. We also explore the effects of MSC-derived exosomes and IL-6 on hypoxia-injured islets. Our data provide new molecular targets for developing MSC applications, and this may ultimately promote the efficiency of clinical islet transplantation.
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Rombough, Peter J. „Oxygen as a constraining factor in egg size evolution in salmonids“. Canadian Journal of Fisheries and Aquatic Sciences 64, Nr. 4 (01.04.2007): 692–99. http://dx.doi.org/10.1139/f07-047.
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Differential survival at low oxygen levels has been proposed as a mechanism for maintaining high within-population variability in egg size in fish. Whether low oxygen levels favour large or small eggs, however, is not clear. To address this question, the effects of egg size on metabolic rates, critical dissolved oxygen levels (Pc), and P50 oxygen levels of Chinook salmon (Oncorhynchus tshawytscha) embryos and alevins were determined. Embryonic metabolic rate expanded at a slower rate with increasing egg mass (allometric constant (b) = 0.30) than did capsule surface area (b = 0.67), indicating that larger eggs have larger surface areas relative to their metabolic demand for oxygen. A relatively larger area, however, did not translate into significant differences in Pc or P50 values at the egg stage. After hatch, metabolic rate expanded at a rate proportional to (egg mass)0.62. Pc levels were significantly higher for alevins from larger eggs for the first but not second half of the alevin stage. Egg size had no significant effect on P50 values at any time during the alevin stage. The modest impact of egg size on hypoxic tolerance of developing Chinook suggests that factors other than oxygen are involved in maintaining high within-population variability in egg size.
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Yıldız, Barış, Nadide Kamiloğlu, Cem Öziç und Yüksel Coşkun. „Effects of hypoxia on the mRNA expressions of TRAILmediated cell death related genes in hypoxia-tolerant rodent (Nannospalax nehringi) and some characteristics of these proteins“. Archives of Biological Sciences, Nr. 00 (2020): 53. http://dx.doi.org/10.2298/abs201119053y.
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The aim of the present study was to determine the mRNA expression profiles of TRAILmediated cell death related genes of the hypoxia-tolerant rodent Nannospalax nehringi under hypoxia. The nucleotide and amino acid sequences of these genes were identified. Captured Nannospalax nehringi were randomly divided into normoxia and hypoxia groups. The hypoxia group was exposed to a 7% O2 + 93% N2 gas mixture for 52 h, while animals in the normoxia group were housed under normoxic conditions. Total RNAs were isolated from brain and lung tissues. The cIAP-1, cIAP-2, XIAP, DcR1, DcR2, FLIP and OPG genes were PCR amplified, and the cIAP-1, cIAP-2, XIAP, OPG, TRAIL and FLIP genes were sequenced. Sequenced genes were translated into amino acid sequences and compared with reliable sequences of closely similar species. The genes in the brain were regulated for protection against hypoxia; however, the genes in the lung were regulated differently. Many mutations and insertions were observed on the conserved regions of the cIAP-1, cIAP-2, XIAP, OPG and TRAIL genes in N. nehringi. We propose that these gene mutations and insertions contribute to the anti-hypoxic properties of N. nehringi.
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Gorim, Linda, und Folkard Asch. „Seed coating reduces respiration losses and affects sugar metabolism during germination and early seedling growth in cereals“. Functional Plant Biology 42, Nr. 2 (2015): 209. http://dx.doi.org/10.1071/fp14142.
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Seed germination and the successful establishment of young seedlings is an important aspect of plant life. Seed coats are used to improve stand establishment and early seedling vigour. Seedlings growing from hydro-absorber coated barley, rye and wheat with coat-shares greater than 75% of the average seed have been shown to promote better seedling growth compared with those seedlings growing from uncoated seeds. We investigated how and why these seedlings performed better by analysing the proportion of grain reserves mobilised for growth and respiration as well as how both sucrose and glucose available in the embryo translated into seedling growth in the presence or absence of seed coats containing hydro-absorber gel. We found that mobilisation efficiency was higher, resulting in higher biomass in these cereals when they were coated. The relationship between sucrose and glucose available to the seedling as well as its correlation with early seedling growth indicate a switch in the enzymatic cleavage of embryonic sucrose from invertase to sucrose synthase. This in turn indicates that in coated seeds, embryonic tissue must be hypoxic leading to a more efficient use of glucose and thus reduced respiration losses during germination.
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Hamlin, Michael J., Helen C. Marshall, John Hellemans und Philip N. Ainslie. „Effect of intermittent hypoxia on muscle and cerebral oxygenation during a 20-km time trial in elite athletes: a preliminary report“. Applied Physiology, Nutrition, and Metabolism 35, Nr. 4 (Juni 2010): 548–59. http://dx.doi.org/10.1139/h10-044.
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The effects of intermittent hypoxic exposure (IHE) on cerebral and muscle oxygenation, arterial oxygen saturation (SaO2), and respiratory gas exchange during a 20-km cycle time trial (20TT) were examined (n = 9) in a placebo-controlled randomized design. IHE (7:3 min hypoxia to normoxia) involved 90-min sessions for 10 days, with SaO2 clamped at ∼80%. Prior to, and 2 days after the intervention, a 20TT was performed. During the final minute of the 20TT, in the IHE group only, muscle oxyhemoglobin (oxy-Hb) was elevated (mean ± 95% confidence interval 1.3 ± 1.2 ΔµM, p = 0.04), whereas cerebral oxy-Hb was reduced (–1.9% ± 1.0%, p < 0.01) post intervention compared with baseline. The 20TT performance was unchanged between groups (p = 0.7). In the IHE group, SaO2 was higher (1.0 ± 0.7Δ%, p = 0.006) and end-tidal PCO2 was lower (–1.2 ± 0.1 mm Hg, p = 0.01) during the final stage of the 20TT post intervention compared with baseline. In summary, reductions in muscle oxy-Hb and systemic SaO2 occurring at exercise intensities close to maximal at the end of a 20TT were offset by IHE, although this was not translated into improved performance.
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Jenkins, Dorothea D., Hunter G. Moss, Truman R. Brown, Milad Yazdani, Sudhin Thayyil, Paolo Montaldo, Maximo Vento et al. „NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes“. Antioxidants 10, Nr. 9 (25.08.2021): 1344. http://dx.doi.org/10.3390/antiox10091344.
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N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.
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Elgogary, Amira, Qingguo Xu, Brad Poore, Jesse Alt, Sarah C. Zimmermann, Liang Zhao, Jie Fu et al. „Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer“. Proceedings of the National Academy of Sciences 113, Nr. 36 (24.08.2016): E5328—E5336. http://dx.doi.org/10.1073/pnas.1611406113.
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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.
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Zhang, Shuai, Brittany Bolduc Lachance, Bilal Moiz und Xiaofeng Jia. „Optimizing Stem Cell Therapy after Ischemic Brain Injury“. Journal of Stroke 22, Nr. 3 (30.09.2020): 286–305. http://dx.doi.org/10.5853/jos.2019.03048.
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Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.
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Saini, Deepak Kumar, Vandana Malhotra, Deepanwita Dey, Neha Pant, Taposh K. Das und Jaya Sivaswami Tyagi. „DevR–DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR“. Microbiology 150, Nr. 4 (01.04.2004): 865–75. http://dx.doi.org/10.1099/mic.0.26218-0.
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Two-component systems play a central role in the adaptation of pathogenic bacteria to the environment prevailing within host tissues. The genes encoding the response regulator DevR (Rv3133c/DosR) and the cytoplasmic portion (DevS201) of the histidine kinase DevS (Rv3132c/DosS), a putative two-component system of Mycobacterium tuberculosis, were cloned and the protein products were overexpressed, purified and refolded as N-terminally His6-tagged proteins from Escherichia coli. DevS201 underwent autophosphorylation and participated in rapid phosphotransfer to DevR in a Mg2+-dependent manner. Chemical stability analysis and site-directed mutagenesis implicated the highly conserved residues His395 and Asp54 as the sites of phosphorylation in DevS and DevR, respectively. Mutations in Asp8 and Asp9 residues, postulated to form the acidic Mg2+-binding pocket, and the invariant Lys104 of DevR, abrogated phosphoryl transfer from DevS201 to DevR. DevR–DevS was thus established as a typical two-component regulatory system based on His-to-Asp phosphoryl transfer. Expression of the Rv3134c–devR–devS operon was induced at the RNA level in hypoxic cultures of M. tuberculosis H37Rv and was associated with an increase in the level of DevR protein. However, in a devR mutant strain expressing the N-terminal domain of DevR, induction was observed at the level of RNA expression but not at that of protein. DevS was translated independently of DevR and induction of devS transcripts was not associated with an increase in protein level in either wild-type or mutant strains, reflecting differential regulation of this locus during hypoxia.
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Theurich, S., HJ Becker, K. Wennhold, H. Schlösser, F. Marbach, M. Garcia-Marquez, A. Shimabukuro-Vornhagen, J. Schreml und M. von Bergwelt-Baildon. „P03.16 Functional defects in B-cells of patients with von-Hippel-Lindau Syndrome“. Journal for ImmunoTherapy of Cancer 8, Suppl 2 (Oktober 2020): A29.1—A29. http://dx.doi.org/10.1136/jitc-2020-itoc7.55.
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Von-Hippel-Lindau (VHL)-disease is an inherited cancer syndrome characterized by a variety of benign and malignant tumors, which develop upon mutation of the second allele of the VHL-tumor suppressor gene. The VHL-protein (pVHL) regulates hypoxia-induced transcription factors (Hif) and by this plays a central role for metabolic cellular adaptations to hypoxic conditions. VHL/Hif regulation plays a well-established role in the development and function of immune cells and already VHL-haploinsufficiency can alter gene expression patterns. In contrast, little is known about primary immune cell functions in VHL-patients. In this study, we analyzed the functional capacity of CD40-stimulated B-cells to act as antigen-presenting cells. We confirmed mono-allelic VHL-gene mutations in B-cells from thirteen VHL-patients and found that their response to CD40-stimulation was significantly reduced. On a functional level this translated to an impaired ability to act as antigen presenting cells leading to impaired T-cell responses in vitro. Taken together, we demonstrate that VHL-haploinsufficiency deregulates B-cell functions following CD40-activation as a new aspect of VHL-syndrome. (The study was registered in the German Clinical Trial Registry (www.drks.de); ID: DRKS00012413).Disclosure InformationS. Theurich: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Verein VHL (von Hippel-Lindau) betroffener Familien e.V.. H.J. Becker: None. K. Wennhold: None. H. Schlösser: None. F. Marbach: None. M. Garcia-Marquez: None. A. Shimabukuro-Vornhagen: None. J. Schreml: None. M. von Bergwelt-Baildon: None.
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Galson, D. L., T. Tsuchiya, D. S. Tendler, L. E. Huang, Y. Ren, T. Ogura und H. F. Bunn. „The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1.“ Molecular and Cellular Biology 15, Nr. 4 (April 1995): 2135–44. http://dx.doi.org/10.1128/mcb.15.4.2135.
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The erythropoietin (Epo) gene is regulated by hypoxia-inducible cis-acting elements in the promoter and in a 3' enhancer, both of which contain consensus hexanucleotide hormone receptor response elements which are important for function. A group of 11 orphan nuclear receptors, transcribed and translated in vitro, were screened by the electrophoretic mobility shift assay. Of these, hepatic nuclear factor 4 (HNF-4), TR2-11, ROR alpha 1, and EAR3/COUP-TF1 bound specifically to the response elements in the Epo promoter and enhancer and, except for ROR alpha 1, formed DNA-protein complexes that had mobilities similar to those observed in nuclear extracts of the Epo-producing cell line Hep3B. Moreover, both anti-HNF-4 and anti-COUP antibodies were able to supershift complexes in Hep3B nuclear extracts. Like Epo, HNF-4 is expressed in kidney, liver, and Hep3B cells but not in HeLa cells. Transfection of a plasmid expressing HNF-4 into HeLa cells enabled an eightfold increase in the hypoxic induction of a luciferase reporter construct which contains the minimal Epo enhancer and Epo promoter, provided that the nuclear hormone receptor consensus DNA elements in both the promoter and the enhancer were intact. The augmentation by HNF-4 in HeLa cells could be abrogated by cotransfection with HNF-4 delta C, which retains the DNA binding domain of HNF-4 but lacks the C-terminal activation domain. Moreover, the hypoxia-induced expression of the endogenous Epo gene was significantly inhibited in Hep3B cells stably transfected with HNF-4 delta C. On the other hand, cotransfection of EAR3/COUP-TF1 and the Epo reporter either with HNF-4 into HeLa cells or alone into Hep3B cells suppressed the hypoxia induction of the Epo reporter. These electrophoretic mobility shift assay and functional experiments indicate that HNF-4 plays a critical positive role in the tissue-specific and hypoxia-inducible expression of the Epo gene, whereas the COUP family has a negative modulatory role.
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Taniguchi, Cullen M., Colleen Wu, Todd Atwood, Peter Maxim und Amato Giaccia. „Intestinal HIF-2 to protect against radiation-induced gastrointestinal syndrome.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): 10629. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10629.
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10629 Background: Gastrointestinal (GI) toxicity accounts for significant morbidity during systemic chemotherapy or abdominopelvic radiation therapy. Unfortunately, there are no effective preventative treatments. Hypoxic signaling through hypoxia-inducible factor-1 (HIF-1) and -2 (HIF-2) is critical for intestinal homeostasis during inflammatory challenges and was posited to play a role in radioprotection. Methods: We stabilized both HIF-1 and HIF-2 pharmacologically with the prolyl hydroxylase inhibitor DMOG and with transgenic mice. Male C57/Bl6 mice eight weeks of age were pretreated with saline or 8mg DMOG 16hrs and 4hrs prior to being irradiated with a single fraction of 20Gy to the abdomen using a modified TLI jig that shields the upper body of the mouse to reduce hematopoietic toxicity. After XRT, the mice got daily doses of saline or DMOG for 5 days. Results: Mice treated with DMOG had a 1.5-fold enrichment of crypt regeneration in the colon as determined by microcolony assay (13.3±3.4 vs 21.2±1.7 crypts/section, saline vs DMOG, n=10/group, p=0.005). Death from GI radiotoxicity can result from compromised epithelial integrity. We tested epithelial and barrier function by gavaging irradiated mice with FITC-dextran, which undetectable in the blood unless the GI epithelia is compromised. Treatment with DMOG decreased FITC-dextran uptake by 4-fold over controls (52.6±14.7 vs 12.4±3.4 mcg/ml, n=6/group, p=0.02). These physiologic improvements translated to improved overall survival with DMOG treatment after being exposed to 20Gy of abdominal radiation (p=0.03). To determine if the radioprotective effect of DMOG was specific to HIF-1 or HIF-2, we overexpressed stabilized HIF1 or HIF2 in the intestinal epithelia using a lox-stop-lox (LSL) system and Villin-Cre. The overexpression of HIF1 had no effect on survival (p=0.22), while mice with intestinal-specific HIF2-overexpression had significantly improved survival after receiving 20Gy of abdominal radiation (p=0.001). Conclusions: Activation of HIF-2 is sufficient to protect mice from lethal doses of abdominal radiation may provide a novel class of treatments to protect the GI epithelium from the deleterious side effects of chemotherapy and radiation.
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Kuroda, Yuko, Kei Kimura, Yuta Masuda, Arito Yamane, Hikaru Hattori, Kenichi Tahara, Ayaka Kaneko et al. „Long Non-Coding RNA MALAT1 Is Associated with the Progression of Multiple Myeloma and Induced By Cellular Stress“. Blood 126, Nr. 23 (03.12.2015): 1759. http://dx.doi.org/10.1182/blood.v126.23.1759.1759.
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Abstract Background: Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed, but not translated, non-coding RNAs capable of influencing diverse cellular processes such as proliferation, apoptosis, and motility. Long non-coding RNA (lncRNAs), which are commonly defined as transcripts >200 nt in length, have emerged as a class of key regulatory RNA. LncRNAs are deregulated in diverse human cancers and associated with disease progression; however, little is known about its role in multiple myeloma (MM). To elucidate the role of lncRNAs in MM, we studied the expression patterns of several well-known lncRNAs in the plasma cells of MM, MGUS and plasmacytoma patients and the function in MM cell lines in vitro. Moreover, to reveal the distinct lncRNA signature comprehensively, we performed next-generation sequencing-based RNA sequencing. Methods: CD138+ plasma cells from bone marrow (BM) mononuclear cells were obtained from 110 MM patients, 48 MGUS patients, 19 control subjects and 1 patient with extramedullary plasmacytoma of the liver and analyzed after obtaining informed consent from all the patients. The expression levels of lncRNAs MALAT1, ANRIL, HOTAIR, HOTTIP, and XIST were determined by a RQ-PCR analysis. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lncRNA in vitro in MM cell lines. The cell lines were then treated with bortezomib, MG132, doxorubicin and hypoxic conditions to evaluate the effects of cytotoxic stress on the lncRNA expression. This study was approved by the IRB of Gunma University Hospital in accordance with the Declaration of Helsinki. Results: A significant higher level of MALAT1 expression was observed in BM plasma cells of MM patients (4.49) compared to MGUS patients (1.51) and control subjects (0.55) (p<0.001). Strikingly, MALAT1 expression in extramedullary plasmacytoma of the liver was 140-fold higher compared with BM plasma cells obtained at the same time of sampling (433.7 vs 3.21). MALAT1 expression was higher in MM patients with t(4;14) and del 17p (10.05 vs 3.90, p=0.049; 5.22 vs 2.76, p=0.03, respectively), but no difference was observed between stages according to the International Staging System (ISS) (p=0.87). Neither the overall survival nor the progression-free survival differed between patients with high and low MALAT1 expression. ANRIL expression levels were diverse according to the patients (range, 0 to 294.3), however, the median expression was significantly higher in MM patients (p<0.001). HOTAIR and HOTTIP expression levels were not detected in most samples, and XIST expression was found only in female patient samples as expected. Interestingly, the MM cell lines KMS12PE, OPM2, KMS11 treated with bortezomib showed elevated MALAT1 expression by 4.3 -21.8 fold and ANRIL by 2.2-4.7 fold; however, this increase was not observed in bortezomib-resistant cell lines. Another proteasome inhibitor, MG132, and a low dose of the cytotoxic drug doxorubicin also elevated both lncRNAs in the cell lines. Hypoxic stress, which has been shown to induce MALAT1 in vascular cells, did not increase either lncRNA. MALAT1 knockdown by GapmeR did not affect cell proliferation. It has been shown that MALAT1 enhances cell motility of lung adenocarcinoma cells by influencing cell motility associated genes; however, the expression of previously reported affected genes, such as HMMR, CTHRC1 and ROD1, was not altered in the MALAT1 knockdown MM cell lines. Although t(4;14) was associated with a high MALAT1 expression in the patient samples, MMSET knockdown by siRNA did not change the MALAT1 expression in the cell lines, thus MMSET was not a regulator of MALAT1. RNA sequencing of MM and MGUS samples revealed a distinct lncRNA expression signature as well as protein coding genes. Conclusion: Significant upregulation of lncRNAs MALAT1 and ANRIL might be associated with MM progression. Given that MALAT1 is associated with lung cancer metastasis, MALAT1 might be strongly associated with extramedullary plasmacytoma formation due to its high expression in liver plasmacytoma. Genotoxic and ER stress induced by therapeutic drugs might upregulate MALAT1 expression, leading to extramedullary extension, which is a recent problem in MM treatment. Determining the distinct lncRNA signature of MM is a current important issue to clarify the molecular mechanisms underlying MM progression for the development of novel therapies. Disclosures No relevant conflicts of interest to declare.
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Patel, Mira, Donna Oksenberg, Abel Silva, Andreas Betz, Brian Metcalf und Uma Sinha. „GTx011, a Novel Agent That Improves Rheological Properties Of Sickle Cell Blood By Increasing Oxygen Affinity For Hemoglobin“. Blood 122, Nr. 21 (15.11.2013): 2207. http://dx.doi.org/10.1182/blood.v122.21.2207.2207.
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Abstract Sickle cell disorder (SCD) is characterized by the presence of non-deformable red blood cells. Literature reports indicate that the T-state structure of hemoglobin (Hb) (highly correlated with the deoxy form) is responsible for the formation of HbS polymers that lead to rigid cells. We hypothesized that the likelihood of polymer formation will be reduced if sufficient HbS remains in the R-state (oxy) conformation. We have designed and synthesized a novel series of compounds that increase the O2 affinity of HbS and improve the rheological properties of SCD blood. In a novel 96-well format oxygen dissociation assay (ODA), compounds including GTx006, GTx007 and GTx011 were all more potent than 5-hydroxy furfural (5HMF), an agent being tested in clinical trials in SCD patients. After two hours of passive deoxygenation, GTx011, at an equimolar concentration to Hb, increases the O2 affinity by six-fold and drastically delays polymerization of HbS. Even at substoichiometric concentrations (GTx011:Hb= 1:3) GTx011 elicits a two-fold improvement in O2 affinity for Hb that translated to 16% more oxy-Hb relative to control (Table 1). We then analyzed the agents in a TCS Hemox analyzer using purified Hb at 25µM. At a GTx011:Hb ratio of 1:3 the oxygen affinity was improved by 15%, while at stoichiometric concentrations, the oxygen affinity was increased by 70% compared to Hb control. These biochemical assays indicated that the GTx agents were altering Hb O2 affinity and should therefore assist in maintaining the oxy conformation of Hb and prevent the formation of polymers.Table 1AssayHb in ODAWashed RBC OECWhole Blood OECViscosityunit(Δoxy state)(%Δp50)(%Δp50)(ΔcP)[Hb]3 µM1 mM1 mM1.5 mM[cmp]1 µM3 µM1 mM3 mM1 mM3 mM1.6 mM8 mM5-HMF<1<1306510470.042.4GTx006210597849711.7>2.5GTx007623697863>802.1>2.5GTx0111656768380>802.5>2.5 To test the agents in a more physiological system, oxygen equilibrium curves (OECs) were measured in washed red blood cells (RBCs) and in whole blood at 20% hematocrit (∼1 mM Hb). In washed RBCs, 5HMF, GTx006, GTx007 and GTx011 at a concentration of 1mM produced partial O2 pressures (p50) of 20, 12, 9 and 7 mm Hg, respectively (control RBCs = 30 mm Hg). To determine the effects of plasma proteins, OECs were measured in whole blood from SCD patients, giving p50s of 27, 18, 11 and 6 mm Hg compared to the control blood p50 of 30 mm Hg (agent concentration of 1 mM). Table 1 shows that 5HMF and GTx006 activities were affected by the presence of plasma proteins but GTx007 and GTx011 activities were not altered. SCD patients develop anemia due to hemolysis, which partially compensates for an increase in blood viscosity caused by the non-deformable RBCs (ssRBCs). We monitored the effect of our agents on SCD patient blood rheology, ex vivo, to determine if they were capable of decreasing the viscosity of SS blood under hypoxic conditions. We incubated whole blood from SCD patients (30% hematocrit, ∼1.5 mM Hb) with 5HMF, GTx006, GTx007 or GTx011 for 30 mins and then subjected the blood to 2 hours of hypoxia (2.4% O2). Blood viscosity was then measured in a cone-plate viscometer at shear rates ranging from 60 s-1 to 415 s-1. Of the four compounds, GTx011 showed the most pronounced improvement in rheologic measures (see Table 1), changing the viscosity from 6.46 cP (no GTx011) to 4.00 cP (equimolar GTx011). Normoxic SCD blood had a viscosity of 4.28 cP. A similar improvement in blood viscosity under physiologic conditions may be predicted to decrease the residence time of ssRBCs in hypoxic tissue, and allow for a lower level of polymerization in individual red blood cells. In addition, GTx011 has also been shown to delay polymerization and delay sickling. Thus, GTx011 has the potential to elicit a decrease in HbS polymer concentration, reducing the likelihood of forming the rigid cells that cause vaso-occlusion in SCD patients. Disclosures: Patel: Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Silva:Global Blood Therapeutics: Employment, Equity Ownership. Betz:Global Blood Therapeutics: Employment, Equity Ownership. Metcalf:Global Blood Therapeutics: Employment, Equity Ownership. Sinha:Global Blood Therapeutics: Employment, Equity Ownership.
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Speth, Jennifer M., Jonathan Hoggatt und Louis M. Pelus. „Enhanced Homing of HSPCs After Treatment with Prostaglandin E2 (PGE2) May Be An Effect of Transcriptional Regulation of CXC Chemokine Receptor 4 (CXCR4) Through Hypoxia Inducible Factor 1α (HIF1α)“. Blood 118, Nr. 21 (18.11.2011): 918. http://dx.doi.org/10.1182/blood.v118.21.918.918.
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Abstract Abstract 918 Hematopoietic stem cell (HSC) transplantation is widely used to treat a number of hematological malignancies. However, to be effective, transplanted HSCs must efficiently “home” to their supportive niches within the bone marrow. Limited HSC number and poor function are complications of transplant in some circumstances, and can lead to impaired immune function and bone marrow failure. Enhancing HSC homing is a strategy to improve stem cell transplantation outcomes. We have previously shown that treatment of mouse or human HSCs with 1μM 16–16 dimethyl PGE2 (dmPGE2) ex vivo increases their bone marrow homing efficiency and engraftment, coordinate with an increase in surface CXCR4 expression. The transcription factor Hypoxia Inducible Factor 1α (HIF1α) has been shown to up-regulate CXCR4 in certain cancer models. In addition, PGE2 has been shown to stabilize HIF1α under normoxic conditions. We hypothesized that the effects of PGE2 on CXCR4 expression and homing might result from stabilization of HIF1α and its subsequent transcriptional activity in the transplanted HSCs. Treatment of lineageneg bone marrow cells with 1μM dmPGE2 resulted in a 33 ± 8.6% increase in HIF1α protein levels over vehicle (p<0.05) measured by Western Blot analysis. In addition, treatment of HSC with the hypoxia mimetic dimethyloxallyl glycine (DMOG) also resulted in an increase in CXCR4 cell surface expression in mouse LinnegSca-1posc-kitpos (SKL) cells (11.3 ± 3.9% MFI over vehicle, p<0.05) and human CD34+ umbilical cord blood cells (20.1 ± 3.6% MFI over vehicle), which was comparable to treatment with dmPGE2. This increase in CXCR4 expression translated to a functional increase in SKL migration to SDF-1 (46.7 ± 1.5% migration compared to 35 ± 3.1% migration in vehicle, p<0.05). To determine whether the effects of PGE2 on CXCR4 were due effects on HIF1 transcriptional activity, we employed two mouse hepatoma cell lines (ARNT- and ARNT+). These cells express detectable levels of CXCR4 as well as all four of the PGE2 G-protein coupled receptors (EP1-4). However the ARNT- cell line lacks the HIF nuclear translocator, and thus lacks HIF1 transcriptional activity. While ARNT+ cells showed the characteristic increase in CXCR4 cell surface protein (91.3 ± 28.7%) and mRNA (5.69-fold increase) after treatment with 1μM dmPGE2, ARNT- cells failed to show a similar up-regulation of CXCR4 protein (15 ± 6.1% increase) and mRNA (0.44-fold increase) after PGE2 treatment. These data suggest that HIF1 transcriptional activity is necessary for PGE2-mediated CXCR4 regulation. To determine whether HIF1α stabilization has similar effects on HSC function after transplant, in vivo homing studies were performed. Pulse-treatment of mouse SKL cells with 5μM DMOG ex vivo for 1 hour resulted in a 2.9-fold increase in homing (p<0.005), compared to a 2.5-fold increase for cells treated with dmPGE2. Treatment of donor cells with the CXCR4 antagonist AMD3100 resulted in a statistically significant reduction in SKL homing (74.8 ± 9%, p<0.05), indicating that DMOG's positive effects on homing are mainly due to CXCR4 up-regulation and are similar to effects seen after dmPGE2 treatment. These data suggest the effects of PGE2 on CXCR4 expression are at least partially due to the stabilization of HIF1α. Due to the importance of HIF1α and its involvement in HSC regulation, PGE2 treatment could also have effects on other pathways associated with the hypoxic response mediated through HIF1α that could be targeted to modulate HSC function. Further studies could potentially identify more specific targets to improve the efficacy of HSCs after transplant. Disclosures: Hoggatt: Fate Therapeutics: Consultancy. Pelus:Fate Therapeutics: Consultancy.
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Simonetti, Giorgia, Samantha Bruno, Carmine Onofrillo, Cristina Papayannidis, Giovanni Marconi, Michele Cavo, Lorenzo Montanaro und Giovanni Martinelli. „Alternative Overexpression of NRF2 or MYC Defines a Subgroup of Poor Prognosis Acute Myeloid Leukemia and Suggests a Novel Therapeutic Strategy By Combined Bromodomain Inhibition and Forced NRF2 Pathway Activation“. Blood 132, Supplement 1 (29.11.2018): 2639. http://dx.doi.org/10.1182/blood-2018-99-117429.
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Abstract Introduction. Inhibition of Bromodomain and extraterminal (BET) proteins was effective against different acute myeloid leukemia (AML) subtypes in preclinical studies (Dawson et al. Nature 2011; Zuber et al. Nature 2011; Dawson et al. Leukemia 2013; Chen et al. Cancer Cell 2014; Gröschel et al. Cell 2014; Zhao et al. Cell Reports 2016). However, the drug had limited clinical activity, suggesting the need of ad hoc combination therapies able to target leukemia stem cells (LSCs) in their microenvironment. Hypoxia is an integral component of the bone marrow microenvironment and plays a crucial role in survival and chemoresistance of LSCs. Aims. The study aims to elucidate the consequences of BETi treatment in AML under hypoxic conditions and identify novel potential combination strategies. Methods. AML cell lines (OCI-AML3: NPM1- and DNMT3A-mutated, Kasumi-1: t(8;21), HL60: MYC-amplified, MOLM-13, NOMO-1: MLL-driven, KG-1: TP53-mutated) were treated with the BET inhibitor (i) GSK1215101A (250/500 nM, 48h) or the NRF2 activator omaveloxolone (NRF2a, 0.2-1 mM, 48h) and with the drug combination (72h) at 1% or 20% O2 concentration. Cell viability, apoptosis and cell cycle were evaluated by trypan blue dye exclusion assay, AnnexinV and PI staining, respectively. Gene expression profiling (HTA2.0, Affymetrix) was carried out on actively translated mRNAs isolated by polysome profiling after 16h of BETi treatment and on 61 primary AML. The TCGA AML dataset was analyzed on the cBioPortal. Gene expression correlation and enrichment analysis were performed by Pearson coefficient and GSEA, respectively. Kaplan-Meier survival curves were compared by Logrank test. Glutathione was quantified by mass spectrometry (Metabolon). Results. BETi induced a dose-dependent reduction of cell viability in AML cells lines under hypoxia (25%-65% decrease at 500 nM) except for HL-60. Under the same conditions, the treatment caused a significant arrest in the G0/G1 phase of the cell cycle in OCI-AML3, Kasumi-1, HL-60 and KG-1 models (p<0.05) and induction of apoptosis in NOMO-1 and Kasumi-1 (40% and 50% AnnexinV+ cells, respectively, p<0.05). BETi reduced the translational rate of Kasumi-1 and OCI-AML3 cells, as determined by a decrease of disome-polysome peaks height. The treatment exacerbated hypoxia-mediated MYC suppression and associated with downregulation of a MYC signature at translational level. Moreover, it induced upregulation of the NRF2 regulator ARNT (p=0.02) and the NRF2 targets CAT, EPHX1, FTH1, GSTM1, MGST1, PRDX1 (p<0.05) under normoxia and/or hypoxia, with reduced KEAP1 mRNA and protein specifically at 1% O2 (p=0.01). These results suggest stabilization of NRF2 protein and activation of the pathway, as strengthened by increased levels of reduced and oxidized glutathione in OCI-AML3 cells (p<0.01). Based on this alternative activation of MYC and NRF2 pathway in AML, we analyzed gene expression and mutation in non-M3 AML from an internal cohort and the TCGA dataset. Upregulation of NRF2 expression and deregulation of MYC (overexpression/driver mutation) occurred in 4% and 9% of cases, respectively (independent of genomic amplification), with mutual exclusivity and an inverse correlation (p=0.03). MYC or NRF2 alterations defined a subgroup of patients with poor overall survival (10 vs. 18.1 months, p=0.04) and progression-free survival (7.2 vs. 17 months, p=0.0006). We then asked whether antioxidant gene expression was a defense response under BETi pressure. However, pharmacological inhibition of NRF2 or glutathione biosynthesis failed to potentiate the anti-leukemic effects of BETi. Conversely, activation of NRF2 pathway, which is effective as single agent on AML cells, potentiates the effects of BETi treatment in non-M3 AML, with reduced cell viability and increased apoptosis. Conclusions. BET protein activity drives alternative NRF2 or MYC overexpression in AML, which defines a subgroup of patients with poor prognosis. NRF2 activation is finely tuned in AML, as both inhibition and activation of the pathway induce cell death. However, NRF2 activation specifically potentiates BETi treatment under hypoxia and normoxia, suggesting a novel combination therapy against AML LSCs. Supported by: EHA Non-Clinical Junior Research Fellowship, ELN, AIL, AIRC, project Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project, Fondazione del Monte BO e RA project. Figure. Figure. Disclosures Cavo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Martinelli:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy; Roche: Consultancy; Ariad/Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau.
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Poh, Christina, Ebaa Alobeidi, Joseph Tuscano, Aaron S. Rosenberg, Rasmus T. Hoeg und Brian A. Jonas. „Complications in Acute Myeloid Leukemia Inductions Prior to Count Recovery: A Feasibility Study for Outpatient Care at an Academic Center“. Blood 136, Supplement 1 (05.11.2020): 28. http://dx.doi.org/10.1182/blood-2020-136333.
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Introduction Adults with newly diagnosed acute myeloid leukemia (AML) who receive intensive remission induction typically remain hospitalized until blood count recovery due to the high risk of infection and bleeding related to pancytopenia. This usually translates into at least 4 weeks of hospitalization, which can lead to reduced quality of life, increased risk of nosocomial infections, significant resource utilization and economic burden. Previous studies conducted at academic centers with large AML populations have suggested that outpatient management following induction chemotherapy is feasible and safe with close follow-up. These studies may have limited generalizability based on exceptional outpatient resources. Thus, this practice has not been widely adopted. To assess the feasibility of early patient discharge at our academic center which provides care for a smaller AML population, where we have a 6-days per week infusion center and hospitalize all AML patients undergoing induction until count recovery, we conducted a retrospective analysis of complications prior to blood count recovery in this patient population. Methods We identified patients ≥18 years with newly diagnosed non-APL AML admitted to the University of California, Davis Medical Center from 1/1/14 to 1/1/19 who received induction chemotherapy with cytarabine/daunorubicin (7+3) or a regimen of similar intensity with first interim bone marrow biopsy showing hypocellularity with <5% blasts. Endpoints included the rate of complete remission, infectious and hemorrhagic complications, transfusions, ICU transfers and death. We grouped timing of complications as those observed prior to and on or after day 15 of induction therapy until discharge. Patients who received a second induction regimen were censored at time of the start of the second regimen. Results Overall, 50 patients were identified; 42 (84%) received 7+3, 3 (6%) received FLAG and 5 (10%) received liposomal daunorubicin-cytarabine induction. Median age was 56 (range 25-81) years. ELN 2017 favorable, intermediate and adverse risk disease was observed in 18 (36%), 20 (40%) and 12 (24%) patients, respectively. Forty-nine (98%) patients with a negative interim marrow achieved a complete remission with first induction therapy. Forty-five (90%) patients had infectious complications at any time (Table 1), with 34 (68%) having infectious complications occurring prior to day 15 of induction. All patients with culture negative neutropenic fever prior to day 15 of induction as their only infectious complication had no further infectious complications throughout hospitalization although all received IV antibiotics until count recovery. Ten (20%) patients had hemorrhagic complications at any time (Table 1), with 9 (18%) having hemorrhagic complications occurring between day 15 of induction and discharge. Median platelet transfusion volume between days 15-21 and 22-discharge was 3.5 (range 1-18) and 0 (range 0-15) units, respectively. Three (6%) patients required ICU transfer. All ICU transfers occurred after day 14 of induction. One patient had hypoxic respiratory failure on admission and required transfer back to the ICU. Death prior to marrow recovery was observed in 1 patient (2%) due to subdural hemorrhage. Conclusion Intensive remission induction in hospitalized patients with newly diagnosed AML is associated with good efficacy and safety outcomes for patients with blast clearance on interim bone marrow biopsy. Although the rate of infectious complications was high, the majority debuted early during hospitalization and the rate of ICU transfers was low. All patients with culture negative neutropenic fever prior to day 15 of induction as their sole infectious complication who were treated with IV antibiotics had no further infectious complications throughout hospitalization. Hemorrhagic complications more commonly occurred later during hospitalization, although platelet transfusion requirements were manageable after day 15 of induction. These data suggest that at our institution, select patients receiving intensive remission induction and without infectious complications could be considered for early discharge and close outpatient follow-up after interim bone marrow biopsy showing hypoplasia. A prospective early discharge study to confirm these findings is being developed. Disclosures Poh: Acrotech: Honoraria. Tuscano:Spectrum: Research Funding; Novartis: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria. Rosenberg:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Jonas:Forma: Research Funding; F. Hoffmann-La Roche: Research Funding; Daiichi Sankyo: Research Funding; AROG: Research Funding; Accelerated Medical Diagnostics: Research Funding; Forty Seven: Research Funding; Jazz: Consultancy, Research Funding; Sigma Tau: Research Funding; Hanmi: Research Funding; Genentech/Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Treadwell: Consultancy; Tolero: Consultancy; Takeda: Consultancy; Pfizer: Research Funding; LP Therapeutics: Research Funding; Incyte: Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding.
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Arvindam, Upasana Sunil, Phillipa Kennedy, Brianna Ettestad, Peter Hinderlie, Gwen Phung, James Lim, Jeff Miller und Martin Felices. „675 Oxygen concentration alters natural killer cell phenotype and function in the solid tumor microenvironment“. Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A713—A714. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0675.
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BackgroundNatural Killer (NK) cells can eliminate cancer cells through the release of cytotoxic granules triggered by interactions with natural ligands or through antibody-dependent cellular cytotoxicity (ADCC).1–3 NK cell-based treatments have had therapeutic success for hematological malignancies but strategies to treat solid tumors have been limited due to immunosuppression within the tumor microenvironment (TME).4–6 An important and understudied aspect of NK cell immunosuppression is the low oxygen (hypoxia) environment created by proliferating tumor cells. We used the novel AVATAR incubator system to model oxygen levels of three key tissues that NK cells inhabit in vivo: the peripheral blood (12% O2), the bone marrow (5% O2 ) and the TME (1% O2).MethodsNK cells were incubated in the AVATAR incubators for 24 hours, 72 hours and 7 days. We conducted a mass cytometry (CyTOF) analysis to assess phenotype, flow cytometry-based assays to assess proliferation and an IncuCyte machine and immunofluorescent imaging to measure cytotoxicity of NK cells incubated at different oxygen conditions. We evaluated NK cell metabolism using Seahorse assays, gene expression using RNA-Seq and are in the process of evaluating epigenetic regulation using ATAC-Seq.ResultsNK cells from the 1% O2 condition express fewer activating receptors (CD16, NKG2D, Nkp30, Nkp46, DNAM-1) and less perforin and granzyme than NK cells from the higher oxygen conditions (figure 1). NK cells in the 1% O2 condition also have decreased aggregation of perforin and granzyme granules at the immune synapse. This translates to reduced natural cytotoxicity and ADCC responses against tumor targets (figure 2). We also observe a sharp decrease in proliferation in the NK cells at 1% O2 (figure 3). This is partly due to an increase in CISH gene expression that makes the cells less responsive to cytokine stimulation.7 The RNA-Seq analysis revealed that NK cell metabolism closely resembles cancer cell metabolism under hypoxic conditions, specifically an increased expression of genes related to glycolysis, amino acid synthesis and central carbon metabolism. This change in metabolism was confirmed using Seahorse assays. We also observed changes in genes related to epigenetic regulation specifically, increases in histone demethylases and decreases in DNA methyltransferases (figure 4).Abstract 675 Figure 1Oxygen concentration alters NK cell phenotype300,000 enriched NK cells were incubated for 24 hrs, 72 hrs and 7 days at noted incubator conditions with 1 ng/ml IL-15. At the end of the incubation, cells were barcoded and stained with a custom panel for CyTOF evaluation. Data is show here for CD16 (A), NKG2D (B), Perforin (C) and Granzyme B (D). N=3 (data concatenated).Abstract 675 Figure 2Oxygen concentration effects NK cell cytotoxicity300,000 enriched NK cells were plated per well in 96-well round-bottom plates with 1 ng/ml IL-15. Plates were inserted in noted incubator conditions for 24 hours, 72 hours or 7 days. At the end of the incubation period NK cells were counted and plated at a 2:1 E:T ratio with fluorescently labeled K562 targets or fluorescently labeled labeled Raji targets + Rituximab (10 ug/ml) and cells were imaged every 30 minutes. Data is shown here for K562 targets (A) and raji targets (B) at the 7 day timepoint. Representative of six separate experiments.Abstract 675 Figure 3Oxygen concentration impacts NK cell proliferation300,000 PMBCs were CellTrace labeled and plated per well in 96-well round-bottom plates with noted treatments. The NK cells were incubated under noted incubator conditions for 7 days. At the end of 7 days, LiveDead dye was used to assess viability (A), while proliferation was assessed by evaluating CellTrace dye dilution on gated (CD56+CD3-) NK cells (B). (N=6)Abstract 675 Figure 4RNA-Seq reveals changes in gene expressionAn RNA-Seq analysis was performed on enriched NK cells incubated in noted oxygen and pressure concentrations for 24 hours, 72 hours or 7 days. A heat map of epigenetic regulation genes (A) and glycolysis genes (B) are shown for the day 7 timepoint. (N=4)ConclusionsThese results indicate that NK cells who enter the solid TME are fundamentally different than those in the bone marrow or the blood stream. Overall, the insights gained from these experiments can help overcome hypoxia induced immune suppression in the tumor microenvironment and improve NK cell-based immunotherapy for solid tumors.AcknowledgementsWe thank XCell biosciences for providing us with the AVATAR incubators used for these experimentsTrial RegistrationN/AEthics ApprovalN/AConsentN/AReferencesVivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9(5):503–10.Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008;27(45):5932–43.Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 2006;6(12):940–52.Miller JS, Soignier Y, Panoskaltsis-mortari A, Mcnearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005;105(8):3051–8.Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 2018;131(23):2515–2527.Björklund AT, Carlsten M, Sohlberg E, Liu LL, Clancy T, Karimi M, et al. Complete remission with reduction of high-risk clones following haploidentical NK-Cell therapy against MDS and AML. Clin Cancer Res 2018;24(8):1834–1844.Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, et al. CIS is a potent checkpoint in NK cell–mediated tumor immunity. Nat Immunol 2016;17(7):816–24.
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Falcon, Jessica M., Dylan Chirman, Alyssa Veneziale, Justin Morman, Katherine Bolten, Shital Kandel, William Querido, Theresa Freeman und Nancy Pleshko. „DMOG Negatively Impacts Tissue Engineered Cartilage Development“. CARTILAGE, 26.10.2020, 194760352096706. http://dx.doi.org/10.1177/1947603520967060.
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Objective Articular cartilage exists in a hypoxic environment, which motivates the use of hypoxia-simulating chemical agents to improve matrix production in cartilage tissue engineering. The aim of this study was to investigate whether dimethyloxalylglycine (DMOG), a HIF-1α stabilizer, would improve matrix production in 3-dimensional (3D) porcine synovial-derived mesenchymal stem cell (SYN-MSC) co-culture with chondrocytes. Design Pellet cultures and scaffold-based engineered cartilage were grown in vitro to determine the impact of chemically simulated hypoxia on 2 types of 3D cell culture. DMOG-treated groups were exposed to DMOG from day 14 to day 21 and grown up to 6 weeks with n = 3 per condition and time point. Results The addition of DMOG resulted in HIF-1α stabilization in the exterior of the engineered constructs, which resulted in increased regional type II collagen deposition, but the stabilization did not translate to overall increased extracellular matrix deposition. There was no increase in HIF-1α stabilization in the pellet cultures. DMOG treatment also negatively affected the mechanical competency of the engineered cartilage. Conclusions Despite previous studies that demonstrated the efficacy of DMOG, here, short-term treatment with DMOG did not have a uniformly positive impact on the chondrogenic capacity of SYN-MSCs in either pellet culture or in scaffold-based engineered cartilage, as evidenced by reduced matrix production. Such 3D constructs generally have a naturally occurring hypoxic center, which allows for the stabilization of HIF-1α in the interior tissue. Thus, short-term addition of DMOG may not further improve this in cartilage tissue engineered constructs.
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Abdulmalik, Osheiza, Piyusha P. Pagare, Boshi Huang, Guoyan G. Xu, Mohini S. Ghatge, Xiaomeng Xu, Qiukan Chen et al. „VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions“. Scientific Reports 10, Nr. 1 (20.11.2020). http://dx.doi.org/10.1038/s41598-020-77171-2.
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AbstractSickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action—as elucidated through crystallographic and biological studies—is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate.
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Hantelys, Fransky, Anne-Claire Godet, Florian David, Florence Tatin, Edith Renaud-Gabardos, Françoise Pujol, Leila H. Diallo et al. „Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation in early hypoxia“. eLife 8 (09.12.2019). http://dx.doi.org/10.7554/elife.50094.
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Hypoxia, a major inducer of angiogenesis, triggers major changes in gene expression at the transcriptional level. Furthermore, under hypoxia, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here, we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) that is able to bind RNA and to activate the FGF1 IRES in hypoxia, but which tends to inhibit several IRESs in normoxia. VASH1 depletion has a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process triggering new vessel formation in ischemic heart.
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Ray, Suman Kumar, und Sukhes Mukherjee. „Imitating Hypoxia and Tumor Microenvironment with Immune Evasion by Employing Three Dimensional in vitro Cellular Models: Impressive Tool in Drug Discovery“. Recent Patents on Anti-Cancer Drug Discovery 16 (28.07.2021). http://dx.doi.org/10.2174/1574892816666210728115605.
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: The heterogeneous tumor microenvironment is exceptionally perplexing and not wholly comprehended. Different multifaceted alignments lead to the generation of oxygen destitute situations within the tumor niche that modulate numerous intrinsic tumor microenvironments. Disentangling these communications is vital for scheming practical therapeutic approaches that can successfully decrease tumor allied chemotherapy resistance by utilizing the innate capability of the immune system. Several research groups have concerned with a protruding role for oxygen metabolism along with hypoxia in the immunity of healthy tissue. Hypoxia in addition to hypoxia-inducible factors (HIFs) in the tumor microenvironment plays an important part in tumor progression and endurance. Although numerous hypoxia-focused therapies have shown promising outcomes both in vitro and in vivo these outcomes have not effectively translated into clinical preliminaries. Distinctive cell culture techniques have utilized as an in vitro model for tumor niche along with tumor microenvironment and proficient in more precisely recreating tumor genomic profiles as well as envisaging therapeutic response. To study the dynamics of tumor immune evasion, three-dimensional (3D) cell cultures are more physiologically important to the hypoxic tumor microenvironment. Recent research has revealed new information and insights into our fundamental understanding of immune systems, as well as novel results that have been established as potential therapeutic targets. There are a lot of patented 3D cell culture techniques which will be highlighted in this review. At present notable 3D cell culture procedures in the hypoxic tumor microenvironment, discourse open doors to accommodate both drug repurposing, advancement, and divulgence of new medications and will deliberate the 3D cell culture methods into standard prescription disclosure especially in the field of cancer biology which will be discussing here.
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Fernandez-Gonzalo, Rodrigo, Adam C. McDonnell, Elizabeth J. Simpson, Ian A. Macdonald, Eric Rullman und Igor B. Mekjavic. „Substantial and Reproducible Individual Variability in Skeletal Muscle Outcomes in the Cross-Over Designed Planica Bed Rest Program“. Frontiers in Physiology 12 (16.07.2021). http://dx.doi.org/10.3389/fphys.2021.676501.
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To evaluate the individual responses in skeletal muscle outcomes following bed rest, data from three studies (21-day PlanHab; 10-day FemHab and LunHab) were combined. Subjects (n = 35) participated in three cross-over campaigns within each study: normoxic (NBR) and hypoxic bed rest (HBR), and hypoxic ambulation (HAMB; used as control). Individual variability (SDIR) was investigated as √(SDExp2–SDCon2), where SDExp and SDCon are the standard deviations of the change score (i.e., post – pre) in the experimental (NBR and HBR) and the control (HAMB) groups, respectively. Repeatability and moderators of the individual variability were explored. Significant SDIR was detected for knee extension torque, and thigh and calf muscle area, which translated into an individual response ranging from 3 to −17% for knee extension torque, −2 to −12% for calf muscle area, and −1 to −8% for thigh muscle area. Strong correlations were found for changes in NBR vs. HBR (i.e., repeatability) in thigh and calf muscle area (r = 0.65–0.75, P < 0.0001). Change-scores in knee extension torque, and thigh and calf muscle area strongly correlated with baseline values (P < 0.001; r between −0.5 and −0.9). Orthogonal partial least squares regression analysis explored if changes in the investigated variables could predict calf muscle area alterations. This analysis indicated that 43% of the variance in calf muscle area could be attributed to changes in all of the other variables. This is the first study using a validated methodology to report clinically relevant individual variability after bed rest in knee extension torque, calf muscle area, and (to a lower extent) thigh muscle area. Baseline values emerged as a moderator of the individual response, and a global bed rest signature served as a moderately strong predictor of the individual variation in calf muscle area alterations.
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Zhou, Dan, Tsering Stobdan, DeeAnn Visk, Jin Xue und Gabriel G. Haddad. „Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells in Drosophila melanogaster“. G3 Genes|Genomes|Genetics 11, Nr. 2 (28.01.2021). http://dx.doi.org/10.1093/g3journal/jkab038.
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Abstract Hypoxia is a critical pathological element in many human diseases, including ischemic stroke, myocardial infarction, and solid tumors. Of particular significance and interest of ours are the cellular and molecular mechanisms that underlie susceptibility or tolerance to low O2. Previous studies have demonstrated that Notch signaling pathway regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanisms mediating Notch-conferred hypoxia tolerance are largely unknown. In this study, we delineate the evolutionarily conserved mechanisms underlying this hypoxia tolerant phenotype. We determined the role of a group of conserved genes that were obtained from a comparative genomic analysis of hypoxia-tolerant D.melanogaster populations and human highlanders living at the high-altitude regions of the world (Tibetans, Ethiopians, and Andeans). We developed a novel dual-UAS/Gal4 system that allows us to activate Notch signaling in the Eaat1-positive glial cells, which remarkably enhances hypoxia tolerance in D.melanogaster, and, simultaneously, knock down a candidate gene in the same set of glial cells. Using this system, we discovered that the interactions between Notch signaling and bnl (fibroblast growth factor), croc (forkhead transcription factor C), or Mkk4 (mitogen-activated protein kinase kinase 4) are important for hypoxia tolerance, at least in part, through regulating neuronal development and survival under hypoxic conditions. Becausethese genetic mechanisms are evolutionarily conserved, this group of genes may serve as novel targets for developing therapeutic strategies and have a strong potential to be translated to humans to treat/prevent hypoxia-related diseases.
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Durrani, Ilhaam Ayaz, Attya Bhatti und Peter John. „The prognostic outcome of ‘type 2 diabetes mellitus and breast cancer’ association pivots on hypoxia-hyperglycemia axis“. Cancer Cell International 21, Nr. 1 (05.07.2021). http://dx.doi.org/10.1186/s12935-021-02040-5.
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AbstractType 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.
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Sandoval Karamian, Amanda G., und Courtney J. Wusthoff. „How Helpful Is aEEG? Context and User Experience Matter“. American Journal of Perinatology, 15.12.2020. http://dx.doi.org/10.1055/s-0040-1721711.
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Objective The aim of the study is to model amplitude-integrated electroencephalography (aEEG) utility to diagnose seizures in common clinical scenarios. Study Design Using reported neonatal seizure prevalence and aEEG sensitivities and specificities, likelihood ratios (LRs) and post-test probabilities were calculated to quantify aEEG utility to diagnose seizures in three typical clinical scenarios. Results Prevalence data supported pretest probabilities for neonatal seizures of 0.4 in neonatal hypoxic ischemic encephalopathy (HIE), 0.27 in bacterial meningitis, and 0.05 in extreme prematurity. Reported sensitivity of 85% and specificity of 90% for seizures with expert aEEG interpretation yielded a positive likelihood ratio (LR+) of 8.7 and a negative likelihood ratio (LR−) of 0.17. Reported sensitivity of 65% and specificity of 70% with intermediate interpretation yielded LR+ 2.17 and LR− 0.5. Reported sensitivity of 40% and sensitivity of 50% with inexperienced interpretation gave LR+ 0.8 and LR− 1.2. These translate the ability to move pretest to post-test probability highly dependent on user expertise. For HIE, a pretest probability of seizure of 0.4 moves to a post-test probability of 0.85 when aEEG is positive for seizures by expert interpretation, and down to 0.1 when aEEG is negative. In contrast, no useful information was gained between pretest and post-test probability by aEEG interpreted as negative or positive for seizure at the inexperienced user level. Similarly, in the models of meningitis or extreme prematurity, incremental information gained from aEEG ranged widely based on interpreter experience. Conclusion aEEG is most useful to screen for neonatal seizures when used in conditions with high seizure prevalence, and when interpretation has a sensitivity and specificity as reported for expert users. In contrast, aEEG can become negligible in providing meaningful clinical information when applied in conditions having lower seizure prevalence or when interpretation has low accuracy. Appropriate patient selection and high quality interpretation are essential for aEEG utility in neonatal seizure detection. Key Points
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Singh, Aditya A., Akash Kharwar und Manoj P. Dandekar. „A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies“. Current Neuropharmacology 19 (07.09.2021). http://dx.doi.org/10.2174/1570159x19666210907092928.
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Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.