Academic literature on the topic 'Cel Hypoxia'
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Journal articles on the topic "Cel Hypoxia"
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Locke, Frederick L., Justin Chou, Saran Vardhanabhuti, Regis Perbost, Peter Dreger, Brian T. Hill, Catherine Lee, et al. "Association of pretreatment (preTx) tumor characteristics and clinical outcomes following second-line (2L) axicabtagene ciloleucel (axi-cel) versus standard of care (SOC) in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 7565. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.7565.
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7565 Background: The Phase 3 randomized ZUMA-7 trial in 2L R/R LBCL showed axi-cel superiority to SOC (salvage chemotherapy and HDT-ASCT) in event-free survival (EFS; hazard ratio [HR], 0.398; P<.0001; Locke et al. N Eng J Med. 2021). We report results of exploratory analyses of tumor characteristics, including preTx tumor burden (TB), tissue hypoxia-related lactate dehydrogenase (LDH) level, and tumor microenvironment (TME). Methods: TB was calculated as the sum of product diameters of ≤6 reference lesions (Locke et al. Blood Adv. 2020). Serum LDH was assessed. PreTx tumor samples were assessed for RNA expression by the NanoString IO 360™ panel and prespecified immune contexture indexes related to T-cell involvement (Immunosign 15 [IS15] and 21 [IS21]; Galon et al. ASCO 2020. #3022). ZUMA-1 data were used for comparison to 3L R/R LBCL. CD19 protein expression was assessed by immunohistochemistry (H-score). Associations between biomarkers and clinical outcomes were assessed using descriptive statistics ( P<.05 was significant). Results: Axi-cel EFS was superior to SOC for both high and low TB (HR, 0.29 and 0.49, respectively; P<.001 for both) and elevated and nonelevated LDH (HR, 0.32 and 0.5, respectively; P<.001 for both). EFS in axi-cel pts was not associated with preTx TB (HR, 1.01 [95% CI, 0.88-1.16]; P=.89) or LDH (HR, 0.98 [95% CI, 0.74-1.29]; P=.86), but was worse in SOC pts with higher preTx TB (HR, 1.17 [95% CI, 1.03-1.32]; P=.01) or higher LDH (HR, 1.29 [95% CI, 1.02-1.63], P =.03). PreTx TB was lower in SOC pts with ongoing response vs nonresponders and pts who relapsed ( P=.07), but not in axi-cel pts ( P=.99). Non-germinal center B-cell (GCB) cell-of-origin subtypes is a poor prognostic factor for EFS in SOC (EFS was significantly worse in SOC pts with non-GCB vs GCB; HR, 1.82 [95% CI, 1.12-2.96]; P=.02) but not in axi-cel. In IO360 analysis, gene expression of B-cell lineage antigens (CD19, CD20, BCMA) and markers highly expressed by tumor cells (CD45RA, IRF8, BTLA) positively associated with objective and durable responses to axi-cel. While axi-cel remained superior to SOC with high ( > median) or low CD19 expression level, the probability of an ongoing response increased with a higher CD19 H-score. PreTx TME IS15 and IS21 scores were generally higher in 2L vs 3L. Conclusions: Axi-cel was superior to SOC in all subgroup analyses, including higher TB and LDH. Durable responses with axi-cel were greatest in tumors with prominent B-cell features, but were superior to SOC regardless of these features. Axi-cel intervention in 2L is supported by durable response rates not impacted by high TB, as seen in 3L axi-cel or 2L SOC. Higher preTx immune involvement in 2L vs 3L tumors suggests high TB may be overcome with axi-cel in patients with a more favorable immune contexture. Clinical trial information: NCT03391466.
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Locke, Frederick L., Justin Chou, Saran Vardhanabhuti, Regis Perbost, Peter Dreger, Brian T. Hill, Catherine Lee, et al. "Association of pretreatment (preTx) tumor characteristics and clinical outcomes following second-line (2L) axicabtagene ciloleucel (axi-cel) versus standard of care (SOC) in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 7565. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.7565.
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7565 Background: The Phase 3 randomized ZUMA-7 trial in 2L R/R LBCL showed axi-cel superiority to SOC (salvage chemotherapy and HDT-ASCT) in event-free survival (EFS; hazard ratio [HR], 0.398; P<.0001; Locke et al. N Eng J Med. 2021). We report results of exploratory analyses of tumor characteristics, including preTx tumor burden (TB), tissue hypoxia-related lactate dehydrogenase (LDH) level, and tumor microenvironment (TME). Methods: TB was calculated as the sum of product diameters of ≤6 reference lesions (Locke et al. Blood Adv. 2020). Serum LDH was assessed. PreTx tumor samples were assessed for RNA expression by the NanoString IO 360™ panel and prespecified immune contexture indexes related to T-cell involvement (Immunosign 15 [IS15] and 21 [IS21]; Galon et al. ASCO 2020. #3022). ZUMA-1 data were used for comparison to 3L R/R LBCL. CD19 protein expression was assessed by immunohistochemistry (H-score). Associations between biomarkers and clinical outcomes were assessed using descriptive statistics ( P<.05 was significant). Results: Axi-cel EFS was superior to SOC for both high and low TB (HR, 0.29 and 0.49, respectively; P<.001 for both) and elevated and nonelevated LDH (HR, 0.32 and 0.5, respectively; P<.001 for both). EFS in axi-cel pts was not associated with preTx TB (HR, 1.01 [95% CI, 0.88-1.16]; P=.89) or LDH (HR, 0.98 [95% CI, 0.74-1.29]; P=.86), but was worse in SOC pts with higher preTx TB (HR, 1.17 [95% CI, 1.03-1.32]; P=.01) or higher LDH (HR, 1.29 [95% CI, 1.02-1.63], P =.03). PreTx TB was lower in SOC pts with ongoing response vs nonresponders and pts who relapsed ( P=.07), but not in axi-cel pts ( P=.99). Non-germinal center B-cell (GCB) cell-of-origin subtypes is a poor prognostic factor for EFS in SOC (EFS was significantly worse in SOC pts with non-GCB vs GCB; HR, 1.82 [95% CI, 1.12-2.96]; P=.02) but not in axi-cel. In IO360 analysis, gene expression of B-cell lineage antigens (CD19, CD20, BCMA) and markers highly expressed by tumor cells (CD45RA, IRF8, BTLA) positively associated with objective and durable responses to axi-cel. While axi-cel remained superior to SOC with high ( > median) or low CD19 expression level, the probability of an ongoing response increased with a higher CD19 H-score. PreTx TME IS15 and IS21 scores were generally higher in 2L vs 3L. Conclusions: Axi-cel was superior to SOC in all subgroup analyses, including higher TB and LDH. Durable responses with axi-cel were greatest in tumors with prominent B-cell features, but were superior to SOC regardless of these features. Axi-cel intervention in 2L is supported by durable response rates not impacted by high TB, as seen in 3L axi-cel or 2L SOC. Higher preTx immune involvement in 2L vs 3L tumors suggests high TB may be overcome with axi-cel in patients with a more favorable immune contexture. Clinical trial information: NCT03391466.
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Ho, A. S., X. Huang, H. Cao, A. C. Koong, and Q. T. Le. "Detection of circulating hypoxia-regulated miR-210 in pancreatic adenocarcinoma patients." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4624. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4624.
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4624 Background: MicroRNAs (miRs) are small non-coding transcripts involved in many cellular mechanisms, including tumorigenesis. miR-210, in particular, has been shown to be induced by hypoxia, over-expressed in several different cancers, and correlated with adverse outcomes in breast cancer. Moreover, since pancreatic adenocarcinomas have been previously shown to be extremely hypoxic, we hypothesized that miR-210 may be elevated in the plasma of these patients compared to non-cancer controls. Here, we compared the circulating plasma levels of miR-210 in pancreatic cancer patients and controls using a novel miRNA extraction approach and quantitative PCR. Methods: Pretreatment EDTA plasma samples were obtained from pancreatic cancer patients and age-matched non-cancer controls. miRNA was extracted from 40ul of plasma and reverse transcribed to cDNA. A known quantity of c. elegans miR-54 was added to the sample as a normalization control. miR-210 and cel-miR-54 were then quantified using TaqMan MicroRNA Assays. The procedure was performed on the initial 11 pairs of age-matched pancreatic cancer patients and non- cancer controls, then validated with a second cohort of 12 pancreatic cancer patients and 11 controls. Results: miR-210 was reliably detected and quantified in small amounts of plasma using the approach developed in our study. There is a statistically significant four-fold increase of mir-210 expression in pancreatic cancer patients compared to normal controls (Student's t-test, p <0.0001). This difference was confirmed in the validation group (Student's t-test, p<0.05). Conclusions: Circulating miR-210 levels can be readily measured from a small quantity of plasma using a novel extraction method. Its expression is significantly higher in the blood of pancreatic cancer patients compared to controls and may potentially serve as a useful biomarker for pancreatic cancer diagnosis. No significant financial relationships to disclose.
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Douiev, Liza, Chaya Miller, Shmuel Ruppo, Hadar Benyamini, Bassam Abu-Libdeh, and Ann Saada. "Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency." Cells 10, no. 2 (February 20, 2021): 452. http://dx.doi.org/10.3390/cells10020452.
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Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of a compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF) and compared to the patient’s cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were quantified by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrated elevated COX4-2 levels in the COX4-1-deficient cells, with a concomitant HIF-1α stabilization, nuclear localization and upregulation of the hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α are upregulated also in normoxia as a compensatory mechanism in COX4-1 deficiency.
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Storti, Paola, Irma Airoldi, Marina Bolzoni, Mirca Lazzaretti, Daniela Guasco, Luca Agnelli, Eugenia Martella, et al. "Hypoxia-Inducible Factor (HIF)-1α Is a Therapeutic Target in Myeloma-Induced Angiogenesis." Blood 118, no. 21 (November 18, 2011): 3927. http://dx.doi.org/10.1182/blood.v118.21.3927.3927.
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Abstract Abstract 3927 Hypoxia-inducible factor (HIF)-1α is a critical trigger and regulator of tumor associated angiogenesis. It has been previously reported that bone marrow (BM) microenvironment is hypoxic in multiple myeloma (MM) patients and that HIF-1α is overexpressed by CD138+ MM cells and modulates the transcriptional and pro-angiogenic profiles of MM cells. The potential role of HIF-1α as a therapeutic target in MM is under investigation. To deepen this issue, in this study we explored the effect of a stable HIF-1α inhibition in MM cells on cell proliferation, survival and on MM-induced angiogenesis either in vitro or in vivo using a plasmocytoma model. Human myeloma cell lines (HMCL)s were screened for HIF-1α protein expression in normoxia condition finding that 2 out 5 HMCLs were positive (JJN3 and RPMI-8226). Anti-HIF-1α Lentivirus sh RNA pool was used for HIF-1α stable knock-out in human myeloma cell lines (HMCL)s whereas the pKLO.1 lentiviral vector was used as the empty control vector. HMCLs have been infected and selected with 0.4 ug/ml puromycin for 21 days and the selected clones screened for HIF-1α, HIF-1β, HIF-2α and HIF-3α. A selective inhibition on HIF-1α mRNA and protein expression was observed both in normoxic and hypoxic conditions. HMCLs proliferation and apoptosis were not affected by HIF-1α inhibition neither in hypoxia nor normoxia. Thereafter the transcriptional profiles on the HMCL JJN3 transduced with shRNA anti-HIF-1α (JJN3-anti-HIF-1α), as compared to those infected with the control vector pKLO.1 (JJN3-pKLO.1) have been analyzed by U133 Plus2.0 Arrays (Affymetrix ®) either in hypoxic or normoxic conditions. The raw intensity signals were extracted from CEL files and normalized using the RMA package for Bioconductor and custom GeneAnnot-based Chip Definition Files in R software. Absolute fold change higher than 1.5 was used to select differentially expressed genes. Among the genes significantly modulated (327 and 361 genes in hypoxic and normoxic condition, respectively) we found that the pro-angiogenic molecules VEGF, IL8, IL10, CCL2, CCL5, MMP9 were down-regulated in JJN3-anti-HIF-1α as compared to JJN3-pKLO.1 either in hypoxic or normoxic conditions. Microarray data were further validated by quantitative real time PCR. In line with this observation, we found that the pro-angiogenic properties of JJN3, evaluated by an in vitro angiogenesis assay (Angio-Kit, TCS), were significantly inhibited by the HIF-1α knock-out. Finally the potential involvement of HIF-1α in MM-induced angiogenesis was assessed in vivo in NOD/SCID mice in a subcutaneous model. We found that the mice which were injected subcutaneously with JJN3-anti-HIF-1α, showed a dramatic reduction of the weight and volume of the plasmocytoma mass than mice inoculated with the JJN3-pKLO.1 (P=0.0007 and P=0.012; respectively). Moreover we observed a significant reduction of the number of vessels X field stained by CD31 antigen (anti-HIF-1α vs. pKLO.1: −76%; P=0.003) and VEGF immunostaining, whereas the Ki67 index of the plasmocytoma mass only showed a slight reduction (anti-HIF-1α vs. pKLO.1: −14%, P=NS). Overall our data indicate that HIF-1α suppression in myeloma cells significantly blocks MM-induced angiogenic switch both in vitro and in vivo and consequently reduces the MM tumoral burden suggesting that HIF-1α is a potential therapeutic target in MM. Disclosures: Bolzoni: Celgene Italy: Research Funding. Giuliani:Celgene: Research Funding; Novartis: Research Funding.
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Wei, Guijie, Jianhua Chen, Ziqi Jing, Yanyi Li, Zhihui Li, Wei Zheng, Xiurui Sun, et al. "Glucose transporter 1 (GLUT1)-targeting and hypoxia-activated mitochondria-specific chemo-thermal therapy via a glycosylated poly(amido amine)/celastrol (PAMAM/Cel) complex." Journal of Colloid and Interface Science 608 (February 2022): 1355–65. http://dx.doi.org/10.1016/j.jcis.2021.10.129.
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Lee, Sohyeon, Yoonyoung Kim, and Eun Seong Lee. "Hypoxia-Responsive Azobenzene-Linked Hyaluronate Dot Particles for Photodynamic Tumor Therapy." Pharmaceutics 14, no. 5 (April 24, 2022): 928. http://dx.doi.org/10.3390/pharmaceutics14050928.
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In this study, we developed ultra-small hyaluronate dot particles that selectively release phototoxic drugs into a hypoxic tumor microenvironment. Here, the water-soluble hyaluronate dot (dHA) was covalently conjugated with 4,4′-azodianiline (Azo, as a hypoxia-sensitive linker) and Ce6 (as a photodynamic antitumor agent), producing dHA particles with cleavable Azo bond and Ce6 (dHA-Azo-Ce6). Importantly, the inactive Ce6 (self-quenched state) in the dHA-Azo-Ce6 particles was switched to the active Ce6 (dequenched state) via the Azo linker (–N=N–) cleavage in a hypoxic environment. In vitro studies using hypoxia-induced HeLa cells (treated with CoCl2) revealed that the dHA-Azo-Ce6 particle enhanced photodynamic antitumor inhibition, suggesting its potential as an antitumor drug candidate in response to tumor hypoxia.
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Shahzad, Moazzam, Muhammad Salman Faisal, Ernie Shippey, Qamar Iqbal, Laila Hashim, Clint Divine, Zahra Mahmoudjafari, et al. "Evolution in Resource Utilization for Unique Toxicities Related to Chimeric Antigen Receptor T Cell Therapy from 2017 to 2020: A Database Review." Blood 138, Supplement 1 (November 5, 2021): 4844. http://dx.doi.org/10.1182/blood-2021-154341.
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Abstract Introduction: Chimeric antigen receptor T cell therapy (CAR-T) is a novel treatment that utilizes T cells by augmenting them using vector viruses to add antigens to target cancer cells. In 2017, FDA approved CD-19 CAR-T for relapsed/refractory diffuse large B-cell lymphoma and acute lymphoblastic leukemia patients ≤ 26yr old. Unique toxicities associated with CAR-T therapy include cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity (ICANS). Lower-grade CRS and ICANS are managed with tocilizumab, an interleukin-6 antagonist, and steroids. Management of higher-grade CRS and ICANS requires intensive care unit (ICU) admission. Our understanding and management of CRS and ICANS continue to evolve. In this analysis, we conducted a retrospective review using the Vizient database® to investigate toxicity incidence and resource utilization among patients admitted for CAR-T therapy between 2017 and 2020. Methods: We used The Vizient® CDB database to analyze admissions for CAR-T infusion for patients over 18 years of age receiving FDA approved CD19 CAR-T axicabtagene ciloleucel (axi-cel) and tisangenlecleucel (tisa-cel) between 2017 to 2020. We compared patients who received CAR-T between October 2017 and March 2018 (group 1) to those who received CAR-T therapy between October 2019 and March 2020 (group 2). Due to the lack of diagnosis code for CRS or ICANS until 2021, surrogates billing codes such as fever, sepsis, dyspnea were used for CRS. In regards to ICANS, we used codes for febrile seizure, febrile convulsions, altered mental status, somnolence, and stupor. In addition, other adverse events such as weakness and nausea were also collected. Results: Eighty-one institutions had performed CAR-T in the period 2017 through 2020. The 2017-2018 period (group 1) included 215 patients, with a median age of 59 (49-68) years, while the CAR-T recipients in 2019-2020 (group 2) had 655 patients with a median age of 62 (52-69) years. Tisa-cel and Axi-cel was administered to 31% (n= 67) and 69% (n= 148) in group 1 and 26% (182) and 74% (n= 517) of group 2 patients respectively. The incidence of sepsis in group 1 was 18% vs. 13% in group 2, with an absolute difference of -5.8% (P value=0.04). Fever and dyspnea were the most common presentations of CRS present in 44.2% and 49% in group 1 and 35% and 28% in group 2, respectively. The incidence of fever decreased by 8.2% (p=0.02) in group 2 compared to group 1. The incidence of hypoxia was 24.7% vs. 20.5%, and the incidence of hypotension was 32.1% and 33.8% in groups 1 and 2, with no statistically significant difference between the two groups (p=0.64 and 0.19). The incidence of neurotoxicity decreased slightly in group 2 compared to group 1, but it was not statistically significant (P= 2723). Overall ICU utilization was 24.7 and 24.6% in both groups (p=0.9). The 30 days mortality in groups 1 and 2 was 6% vs. 3.7%. Tocilizumab utilization decreased by 20%, and dexamethasone or equivalent steroid usage decreased by 70% in group 2 compared to group 1. (Table 1) Conclusions: The incidence of CRS and ICANS among recipients of CAR-T remains high, with up to one-fourth of the patients requiring ICU, which has remained static. However, the general use of tocilizumab and steroids has decreased by 20% and 70%, respectively, possibly due to the implementation of consensus grading and operation protocols that may have increased awareness and judicious early interventions. Figure 1 Figure 1. Disclosures Mahmoudjafari: Incyte: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.
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Thompson, Alexis A., Janet L. Kwiatkowski, John B. Porter, Suradej Hongeng, Evangelia Yannaki, Andreas E. Kulozik, Martin G. Sauer, et al. "Favorable Outcomes in Pediatric Patients in the Phase 3 Hgb-207 (Northstar-2) and Hgb-212 (Northstar-3) Studies of Betibeglogene Autotemcel Gene Therapy for the Treatment of Transfusion-Dependent β-Thalassemia." Blood 136, Supplement 1 (November 5, 2020): 52–54. http://dx.doi.org/10.1182/blood-2020-135857.
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Introduction Betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy is being evaluated for the treatment of transfusion-dependent β-thalassemia (TDT). Initial positive results of beti-cel in the phase 3 studies, HGB-207 (NCT02906202; non-β0/β0 genotypes) and HGB-212 (NCT03207009; β0/β0, β0/β+ IVS-I-110 and β+ IVS-I-110/β+ IVS-I-110 genotypes), showed 10/12 adult patients achieved transfusion independence. The studies expanded enrollment to include adolescents and children. We present interim results from pediatric patients <18 yrs who received beti-cel in HGB-207 and HGB-212 as of 3 March 2020. Methods After mobilization and apheresis, autologous CD34+ cells were transduced ex vivo with BB305 lentiviral vector, containing a modified human β-globin gene to produce beti-cel drug product (DP). Patients underwent busulfan myeloablation and infusion with beti-cel and were then followed longitudinally. Transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without transfusions for ≥12 mo) was the primary endpoint in HGB-207 and a secondary endpoint in HGB-212. Transfusion reduction (≥60% reduction in transfusion volume between Month 12 to 24 versus baseline) is the primary endpoint in HGB-212. Hb levels, TI characteristics, and quality of life were secondary endpoints. Assessments of ineffective erythropoiesis were exploratory. Data presented as median (min-max). Results Twenty-four pediatric patients were treated including 13 patients <12 yrs old (207: n=8; 212: n=5) and 11 patients ≥12 to <18 yrs old (207: n=6; 212: n=5). Patient, DP, and engraftment characteristics are described in the Table. All patients achieved neutrophil engraftment. Twenty-one patients with >3 mo follow-up achieved platelet engraftment and had platelets ≥100 x109/L by Month 12; one 17-yr old patient did not have platelets ≥100 x109/L until Month 15. In HGB-207, 6/7 (86%) patients <12 yrs and 6/6 (100%) patients ≥12 to <18 yrs with >3 mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 3/4 (75%) evaluable patients <12 yrs with weighted average Hb during TI of 10.0 (9.4-10.3) g/dL. At last visit, gene therapy-derived HbAT87Q in these patients was 5.1-7.1 g/dL. In patients ≥12 to <18 yrs, all 6 patients achieved TI with weighted average Hb during TI of 11.6 (11.3-12.3) g/dL. These patients had 8.4-10.5 g/dL HbAT87Q at last visit. Myeloid:erythroid (M:E) ratio in patients <12 yrs with TI improved from 1:3.7-1:1.1 at baseline to 1:2-1.5:1 at Month 12; in patients ≥12 to <18 yrs with TI, M:E ratio improved from 1:7.3-1.6:1 at baseline to 1:2.7-1.9:1 at Month 12. Patients <18 yrs who achieved TI in HGB-207 had an improved health state today score as assessed using EQ-5D-Y from 67 (50-96) at baseline (n=7) to 92.5 (85-95) at Month 12 (n=6). In HGB-212, 3/5 (60%) patients <12 yrs and 4/4 (100%) patients ≥12 to <18 yrs with >3mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 1/2 evaluable patients <12 yrs. Weighted average Hb during TI was 10.3 g/dL and HbAT87Q was 9.2 g/dL at last visit in this patient. All 3 evaluable patients ≥12 to <18 yrs achieved TI with weighted average Hb of 9.6 (9.5-12.8) g/dL. HbAT87Q in these patients was 8.0-10.9 g/dL at last visit. The M:E ratio in the patient <12 yrs with TI improved from 1:4.7 at baseline to 1.2:1 at Month 12. In the 2 patients ≥12 to <18 yrs with baseline and Month 12 assessments, M:E ratios improved from 1:5.1 to 1:1.4 and 1:3.3 to 1:1.8. Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients aged <12 yrs in either study were febrile neutropenia (n=9), stomatitis (n=6), decreased appetite (n=4), increased alanine aminotransferase (n=3), and epistaxis (n=3); in patients ≥12 to <18 yrs, these were stomatitis (n=8), febrile neutropenia (n=3) and hypoxia (n=3). Grade 4 veno-occlusive disease occurred in 2 patients ≥12 to <18 yrs and one grade 2 event occurred in a patient <12 yrs; all cases were successfully treated with defibrotide. Neither replication-competent lentivirus, insertional oncogenesis, nor clonal dominance were observed. Summary Interim results in HGB-207 and HGB-212 show that after treatment with beti-cel, pediatric patients <18 yrs achieved transfusion independence with comparable rates as in adults, suggesting that beti-cel gene therapy represents an effective treatment option across ages. The safety profile of gene therapy with beti-cel was consistent with busulfan myeloablation. Disclosures Thompson: CRISPR/Vertex: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Kwiatkowski:Novartis: Research Funding; Agios: Consultancy; Sangamo: Research Funding; bluebird bio,Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Imara: Consultancy; BMS: Consultancy; Terumo Co: Research Funding; Celgene: Consultancy. Porter:Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; La Jolla Pharmaceuticals: Honoraria; Silence Therapeutics: Honoraria; Protagonist Therapeutics: Honoraria; BMS: Consultancy, Honoraria. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thuret:Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Lal:Insight Magnetics: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding; Agios Pharmaceuticals: Consultancy; Chiesi USA: Consultancy; La Jolla Pharmaceutical Company: Research Funding; bluebird bio, Inc.: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Liu:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters:Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Yang, B. C., and J. L. Mehta. "Alterations in pulmonary artery tone during repeated episodes of hypoxia." American Journal of Physiology-Lung Cellular and Molecular Physiology 269, no. 3 (September 1, 1995): L293—L298. http://dx.doi.org/10.1152/ajplung.1995.269.3.l293.
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To examine the basis of pulmonary constriction during chronic hypoxia, rat pulmonary artery rings were precontracted and exposed to multiple episodes of hypoxia. The first hypoxic episode resulted in a transient contraction, followed by potent relaxation, and then a slow sustained contraction. Repeated hypoxic exposure resulted in stronger initial contraction and attenuated relaxation. Prolongation of the normoxic interval between hypoxic episodes reversed the attenuation of hypoxic relaxation. Pulmonary artery rings that were deendothelialized or treated with the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester or oxyhemoglobin displayed only hypoxic relaxation without initial or late contractions and no attenuation of relaxation during repeated hypoxia. Pretreatment of rings with indomethacin or adenosine or endothelin receptor antagonists had no effect on the hypoxia-mediated alterations. Thus repetitive exposure to hypoxia results in an increase in initial contraction and a decrease in relaxation of pulmonary artery rings. Frequency of hypoxic episodes and endothelial integrity determine pulmonary tone during repeated hypoxia. However, cyclooxygenase products, adenosine, or endothelin do not play a role in hypoxia-mediated changes in rat pulmonary artery tone.
Dissertations / Theses on the topic "Cel Hypoxia"
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Ljungkvist, Anna. "Imaging the tumor microenvironment : the dynamics and modification of hypoxia." Doctoral thesis, Umeå : Univ, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-106.
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Lawrentschuk, Nathan Leo. "Hypoxia and angiogenesis in renal cell carcinoma." Connect to thesis, 2009. http://repository.unimelb.edu.au/10187/6790.
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Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans.Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16
Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated.
Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17
Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18
Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.
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Lester, Robin D. "Hypoxia activated cell signaling receptors in cancer." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3297526.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed April 28, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 114-134).
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Schioppa, Tiziana. "Effects of tumour hypoxia on cell migration." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434200.
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Cell adaptation to hypoxia requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via- angiogenesis) and metabolic adaptation (via glycolisis). During migration and invasion of normal and pathological tissues, cells may encounter different oxygen levels, due to poor or altered vascularization, and recent evidence has suggested that chemotaxis is a cell function which may be affected by oxygen availability. This thesis describes how oxygen avaibility is a determinant parameter in the setting of chemotactic responsiveness to Stromal-Derived Factor 1 (SDF-1, CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor CXCR4, in different cell types (monocytes, monocyte-derived macrophages, tumor associated macrophages, endothelial cells, cancer cells and dendritic cells) as both mRNA and protein expression, which is paralleled by increased chemotactic responsiveness to its specific ligand. Furthermore, preliminary results on dendritic cells (DC) show that hypoxia may affect their maturation (CCR7'°'/CCR5h'gh) and functions. In particular, hypoxia-derived DC do not migrate in response to the CCR7 ligand CCL 19, while they do express higher levels of pro-inflammatory cytokines (IL-12, TNF-a), as compared to normoxia-derived DC. CXCR4 induction by hypoxia is dependent on both activation of hypoxia-inducible factor 1 (HIF-la) and transcript stabilization. Our data identify the hypoxia/HIF-1/CXCR4 pathway as a relevant molecular circuit in the functional tuning of the chemokine system and provide novel insights into the mechanisms controlling cell migration in hypoxic regions, with potential relevance in the pathogenesis of human diseases, including chronic inflammatory diseases and cancer
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Ledaki, Ioanna I. "Heterogeneity of tumour response to hypoxia : carbonic anhydrase IX induction defines a subpopulation of hypoxic cells with stem cell properties and drug resistance." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:757a8e79-b20d-496c-b69b-4d6a3b7b56e3.
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Carbonic anhydrase IX (CA9) is strongly induced by hypoxia and its overexpression is associated with poor therapeutic outcome in cancer. The function of CAIX is to catalyze the reversible hydration of CO2 to bicarbonate and a proton. This helps hypoxic tumours to maintain a more neutral intracellular pH (pHi) promoting survival, but produces a more acidic extracellular (pHe) which promotes invasion and metastasis. Recent evidence has expanded on the role of hypoxia and CAIX by relating them to stem cell niches. In this study, taking advantage of the transmembrane location of CAIX, we show for the first time, a direct marked heterogeneity in response to hypoxia within each tumour cell population studied, associated with major biological differences. Based on CAIX expression pattern under hypoxic conditions, we identify, isolate and characterize two distinct populations of tumour cells, one that express CAIX and the other that does not. Interestingly, we discover that the CAIX positive population is enriched with cells expressing cancer stem cell markers. These include ALDHA1, IGF1, LIN28 and genes involved in epithelial-mesenchymal transition (EMT) and multi-drug resistance (i.e. WNT2, TWIST1, and ABCC2). Accordingly, CAIX+ve cells show higher self-renewal capacity and form tumours significantly faster compared to the CAIX-ve population. Importantly, functional suppression of CAIX in vitro and in vivo, in two breast cancer cell lines resulted in the downregulation of breast cancer stem cell signatures, suggesting that CAIX is not just a marker of stemness but also a regulator of stemness. The molecular mechanism underlying the differential expression of CAIX in the two populations is not HIF-1α-dependent, but instead driven by hypoxia-induced reorganization of chromatin structure. In line with this, we provide experimental evidence showing that the genomic locus encoding CA9 has a more “open” and transcriptionally active chromatin structure in CAIX+ve cells, and a condense and transcriptionally silent chromatin structure in the CAIX-ve cells. Given that HIF induces the transcription of CA9 by binding to hypoxia response elements (HREs) in its promoter we show a significant reduction in binding of HIF to the CA9 promoter of the negative population. We suggest that the reduce HIF binding is a result of the compact chromatin structure of CA9 promoter of the negative cells. Analysis of the transcriptome of the positive and negative populations suggests a symbiotic relationship between these two subpopulations and their environment, likely required to promote tumour growth. This is based on the following observations: Firstly, we identified that CAIX-ve cells express high levels of cytokines and based on this, we suggest that the cytokines secreted by CAIX-ve cells may transmit paracrine signals that regulate the CAIX+ve cells, thus providing a wider hypoxia tolerant microenvironment to protect the stem cell population. Secondly, we identified a metabolic heterogeneity between the CAIX+ve and CAIX-ve cells. The CAIX+ve cells show an upregulation of genes implicated in oxidative phosphorylation, TCA cycle and fatty acid synthesis. Whereas in CAIX-ve cells there is an upregulation of genes implicated in autophagy and mitophagy. Given the above together with the upregulation of oxidative phosphorylation and TCA cycle in the CAIX+ve cells, we proposed the existence of a metabolic symbiosis between the CAIX+ve and CAIX-ve cells. We postulate that the catabolic process such as autophagy and mitophagy in the CAIX-ve cells may results in the overproduction of high-energy metabolites such as lactate, glutamine and ketone bodies which in turns they are been utilized by CAIX+ve cells to fuel mitochondria respiration. Finally, we also demonstrated that in the CAIX+ve cells mTORC1 signaling is upregulated, and contributes to the regulation of CAIX expression. Given the role of mTORC1 in stem cell maintenance and EMT as well as the interdependence of mTORC1 and CAIX expression in the CAIX+ve cells we suggest that mTORC1 signaling may be the critical factor by which CAIX regulates stemness. Interestingly, the subpopulations show a differential sensitivity to HDAC inhibitors, NaBu and SAHA as treatment of MCF7 breast cancer cell line and HCT116 colon cancer cell line leads to elimination of the CAIX+ve population. This is not driven by the downregulation of HIF-1α, the major transcriptional regulator of CAIX. In contrast, we demonstrate that SAHA causes downregulation mTORC1. This suggests that SAHA-induced downregulation of CAIX expression could be due to its effect on mTORC1 pathway. Of wider significance, our findings show that tumours are not homogenous in their response to hypoxia, and distinct signal transduction networks regulate different populations of cells within the tumour. This highlights the need for the utilization of biomarkers, which reveal distinct functional hypoxia profiles of human cancers, and permit the stratification of tumours. Furthermore, the identification of epigenetic regulation of the histones in response to hypoxia for highly selective gene regulation, provides a connection between the epigenetic mechanisms under environmental stress and cancer progression, and is model for development of novel epigenetic cancer therapeutic drugs.
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Nilsson, Ingrid. "Hypoxia, PDGF and VEGF in Vascular Development." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6894.
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Bedessem, Baptiste. "Contributions à l'étude de la réponse moléculaire à l'hypoxie : Modélisation mathématique et expérimentations sur cellules FUCCI." Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAS024/document.
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Les effets biologiques de l'hypoxie sont très étudiés aujourd'hui, principalement en raison du rôle crucial que jouent les conditions d'oxygénation dans le développement des cancers.Depuis plusieurs années, une littérature foisonnante tente ainsi de décrire les multiples aspects de la réponse moléculaire, cellulaire et physiologique à l'hypoxie. La complexité des voies de signalisation impliquées et la diversité de leurs effets cellulaires rendent la tâche délicate. Cet état de fait se reflète dans la pluralité des méthodes utilisées, depuis les simulations numériques jusqu'aux approches expérimentales.Dans cette thèse, j'ai abordé ce sujet sur la base de deux outils: la modélisation mathématique et une démarche expérimentale utilisant les cellules HeLa-FUCCI. Cette lignée cellulaire récemment développée est en effet un instrument de choix encore peu exploité. Par une construction génétique liant des protéines du cycle cellulaire à un fluorophore, elle rend possible l'étude, en continue, de la dynamique du cycle en microscopie de fluorescence. Nous avons ainsi pu analyser plusieurs aspects de la réponse cellulaire à l'hypoxie, dans un contexte tumoral.Dans un premier temps, nous avons cherché à caractériser mathématiquement les liens tissés entre le cycle cellulaire et les voies de signalisation de l'hypoxie, centrées sur le facteur de transcription HiF-1. Ce modèle propose un explication simple à l'arrêt du cycle observé notamment dans les cellules tumorales en conditions hypoxiques. Nous avons ainsi montré que l'induction de chimiorésistance pouvait se concevoir comme une entrée facilitée en quiescence des cellules cancéreuses. Dans le but de valider ces observations, nous avons ensuite cherché à quantifier expérimentalement la dynamique de la prolifération cellulaire en utilisant les cellules HeLa-FUCCI. Comme il est apparu que les fluorophores qu'elles portent sont sensibles au manque d'oxygène, nous avons testé différentes molécules couramment utilisées pour induire HiF-1 et mimer l'hypoxie (DFO et CoCl2). De cette étude ont émergé des résultats originaux quant à la dynamique de blocage du cycle des cellules HeLa en présence de chélateurs du fer.Si les conditions hypoxiques ne sont pas favorables à l'utilisation des cellules FUCCI, nous avons pu en revanche montrer qu'elles étaient tout à fait adaptées à l'étude de la dynamique du cycle cellulaire en condition de réoxygénation. De manière intéressante, nous avons alors pu observer un ralentissement significatif de la phase S après retour à la normoxie. Afin d'apporter un éclairage théorique à cette observation, nous avons proposé un modèle mathématique de la dynamique de régulation de HiF-1 en conditions d'oxygène fluctuantes, basé sur le couple HiF-1/pVHL, dont les relations sont pensées dans un cadre compartimenté (noyau/cytoplasme). Ce modèle simple reproduit fidèlement les caractéristiques principales de la réponse cellulaire à l'hypoxie. En outre, en simulant les conséquences d'une réoxygénation brutale, nous avons observé la genèse de fortes instabilités du niveau intracellulaire de HiF-1. Enfin, nous avons mené une étude expérimentale de la compartimentation de HiF-1. L'outil FUCCI permet en effet d'observer simultanément l'avancement du cycle (en microscopie de fluorescence), et la localisation intra-cellulaire de HiF-1(par immunomarquage). Nous avons pu montrer que la variabilité de la localisation de HiF-1α n'était pas due à la progression dans le cycle. Elle est donc certainement liée soit à des différences génétiques inter-cellulaire, soit à une stochasticité de la régulation de HiF-1The biological effects of hypoxia are intensively studied today, mainly because of the crucial role played by oxygenation conditions during the development of cancers.For several years, a huge literature aims at describing the multiple aspects of the molecular, cellular and physiological responses to hypoxia. The complexity of the pathways which are involved and the diversity of their cellular effects make this task difficult.This situation is reflected in the plurality of the methods used, from the numerical simulations to the experimental approaches.In this thesis, I studied this subject using two tools: mathematical modeling and experimental approaches using HeLa-FUCCI cells.This recently developed cell line is an interesting tool not yetmuch exploited. By a genetic construction linking cell cycle proteins to a fluorophore, it makes possible the study of cell cycle dynamics using fluorescent microscopy.We could analyze various aspects of the cellular response to hypoxia, in a tumoral context. In a first time,we tried to mathematically characterize the links existing between cell cycle and the hypoxia pathways,driven by HiF-1.This model proposed a simple explanation to the cell cycle arrest notably observed in the tumor cells in hypoxicconditions.We then showed that the induction of chemoresistances could be considered as an entry into quiescence of tumor cells.In order to validate these observations we then tried to experimentally quantify the dynamics of cell proliferation using HeLa-FUCCI cells. As it appeared that the fluorophores were sensitive tothe lack of oxygen, we tested different molecules currently used to induceHiF-1 and mimic hypoxia (DFO and COCl2).From this study have emerged original results about the dynamics of cell cyclearrest of HeLa cells in presence of iron-chelators.If hypoxic conditions are not favorable to the use of HeLa-FUCCI cells, we could show that they were totally adapted to the study of cell cycle dynamics during reoxygenation.Interestingly, we then could observe a significant slowing down of the S-phase after the return to normoxia. In order to bring theoretical elements to this observation, we proposed a mathematical model of the dynamics of HiF-1 regulation in fluctuating oxygen conditions, based on thepVHL/HiF-1 couple, in the frame of a nucleo-cytoplasmic compartmentalization of HiF-1.This simple model well reproduce the main characteristics of the cell response to hypoxia.Besides, by simulating the consequences of a sudden reoxygenation, we observed the genesis of strong instabilities of HiF-1 intracellular level.Finally, we propose an experimental study of HiF-1 compartmentalization.Indeed, the FUCCI cells allow to simultaneously observe cell cycle progression (using fluorescent microscopy),and HiF-1 intra-cellular localization (with immunomarkage). We then could show that the variability of HiF-1 localization was not due to the progression into the cell cycle. Then, it is certainly linked to inter-cellular genetic differences, or to a stochasticity of HiF-1 regulation
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Lidgren, Anders. "Hypoxia inducible factor-1α in renal cell carcinoma." Doctoral thesis, Umeå universitet, Kirurgisk och perioperativ vetenskap, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1462.
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Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.
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Del, Sole Marianna <1981>. "Effect of hypoxia and hyperglycemia on cell bioenergetics." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4732/.
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Mitochondria have a central role in energy supply in cells, ROS production and apoptosis and have been implicated in several human disease and mitochondrial dysfunctions in hypoxia have been related with disorders like Type II Diabetes, Alzheimer Disease, inflammation, cancer and ischemia/reperfusion in heart.
When oxygen availability becomes limiting in cells, mitochondrial functions are modulated to allow biologic adaptation. Cells exposed to a reduced oxygen concentration readily respond by adaptive mechanisms to maintain the physiological ATP/ADP ratio, essential for their functions and survival. In the beginning, the AMP-activated protein kinase (AMPK) pathway is activated, but the responsiveness to prolonged hypoxia requires the stimulation of hypoxia-inducible factors (HIFs).
In this work we report a study of the mitochondrial bioenergetics of primary cells exposed to a prolonged hypoxic period . To shine light on this issue we examined the bioenergetics of fibroblast mitochondria cultured in hypoxic atmospheres (1% O2) for 72 hours. Here we report on the mitochondrial organization in cells and on their contribution to the cellular energy state. Our results indicate that prolonged hypoxia cause a significant reduction of mitochondrial mass and of the quantity of the oxidative phosphorylation complexes. Hypoxia is also responsible to damage mitochondrial complexes as shown after normalization versus citrate synthase activity.
HIF-1α plays a pivotal role in wound healing, and its expression in the multistage process of normal wound healing has been well characterized, it is necessary for cell motility, expression of angiogenic growth factor and recruitment of endothelial progenitor cells. We studied hypoxia in the pathological status of diabetes and complications of diabetes and we evaluated the combined effect of hyperglycemia and hypoxia on human dermal fibroblasts (HDFs) and human dermal micro-vascular endothelial cells (HDMECs) that were grown in high glucose, low glucose concentrations and mannitol as control for the osmotic challenge.I mitocondri hanno un ruolo fondamentale nella produzione di energia nella cellula, ma sono coinvolti anche in altri processi tra cui la produzione di ROS e l’apoptosi. Disfunzioni del metabolismo mitocondriale sono state associate a diversi disordini, tra cui: diabete di tipo II, malattia si Alzheimer, infiammazione, cancro ed ischemia cardiaca. Quando i livelli di ossigeno nella cellula diventano limitanti, la funzione mitocondriale viene modulata per consentire l’adattamento biologico. La via dell’AMP- activated protein kinase (AMPK) ha il compito di monitorare lo stato energetico della cellula mantenendo i livelli fisioligici di ATP/ADP. In seguito all’esposizione prolungata in ambiente ipossico, l’attivazione di HIF-1 e’ in grado di upregolare diversi geni coinvolti nella sopravvivenza cellulare a basse concentrazioni di ossigeno. In questo lavoro, e’ stata valutata la bioenergetica mitocondriale in fibroblasti primari coltivati a basse concentrazioni di ossigeno (1 % O2) per 72 ore; in particolare, abbiamo preso in considerazione l’organizzazione mitocondriale nella cellula e il loro contributo nel mantenere lo stato energetico cellulare. I nostri risultati indicano che l’esposizione prolungata all’ipossia causa una significativa riduzione della massa mitocondriale e della quantita’ dei complessi della fosforilazione ossidativa, nonostante le cellule siano in grado di mantenere i livelli intracellulari di ATP. Inoltre abbiamo studiato l’ipossia nel contesto patologico del diabete ed in particolare delle complicanze del diabete. E’ noto che l’iperglicemia e l’ipossia, dovuta ad ischemia a danni vascolari, hanno un ruolo importante nell’insorgenza delle complicanze del diabete. HIF-1α rappresenta uno stimolo nella rigenerazione delle ferite, in quanto stimola la vascolarizzazione e la migrazione dei cheranociti ed e’ stato ipotizzato che le cellule perdano la capacita’ di adattarsi e rispondere all’ipossia quando sono coltivate in presenza di elevate concentrazioni di glucosio (>25 mM). Abbiamo valutato il ruolo della destabilizzazione di HIF-1α nella produzione di ROS, considerati i principali responsabili della progressione del diabete.
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Milani, Manuela. "Cell stress response and hypoxia in breast cancer." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:74d3bf91-9888-4e9e-b5e1-7d5d2d476174.
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During severe hypoxia (<0.01% oxygen) the protein folding machinery becomes dysfunctional, resulting in the accumulation of unfolded proteins with consequent endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) and autophagy, a process involved in the physiological turnover of cytoplasmic components. The link between the UPR and autophagy is not clearly defined. The aim of this thesis is to investigate the role of the induction of UPR under severe hypoxia in tumour survival and resistance to therapy. The results of this research suggest that the activating transcription factor 4 (ATF4), a component of the PKR-like ER kinase (PERK) pathway, fundamental in the UPR, is required for the ER-stress induced upregulation of autophagy. Mechanisms other than hypoxia for UPR induction were investigated, using the proteasome inhibitor bortezomib (BZ). BZ treatment increased ATF4 protein levels in MCF7 cells, even transfected with short-interference RNA (siRNA) against the classical UPR activator PERK, suggesting that the proteasomal stabilization is likely the main mechanism for ATF4 protein accumulation. The induction of autophagy by BZ is dependent upon the upregulation of the microtubule-associated protein 1 light chain 3B (LC3B), an autophagy marker, by ATF4 and acts as a survival mechanism. Hypoxia, UPR and autophagy markers (such as Pimonidazole, carbonic anhydrases IX (CAIX), C/EBP homologous protein (CHOP) and LC3B) were evaluated by immunohistochemical approach in spheroids, xenografts models and breast cancer samples. CHOP immunohistochemical staining was performed in breast cancer sections from a series of patients. CHOP was expressed in cells surrounding necrotic areas. No correlation were found with clinical outcome and further studies are needed.
Books on the topic "Cel Hypoxia"
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Chiarotto, James Anthony. Hypoxia-induced upregulation of VEGF mRNA in cervical cancer cell lines. Ottawa: National Library of Canada, 1998.
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Low, Eddy Wai-Mang. Reactions toward the synthesis of minor-groove binding hypoxic cell sensitizers. Ottawa: National Library of Canada = Bibliothèque nationale du Canada, 1993.
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Cheng, Phillip Ming-Da. Relationship between modulation of Glomus Cell K+ current and hypoxia transduction in the rat carotid body. [New Haven, Conn: s.n.], 1997.
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1947-, Haddad Gabriel G., and Lister George 1947-, eds. Tissue oxygen deprivation: From molecular to integrated function. New York: M. Dekker, 1996.
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Jean-Marc, Pequignot, ed. Chemoreception: From cellular signaling to functional plasticity. New York: Kluwer Academic/Plenum Publishers, 2003.
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Koumenis, Constantinos, Amato Giaccia, and Ester Hammond. Tumor Microenvironment and Cellular Stress: Signaling, Metabolism, Imaging, and Therapeutic Targets. Springer, 2016.
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Koumenis, Constantinos, Amato Giaccia, and Ester Hammond. Tumor Microenvironment and Cellular Stress: Signaling, Metabolism, Imaging, and Therapeutic Targets. Springer London, Limited, 2013.
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Koumenis, Constantinos, Amato Giaccia, and Ester Hammond. Tumor Microenvironment and Cellular Stress: Signaling, Metabolism, Imaging, and Therapeutic Targets. Springer, 2013.
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Pastorekova, Silvia, and Juraj Kopacek. Tumour Hypoxia: Molecular Mechanisms and Clinical Implications. Lang GmbH, Internationaler Verlag der Wissenschaften, Peter, 2012.
Find full textBook chapters on the topic "Cel Hypoxia"
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Bonny, Christophe. "Blocking Stress Signaling Pathways with Cell Permeable Peptides." In Hypoxia and Exercise, 133–43. Boston, MA: Springer US, 2006. http://dx.doi.org/10.1007/978-0-387-34817-9_12.
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Schmierer, Bernhard. "Cell Cycle Signaling, Hypoxia." In Encyclopedia of Systems Biology, 311–14. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4419-9863-7_45.
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West, John B. "Acclimatization and Adaptation: Organ to Cell." In Response and Adaptation to Hypoxia, 177–90. New York, NY: Springer New York, 1991. http://dx.doi.org/10.1007/978-1-4614-7574-3_16.
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Harrison, George H., and Jeremy Wright. "Hypoxic Cell Radiosensitizers." In Cancer Management in Man, 170–78. Dordrecht: Springer Netherlands, 1989. http://dx.doi.org/10.1007/978-94-009-2536-6_13.
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Coleman, C. Norman. "Hypoxic Cell Sensitizers." In Concomitant Continuous Infusion Chemotherapy and Radiation, 77–84. Berlin, Heidelberg: Springer Berlin Heidelberg, 1991. http://dx.doi.org/10.1007/978-3-642-84186-6_8.
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Younts, Thomas James, and Jr Francis “Monty” Hughes. "Emerging Role of Water Channels in Regulating Cellular Volume During Oxygen Deprivation and Cell Death." In Brain Hypoxia and Ischemia, 79–96. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60327-579-8_5.
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Masuda, Seiji, Sung-Kwon Moon, Taiho Kambe, Masaya Nagao, and Ryuzo Sasaki. "Hypoxia-Induced Production of Recombinant Erythropoietin Using Hypoxia-Response Enhancer." In Animal Cell Technology: Basic & Applied Aspects, 139–43. Dordrecht: Springer Netherlands, 2002. http://dx.doi.org/10.1007/978-94-017-0728-2_25.
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Tavassoli, Mahvash, and Yae-eun Suh. "Hypoxia in Head and Neck Cancer." In Squamous cell Carcinoma, 59–95. Dordrecht: Springer Netherlands, 2017. http://dx.doi.org/10.1007/978-94-024-1084-6_3.
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Pietersma, Anneke, Netty de Jong, Johan F. Koster, and Wim Sluiter. "Hypoxia and Endothelial Cell Adhesiveness." In Signalling Mechanisms — from Transcription Factors to Oxidative Stress, 241–50. Berlin, Heidelberg: Springer Berlin Heidelberg, 1995. http://dx.doi.org/10.1007/978-3-642-79675-3_19.
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Jögi, Annika. "Tumour Hypoxia and the Hypoxia-Inducible Transcription Factors: Key Players in Cancer Progression and Metastasis." In Tumor Cell Metabolism, 65–98. Vienna: Springer Vienna, 2015. http://dx.doi.org/10.1007/978-3-7091-1824-5_4.
Full textConference papers on the topic "Cel Hypoxia"
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Das, Saikat. "Low dose radiation and chemotherapy significantly reduces hypoxic cell population in locally advanced cervix cancer-results of a phase II study." In 16th Annual International Conference RGCON. Thieme Medical and Scientific Publishers Private Ltd., 2016. http://dx.doi.org/10.1055/s-0039-1685259.
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Introduction: Tumor hypoxia is one of the major causes of high incidence of treatment failures to chemoradiation which is the standard of care in locally advanced cervical cancer. The necessity of newer treatment options that can circumvent hypoxia is highly relevant in this group. Use of low dose radiation to enhance the efficacy of cell cycle specific chemotherapy by mechanism of chemopotentiation is one of the elegant approaches reported in the literature. We have already published the feasibility, efficacy and tolerance of low dose radiation and chemotherapy in neoadjuvant setting in cervical cancer. In this report we evaluated the role of this novel treatment regimen in reducing the hypoxic tumor cell population in cervical cancer. Methods: Total 24 patients with stage IIB-IIIB squamous cell carcinoma cervix were treated with initial 2 cycles of paclitaxel and carboplatin and concurrent low dose radiotherapy prior to standard chemoradiation. Response was assessed clinically, radiologically (by MRI) and pathologically (four quadrant representative punch biopsy from the cervix) after 3 weeks of neoadjuvant treatment prior to chemoradiation. Immunohistochemistry of HIF-1a was done in the biopsy samples to determine the proportion, intensity and scoring of hypoxic cells. Results: The proportion of positivity of base line HIF-1α was 42% (10 out of 24 patients). Low, moderate and high expressions were seen in 8%, 17% and 17% respectively. We observed nuclear positivity in 20%, and fine granular perinuclear cytoplasmic positivity in 80% cases. We failed to observe any association between expressions of HIF 1α in relation to the distance from blood vessels in tumor cord. The average age of patients in hypoxia positive and negative groups were 51.7 vs 48.36 yrs (p > 0.05). There was no difference of mean hemoglobin level (11.3 to 11.1, p > 0.05.) or MRI based tumor volume at baseline (57.1 vs. 52.4, p > 0.05) in HIF 1α positive and negative groups respectively. Low dose radiation and chemotherapy significantly reduced the tumor volume in bulky hypoxic tumors. The tumor volume reduction rate (TVRR) was significantly higher in hypoxic group (TVRR HIF_neg vs. TVRR HIF_pos 68.9 vs. 86.3, p = 0.02, t-test). There was significant improvement of diffusion MRI derived apparent diffusion coefficient (ADC) in hypoxic tumors with low dose radiation and chemotherapy (0.75 vs. 1.27, p = 0.12, Wilcoxon signed-rank test). Median score of percentage of hypoxic cells after neoadjuvant treatment were significantly higher in patients who developed subsequent local recurrence than the rest of the group (77% vs. 5% p = 0.009, Mann Whitney U test). Conclusion: Overall all HIF 1 positivity was 42% in the present study. A predominantly perinuclear pattern of HIF 1 staining was found in cervix cancer. Low dose radiation and chemotherapy significantly reduced the hypoxic tumor bulk in cervical cancer.
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Oppegard, Shawn C., and David T. Eddington. "Modulation of Oxygen Tensions via Microfabricated Devices." In ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53093.
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Oxygen is a key modulator of many cellular pathways and plays an important role in a number of cellular behaviors. The hypoxic inducible factor 1α (HIF-1α) is often considered the master regulator of the cellular response to oxygen tension (1). HIF-1α is a transcription factor involved in angiogenesis, glucose transport and glycolysis, apoptosis, migration, and differentiation, among many other functions (2). Unfortunately devices permitting in vitro oxygen modulation fail to meet the needs of biomedical research due to the inability to effectively mimic conditions found in vivo. The gold standard for hypoxia work is the hypoxic chamber, but the tool requires hours for equilibration and is not effective at generating very low oxygen levels (3). As an example demonstrating this disadvantage, cancer tumor oxygenation can change in the span of minutes (4). Intermittent hypoxia, or the changing of oxygen over time, has been shown to be important in heart attack, stroke, and sleep apnea as well. Other microfluidic approaches, although offering more oxygen control, are often difficult to disseminate to other labs due to the requirement of specialized methods and equipment for their operation. In this work, a microfabricated technology has been developed to grant precise control the temporal and spatial oxygen concentration exposed to both cell monolayers in the multiwell plate as well as with 3-D cell-seeded constructs. The concept is adaptable to both pre-established and novel experiments depending on the needs of the researcher. The devices are simple to use and require minimal additional equipment beyond what is available to a standard cell culture lab.
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Svirskaya, A. V., M. A. Yakauleva, D. B. Nizheharodava, and M. M. Zafranskaya. "EFFECT OF HYPOXIA ON IMMUNOMODULATORY PROPERTIES OF MULTIPOTENT MESENCHYMAL STROMAL CELLS." In SAKHAROV READINGS 2022: ENVIRONMENTAL PROBLEMS OF THE XXI CENTURY. International Sakharov Environmental Institute of Belarusian State University, 2022. http://dx.doi.org/10.46646/sakh-2022-2-94-97.
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This study characterizes the effect of hypoxia on human multipotent mesenchymal stromal cells ability to modulate mitogen-stimulated proliferation of peripheral blood mononuclear cells, what can be used for optimization of biomedical cell products protocols using for cell therapy of pathological conditions accompanied by hypoxia.
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Luigi, Varesio, Paolo Fardin, Rogier Versteeg, Fabiola Blengio, Annalisa Barla, and Maria Carla Bosco. "Abstract 2002: Cell reprogramming by hypoxia." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2002.
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Leahy, Rachel, Weiling Xu, Suzy A. A. Comhair, and Serpil C. Erzurum. "Hypoxia In Airway Epithelial Cell Differentiation." In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5115.
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Gao, S., M. Emin, R. Shah, A. Jimenez, and S. Jelic. "Intermittent Hypoxia Disrupts Endothelial Cell Cholesterol Trafficking." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a4702.
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te Boekhorst, Veronika, Liying Jiang, Steffi Lehmann, Alba Zuidema, and Peter Friedl. "Abstract 5062: Hypoxia-induced amoeboid cancer cell migration." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-5062.
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Masamoto, Kazuto, Kotaro Oka, Hirosuke Kobayashi, Yuki Sannohe, Naosada Takizawa, and Kazuo Tanishita. "Distribution of Oxygen Tension in Neocortical Areas in the Rat Somatosensory Cortex." In ASME 2000 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2000. http://dx.doi.org/10.1115/imece2000-2627.
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Abstract The purpose of this study is to identify the localized differentiation of oxygen transport in the brain. We measured oxygen tension in three neocortical areas (FL, HL, and Tr) of the rat somatosensory cortex by microcoaxial needle electrodes. The structure of neocortical area is characterized by the variation of cell shape, spatial distribution and size, which results in the following three types of the oxygen tension distribution; random, fluctuation, and hypoxia.
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Vanderpool, Rebecca, and Naomi C. Chesler. "The Effects of Vasoactive Agents on Impedance Measures in the Pulmonary Circulation of Mice." In ASME 2007 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2007. http://dx.doi.org/10.1115/sbc2007-176450.
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Pulmonary hypertension is a potentially fatal disease, resulting from chronic obstructive or interstitial lung disease, recurrent pulmonary emboli, antecedent heart disease, hypoxia or other unknown causes [1]. Pulmonary hypertension causes vascular remodeling with smooth muscle cell (SMC) hyperplasia and hypertrophy and accumulation of collagen and elastin [2]. This remodeling increases pulmonary vascular resistance, which can lead to increases in steady right ventricular work [3]. The effects of remodeling on pulmonary vascular impedance, which determines pulsatile right ventricular work, remain incompletely described. We have previously quantified the effects of chronic hypoxia-induced pulmonary hypertension (HPH) on pulmonary vascular impedance [4] but did not investigate the role of SMC tone either before or after HPH. The aim of this study was to investigate the effects of normal and increased SMC tone on pulsatile pulmonary hemodynamics before and after HPH-induced pulmonary vascular remodeling. We hypothesized that SMC contraction would increase input resistance but decrease the speed of wave reflections. We also hypothesized that increased arteriolar muscularization after HPH would lead to greater increases in resistance and greater decreases in wave reflections with increased SMC tone.
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Bakhtiar, H., and I. Singh. "A Curious Case of Hypoxia: Pulmonary T- Cell Lymphoma." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6326.
Full textReports on the topic "Cel Hypoxia"
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Nielsen, T. B., and J. L. Kidwell. Cell Biology of Hypoxia, 1996. Fort Belvoir, VA: Defense Technical Information Center, September 1996. http://dx.doi.org/10.21236/ada340589.
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Czerwaty, Katarzyna, Karolina Dżaman, Krystyna Maria Sobczyk, and Katarzyna Irmina Sikrorska. The Overlap Syndrome of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease: A Systematic Review. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, November 2022. http://dx.doi.org/10.37766/inplasy2022.11.0077.
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Review question / Objective: To provide the essential findings in the field of overlap syndrome of chronic obstructive pulmonary disease and obstructive sleep apnea, including prevalence, possible predictors, association with clinical outcomes, and severity compared to both chronic obstructive pulmonary disease and obstructive sleep apnea patients. Condition being studied: OSA is characterized by complete cessation (apnea) or significant decrease (hy-popnea) in airflow during sleep and recurrent episodes of upper airway collapse cause it during sleep leading to nocturnal oxyhemoglobin desaturations and arousals from rest. The recurrent arousals which occur in OSA lead to neurocognitive consequences, daytime sleepiness, and reduced quality of life. Because of apneas and hypopneas, patients are experiencing hypoxemia and hypercapnia, which result in increasing levels of catecholamine, oxidative stress, and low-grade inflammation that lead to the appearance of cardio-metabolic consequences of OSA. COPD is a chronic inflammatory lung disease defined by persistent, usually pro-gressive AFL (airflow limitation). Changes in lung mechanics lead to the main clini-cal manifestations of dyspnea, cough, and chronic expectoration. Furthermore, patients with COPD often suffer from anxiety and depression also, the risk of OSA and insomnia is higher than those hospitalized for other reasons. Although COPD is twice as rare as asthma but is the cause of death eight times more often.