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Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors.
Schneider, MA, Linecker, M, Fritsch, R, Muehlematter, UJ, Stocker, D, Pestalozzi, B, Samaras, P, Jetter, A, Kron, P, Petrowsky, H, et al
Nature communications. 2021;(1):3807
Abstract
Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.
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Exposure to Normobaric Hypoxia Combined with a Mixed Diet Contributes to Improvement in Lipid Profile in Trained Cyclists.
Płoszczyca, K, Czuba, M, Langfort, J, Baranowski, M
Nutrients. 2021;(10)
Abstract
This study aimed to analyze the effects of live high-train low method (LH-TL) and intermittent hypoxic training (IHT) with a controlled mixed diet on lipid profile in cyclists. Thirty trained male cyclists at a national level with at least six years of training experience participated in the study. The LH-TL group was exposed to hypoxia (FiO2 = 16.5%) for 11-12 h a day and trained under normoxia for 3 weeks. In the IHT group, participants followed the IHT routine three times a week under hypoxia (FiO2 = 16.5%) at lactate threshold intensity. The control group (N) lived and trained under normoxia. The results showed that the 3-week LH-TL method significantly improved all lipid profile variables. The LH-TL group showed a significant increase in HDL-C by 9.0% and a decrease in total cholesterol (TC) by 9.2%, LDL-C by 18.2%, and triglycerides (TG) by 27.6%. There were no significant changes in lipid profiles in the IHT and N groups. ∆TG and ∆TC were significantly higher in the LH-TL group compared to the N group. In conclusion, hypoxic conditions combined with a mixed diet can induce beneficial changes in lipid profile even in highly trained athletes. The effectiveness of the hypoxic stimulus is closely related to the hypoxic training method.
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Individualising care in severe bronchopulmonary dysplasia: a series of N-of-1 trials comparing transpyloric and gastric feeding.
Jensen, EA, Zhang, H, Feng, R, Dysart, K, Nilan, K, Munson, DA, Kirpalani, H
Archives of disease in childhood. Fetal and neonatal edition. 2020;(4):399-404
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Abstract
OBJECTIVE Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia. DESIGN N-of-1 multiple crossover trials with individual patient and pooled data analyses. SETTING Level IV intensive care nursery. PATIENTS Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016. INTERVENTION N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order. MAIN OUTCOME MEASURES The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO2 ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO2 ≤80% and mean daily fraction of inspired oxygen. RESULTS Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5). CONCLUSIONS Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants. TRIAL REGISTRATION NUMBER NCT02142621.
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Transcerebral exchange kinetics of large neutral amino acids during acute inspiratory hypoxia in humans.
Dahl, RH, Berg, RMG, Taudorf, S, Bailey, DM, Lundby, C, Christensen, M, Larsen, FS, Møller, K
Scandinavian journal of clinical and laboratory investigation. 2019;(8):595-600
Abstract
Hypoxaemia is present in many critically ill patients, and may contribute to encephalopathy. Changes in the passage of large neutral amino acids (LNAAs) across the blood-brain barrier (BBB) with an increased cerebral influx of aromatic amino acids into the brain may concurrently be present and also contribute to encephalopathy, but it has not been established whether hypoxaemia per se may trigger such changes. We measured cerebral blood flow (CBF) in 11 healthy men using the Kety-Schmidt technique and obtained paired arterial and jugular-venous blood samples for the determination of LNAAs by high performance liquid chromatography at baseline and after 9 hours of poikilocapnic normobaric hypoxia (12% O2). Transcerebral net exchange was determined by the Fick principle, and transport of LNAAs across the BBB was determined mathematically. Hypoxia increased both the systemic and corresponding cerebral delivery of the aromatic amino acid phenylalanine, and the branched-chain amino acids leucine and isoleucine. Despite this, the transcerebral net exchange values and mathematically derived brain extracellular concentrations for all LNAAs were unaffected. In conclusion, the observed changes in circulating LNAAs triggered by hypoxaemia do not affect the transcerebral exchange kinetics of LNAAs to such an extent that their brain extracellular concentrations are affected.
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Chronic high-dose beetroot juice supplementation improves time trial performance of well-trained cyclists in normoxia and hypoxia.
Rokkedal-Lausch, T, Franch, J, Poulsen, MK, Thomsen, LP, Weitzberg, E, Kamavuako, EN, Karbing, DS, Larsen, RG
Nitric oxide : biology and chemistry. 2019;:44-52
Abstract
Dietary nitrate (NO3-) supplementation via beetroot juice (BR) is known to improve endurance performance in untrained and moderately trained individuals. However, conflicting results exist in well-trained individuals. Evidence suggests that the effects of NO3- are augmented during conditions of reduced oxygen availability (e.g., hypoxia), thereby increasing the probability of performance improvements for well-trained athletes in hypoxia vs. normoxia. This randomized, double-blinded, counterbalanced-crossover study examined the effects of 7 days of BR supplementation with 12.4 mmol NO3- per day on 10-km cycling time trial (TT) performance in 12 well-trained cyclists in normoxia (N) and normobaric hypoxia (H). Linear mixed models for repeated measures revealed increases in plasma NO3- and NO2- after supplementation with BR (both p < 0.001). Further, TT performance increased with BR supplementation (∼1.6%, p < 0.05), with no difference between normoxia and hypoxia (p = 0.92). For respiratory variables there were significant effects of supplementation on VO2 (p < 0.05) and VE (p < 0.05) such that average VO2 and VE during the TT increased with BR, with no difference between normoxia and hypoxia (p ≥ 0.86). We found no effect of supplementation on heart rate, oxygen saturation or muscle oxygenation during the TT. Our results provide new evidence that chronic high-dose NO3- supplementation improves cycling performance of well-trained cyclists in both normoxia and hypoxia.
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Iron Prevents Hypoxia-Associated Inflammation Through the Regulation of Nuclear Factor-κB in the Intestinal Epithelium.
Simmen, S, Cosin-Roger, J, Melhem, H, Maliachovas, N, Maane, M, Baebler, K, Weder, B, Maeyashiki, C, Spanaus, K, Scharl, M, et al
Cellular and molecular gastroenterology and hepatology. 2019;(2):339-355
Abstract
BACKGROUND & AIMS Hypoxia-associated pathways influence the development of inflammatory bowel disease. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are regulated by iron-dependent hydroxylases. Signals reflecting oxygen tension and iron levels in enterocytes regulate iron metabolism. Conversely, iron availability modulates responses to hypoxia. In the present study we sought to elucidate how iron influences the responses to hypoxia in the intestinal epithelium. METHODS Human subjects were exposed to hypoxia, and colonic biopsy specimens and serum samples were collected. HT-29, Caco-2, and T84 cells were subjected to normoxia or hypoxia in the presence of iron or the iron chelator deferoxamine. Changes in inflammatory gene expression and signaling were assessed by quantitative polymerase chain reaction and Western blot. Chromatin immunoprecipitation was performed using antibodies against nuclear factor (NF)-κB and primers for the promoter of tumor necrosis factor (TNF) and interleukin (IL)1β. RESULTS Human subjects presented reduced levels of ferritin in the intestinal epithelium after hypoxia. Hypoxia reduced iron deprivation-associated TNF and IL1β expression in HT-29 cells through the induction of autophagy. Contrarily, hypoxia triggered TNF and IL1β expression, and NF-κB activation in Caco-2 and T84 cells. Iron blocked autophagy in Caco-2 cells, while reducing hypoxia-associated TNF and IL1β expression through the inhibition of NF-κB binding to the promoter of TNF and IL1β. CONCLUSIONS Hypoxia promotes iron mobilization from the intestinal epithelium. Hypoxia-associated autophagy reduces inflammatory processes in HT-29 cells. In Caco-2 cells, iron uptake is essential to counteract hypoxia-induced inflammation. Iron mobilization into enterocytes may be a vital protective mechanism in the hypoxic inflamed mucosa.
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Appetite Regulations After Sprint Exercise Under Hypoxic Condition in Female Athletes.
Kojima, C, Kasai, N, Ishibashi, A, Murakami, Y, Ebi, K, Goto, K
Journal of strength and conditioning research. 2019;(7):1773-1780
Abstract
Kojima, C, Kasai, N, Ishibashi, A, Murakami, Y, Ebi, K, and Goto, K. Appetite regulations after sprint exercise under hypoxic condition in female athletes. J Strength Cond Res 33(7): 1773-1780, 2019-The present study determined changes in appetite-regulating hormones and energy intake after high-intensity interval exercise (HIIT) under hypoxic conditions (HYP) in trained female athletes. Fifteen female athletes completed 3 trials on different days of either HIIT under HYP, HIIT under normoxic conditions (NOR), or rest in normoxia (CON). Exercise trials consisted of 2 successive sets of 8 repeated bouts of a 6-second maximal sprint separated by a 30-second rest. Blood samples were obtained to measure plasma acylated ghrelin, glucagon-like peptide-1 (GLP-1), and metabolite concentrations. Energy intake during an ad libitum buffet meal test was evaluated 30 minutes after exercise or rest. Plasma acylated ghrelin concentrations decreased significantly after exercise (p ≤ 0.001), but no difference was observed between the HYP and NOR. Plasma GLP-1 concentrations did not differ after exercise, with no difference between the HYP and NOR. Although absolute energy intake in the HYP (634 ± 67 kcal) and NOR (597 ± 63 kcal) was significantly lower than that in the CON (756 ± 63 kcal, p = 0.006), no difference was observed between the HYP and NOR. These results show that HIIT under hypoxic and NOR lowered plasma acylated ghrelin concentrations and energy intake.
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Living and Training at 825 m for 8 Weeks Supplemented With Intermittent Hypoxic Training at 3,000 m Improves Blood Parameters and Running Performance.
Wonnabussapawich, P, Hamlin, MJ, Lizamore, CA, Manimmanakorn, N, Leelayuwat, N, Tunkamnerdthai, O, Thuwakum, W, Manimmanakorn, A
Journal of strength and conditioning research. 2017;(12):3287-3294
Abstract
Wonnabussapawich, P, Hamlin, MJ, Lizamore, CA, Manimmanakorn, N, Leelayuwat, N, Tunkamnerdthai, O, Thuwakum, W, and Manimmanakorn, A. Living and training at 825 m for 8 weeks supplemented with intermittent hypoxic training at 3,000 m improves blood parameters and running performance. J Strength Cond Res 31(12): 3287-3294, 2017-We aimed to investigate the effect of an 8-week low-altitude training block supplemented with intermittent hypoxic training, on blood and performance parameters in soccer players. Forty university-level male soccer players were separated into altitude (n = 20, 825 m) or sea-level (n = 20, 125 m) groups. Before (1-2 days ago) and after (1 and 14 days later) training, players were asked to give a resting venous blood sample and complete a series of performance tests. Compared with sea level, the altitude group increased erythropoietin, red blood cell (RBC) count, and hematocrit 1 day after training (42.6 ± 24.0%, 1.8 ± 1.3%, 1.4 ± 1.1%, mean ± 95% confidence limits (CL), respectively). By 14 days after training, only RBC count and hemoglobin were substantially higher in the altitude compared with the sea-level group (3.2 ± 1.8%, 2.9 ± 2.1% respectively). Compared with sea level, the altitude group 1-2 days after training improved their 50-m (-2.9 ± 1.4%) and 2,800-m (-2.9 ± 4.4%) run times and demonstrated a higher maximal aerobic speed (4.7 ± 7.4%). These performance changes remained at 14 days after training with the addition of a likely higher estimated V[Combining Dot Above]O2max in the altitude compared with the sea-level group (3.2 ± 3.0%). Eight weeks of low-altitude training, supplemented with regular bouts of intermittent hypoxic training at higher altitude, produced beneficial performance improvements in team-sport athletes, which may increase the viability of such training to coaches and players that cannot access more traditional high altitude venues.
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VESTPD as a measure of ventilatory acclimatization to hypobaric hypoxia.
Loeppky, JA, Sheard, AC, Salgado, RM, Mermier, CM
Physiology international. 2016;(3):377-391
Abstract
This study compared the ventilation response to an incremental ergometer exercise at two altitudes: 633 mmHg (resident altitude = 1,600 m) and following acute decompression to 455 mmHg (≈4,350 m altitude) in eight male cyclists and runners. At 455 mmHg, the VESTPD at RER <1.0 was significantly lower and the VEBTPS was higher because of higher breathing frequency; at VO2max, both VESTPD and VEBTPS were not significantly different. As percent of VO2max, the VEBTPS was nearly identical and VESTPD was 30% lower throughout the exercise at 455 mmHg. The lower VESTPD at lower pressure differs from two classical studies of acclimatized subjects (Silver Hut and OEII), where VESTPD at submaximal workloads was maintained or increased above that at sea level. The lower VESTPD at 455 mmHg in unacclimatized subjects at submaximal workloads results from acute respiratory alkalosis due to the initial fall in HbO2 (≈0.17 pHa units), reduction in PACO2 (≈5 mmHg) and higher PAO2 throughout the exercise, which are partially pre-established during acclimatization. Regression equations from these studies predict VESTPD from VO2 and PB in unacclimatized and acclimatized subjects. The attainment of ventilatory acclimatization to altitude can be estimated from the measured vs. predicted difference in VESTPD at low workloads after arrival at altitude.
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On the combined effects of normobaric hypoxia and bed rest upon bone and mineral metabolism: Results from the PlanHab study.
Rittweger, J, Debevec, T, Frings-Meuthen, P, Lau, P, Mittag, U, Ganse, B, Ferstl, PG, Simpson, EJ, Macdonald, IA, Eiken, O, et al
Bone. 2016;:130-8
Abstract
Bone losses are common as a consequence of unloading and also in patients with chronic obstructive pulmonary disease (COPD). Although hypoxia has been implicated as an important factor to drive bone loss, its interaction with unloading remains unresolved. The objective therefore was to assess whether human bone loss caused by unloading could be aggravated by chronic hypoxia. In a cross-over designed study, 14 healthy young men underwent 21-day interventions of bed rest in normoxia (NBR), bed rest in hypoxia (HBR), and hypoxic ambulatory confinement (HAmb). Hypoxic conditions were equivalent to 4000m altitude. Bone metabolism (NTX, P1NP, sclerostin, DKK1) and phospho-calcic homeostasis (calcium and phosphate serum levels and urinary excretion, PTH) were assessed from regular blood samples and 24-hour urine collections, and tibia and femur bone mineral content was assessed by peripheral quantitative computed tomography (pQCT). Urinary NTX excretion increased (P<0.001) to a similar extent in NBR and HBR (P=0.69) and P1NP serum levels decreased (P=0.0035) with likewise no difference between NBR and HBR (P=0.88). Serum total calcium was increased during bed rest by 0.059 (day D05, SE 0.05mM) to 0.091mM (day D21, P<0.001), with no additional effect by hypoxia during bed rest (P=0.199). HAmb led, at least temporally, to increased total serum calcium, to reduced serum phosphate, and to reduced phosphate and calcium excretion. In conclusion, hypoxia did not aggravate bed rest-induced bone resorption, but led to changes in phospho-calcic homeostasis likely caused by hyperventilation. Whether hyperventilation could have mitigated the effects of hypoxia in this study remains to be established.