Novel progestogenic androgens for male contraception: design, synthesis, and activity of C7 α-substituted testosterone†.

Male contraceptive development has included use of testosterone (T) with or without a progestin or the use of a single molecule such as progestogenic androgens (PA) for suppression of testicular T production. Expanding upon the vast amount of data accumulated from nortestosterone (NT), NT analogs, and their prodrugs, a new series of PA, the C7 methyl, and ethyl α-substituted T analogs 7α-Methyltestosterone (7α-MT) and 7α-Ethyltestosterone (7α-ET), respectively, were hypothesized and designed to have superior androgenic and progestogenic activities when compared with parent T. Results from androgen receptor and progesterone receptor competitive binding and transcriptional activation assays showed favorable activities for these T analogs. Additionally, 7α-MT and 7α-ET were shown to be active substrates for aromatase in vitro, mitigating a potential negative impact on bone mineral density with long-term use. In conjunction with this observation, the diminished metabolism of these T analogs by 5α-reductase may reduce potential concerns for prostatic growth. In the Hershberger in vivo rat bioassay, 7α-MT and 7α-ET showed superior androgenic and anabolic activities as compared with T. These C7 α-substituted T analogs also showed clear progestogenic activity in the McPhail bioassay which evaluated endometrial glandular arborization in a rabbit model. The discovery of aromatizable molecules with reduced metabolism by 5α-reductase that have androgenic, anabolic, and progestogenic properties indicates that the core and/or prodrugs of 7α-MT and 7α-ET are promising molecules for further development as male contraceptive PAs.

Repeated Short-Term Bouts of Hyperoxia Improve Aerobic Performance in Acute Hypoxia.

ABSTRACT: Faulhaber, M, Schneider, S, Rausch, LK, Dünnwald, T, Menz, V, Gatterer, H, Kennedy, MD, and Schobersberger, W. Repeated short-term bouts of hyperoxia improve aerobic performance in acute hypoxia. J Strength Cond Res 37(10): 2016-2022, 2023-This study aimed to test the effects of repeated short-term bouts of hyperoxia on maximal 5-minute cycling performance under acute hypoxic conditions (3,200 m). Seventeen healthy and recreationally trained individuals (7 women and 10 men) participated in this randomized placebo-controlled cross-over trial. The procedures included a maximal cycle ergometer test and 3 maximal 5-minute cycling time trials (TTs). TT1 took place in normoxia and served for habituation and reference. TT2 and TT3 were conducted in normobaric hypoxia (15.0% inspiratory fraction of oxygen). During TT2 and TT3, the subjects were breathing through a face mask during five 15-second periods. The face mask was connected through a nonrebreathing T valve to a 300-L bag filled with 100% oxygen (intermittent hyperoxia) or ambient hypoxic air (placebo). The main outcome was the mean power output during the TT. Statistical significance level was set at p < 0.05. The mean power output was higher in the intermittent hyperoxia compared with the placebo condition (255.5 ± 49.6 W vs. 247.4 ± 48.2 W, p = 0.001). Blood lactate concentration and ratings of perceived exertion were significantly lower by about 9.7 and 7.3%, respectively, in the intermittent hyperoxia compared with the placebo condition, whereas heart rate values were unchanged. IH application increased arterial oxygen saturation (82.9 ± 2.6% to 92.4 ± 3.3%, p < 0.001). Repeated 15-second bouts of hyperoxia, applied during high-intensity exercise in hypoxia, are sufficient to increase power output. Future studies should focus on potential dose-response effects and the involved mechanisms.

The Effects of Exercise Therapy Moderated by Sex in Rehabilitation of COVID-19.

Standardized exercise therapy programs in pulmonary rehabilitation have been shown to improve physical performance and lung function parameters in post-acute COVID-19 patients. However, it has not been investigated if these positive effects are equally beneficial for both sexes. The purpose of this study was to analyze outcomes of a pulmonary rehabilitation program with respect to sex differences, in order to identify sex-specific pulmonary rehabilitation requirements. Data of 233 post-acute COVID-19 patients (40.4% females) were analyzed before and after a three-week standardized pulmonary rehabilitation program. Lung function parameters were assessed using body-plethysmography and functional exercise capacity was measured by the Six-Minute Walk Test. At post-rehabilitation, females showed a significantly smaller improvement in maximal inspiration capacity and forced expiratory volume (F=5.86, ω2=.02; p<0.05) than males. Exercise capacity improvements between men and women did not differ statistically. Females made greater progress towards reference values of exercise capacity (T(231)=-3.04; p<0.01) and forced expiratory volume in the first second (T(231)=2.83; p<0.01) than males. Sex differences in the improvement of lung function parameters seem to exist and should be considered when personalizing standardized exercise therapies in pulmonary rehabilitation.

Extreme sports performance for more than a week with severely fractured sleep.

PURPOSE: Severely fractured sleep is mostly portrayed negatively, but investigations in extreme sports show that humans can maintain performance with a minimum of sleep. With two cases of long-lasting extreme sports performances, we demonstrate that severely fragmented sleep does not necessarily lead to a deterioration of physical and cognitive performance. METHODS: We performed continuous polysomnography on a 34 year-old skier for 11 days and nights during a world record attempt in long-term downhill skiing and monitored a 32 year-old cyclist during the Race Across America for 8.5 days via sleep and activity logs. RESULTS: The skier slept fractured fashion in 15-16 naps with a daily average of 6 h consisting of 77% in sleep stage 1 and 2, 11% in stage 3, and 13% in stage REM. The cyclist slept a total of 7 h and 52 min in 8.5 days, split up into 11 short naps and 6 sleep periods. The average duration of napping was 8.8 min and of sleep 64.2 min. CONCLUSIONS: These two cases demonstrate that outstanding performances are possible with severely fractured sleep and/or sleep deprivation. In well-trained athletes, breaking new recordsis possible despite extreme sleep habits.

Periodic breathing in healthy young adults in normobaric hypoxia equivalent to 3500 m, 4500 m, and 5500 m altitude.

PURPOSE: The occurrence of periodic breathing (PB) at high altitude during sleep and the quality of sleep are individually different and influenced by multiple factors including sex. Although poor sleep quality at high altitude might not be directly linked to oxygen desaturations, the PB upsurge at high altitude leads to significant oscillations in oxygen saturation. METHODS: Thirty-three students were recruited. Participants were randomly assigned to three groups (A, B, C) sleeping one full night in a dormitory with normobaric hypoxia at a FIO2 of 14.29% (A), a FIO2 of 12.47% (B), or a FIO2 of 10.82% (C). Full polysomnography was performed in each participant. RESULTS: Mean total sleeping time decreased significantly with increasing hypoxia (p < 0.001). Respiratory events changed from central hypopneas to central apneas (CA) with increasing hypoxia: CA = 17.8%, 50.0%, 92.2% of AHI (37.96 events per hour (n/h), 68.55 n/h, 93.44 n/h). AHI (p = 0.014) and time duration of respiratory events (p = 0.003) were significantly different between sexes, both greater in men. REM sleep was reduced. CONCLUSIONS: Men tend to be more prone to PB in normobaric hypoxia. Further research should implicate a longer acclimatization period around simulated 4500 m in order to find out if the exponential increase in PB between 4500 m and 5500 m could be shifted to lower hypoxic levels, i.e., higher altitudes.

Characterization of Batracylin-induced Renal and Bladder Toxicity in Rats.

Batracylin (NSC-320846) is a dual inhibitor of DNA topoisomerases I and II. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed. To further investigate batracylin's mechanism of toxicity, studies were conducted in Fischer 344 rats. Once daily oral administration of 16 or 32 mg/kg batracylin to rats for 4 days caused overt toxicity. Abnormal clinical observations and adverse effects on clinical pathology, urinalysis, and histology indicated acute renal damage and urothelial damage and bone marrow dysfunction. Scanning electron microscopy revealed sloughing of the superficial and intermediate urothelial layers. DNA damage was evident in kidney and bone marrow as indicated by histone γ-H2AX immunofluorescence. After a single oral administration of 16 or 32 mg/kg, the majority of batracylin was converted to N-acetylbatracylin (NAB) with a half-life of 4 hr to 11 hr. Mesna (Mesnex™), a drug known to reduce the incidence of hemorrhagic cystitis induced by ifosfamide or cyclophosphamide, was administered to rats prior to batracylin, but did not alleviate batracylin-induced bladder and renal toxicity. These findings suggest that batracylin results in DNA damage-based mechanisms of toxicity and not an acrolein-based mechanism of toxicity as occurs after ifosfamide or cyclophosphamide administration.

Tenofovir disoproxil fumarate: toxicity, toxicokinetics, and toxicogenomics analysis after 13 weeks of oral administration in mice.

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against HIV and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50-1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology end points. Plasma levels and systemic exposure of tenofovir increased less than dose proportionally and were similar on days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, after 4 and 13 weeks, cytomegaly was observed in mice treated with 1000 mg/kg of TDF, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression.

Sex-specific analysis of hiking accidents in the Austrian Alps: a follow-up from 2015 to 2021.

Background: Hiking is one of the most popular leisure sport activities practiced in the Alps during the summer season, but bears the risk of mountain emergencies, accidents, and fatalities. This paper provides an updated analysis of hiking accidents for the years 2015 to 2021 in the Austrian Alps, thereby outlining fatal and non-fatal accident characteristics. Methods: For this retrospective analysis, mountain hiking accidents documented by the Austrian Alpine Police during a 7-year period were screened for potential exclusion criteria. The final sample size consisted of 7368 accidents and 7552 victims. The outcome measures were mainly specified by sex, age, injury degree, injury location, pathophysiological characteristics, and cause of injury. Results: The overall annual number of accidents showed a continuous increase from 428 in 2015 to 544 in 2021. In total, 7.1% of the total victims died during the 7-year period, with male hikers being significantly more affected than female hikers (m: 80.8%, f: 19.2%; p ≤ 0.001). The sex specific distribution for non-fatal hiking accidents was 55.9% in women and 44.1% in men. Male victims showed significantly more frequent cardiovascular events (m: 78.5%, f: 21.5%), multiple injuries (m: 60.2%, f: 39.8%), and wounds/blood loss (m: 57.4%, f: 42.6%) than female victims, whereas women showed more fractures (m: 31.5%, f: 68.5%) than men (p ≤ 0.001). Additionally, men were more likely to injure their abdomen/chest (3.7%), head (14.1%), and multiple body parts (26.5%), whereas women were more likely to injure their ankle or foot (42.3%). Finally, men were more likely to have an accident during the ascent (24.1%), whereas women during the descent (69.0%) (p ≤ 0.001). Conclusion: This paper provides the latest data and a deeper insight into sex-specific characteristics of mountain hiking accidents in the Austrian Alps.

Effects of activity-oriented physiotherapy with and without eye movement training on dynamic balance, functional mobility, and eye movements in patients with Parkinson's disease: An assessor-blinded randomised controlled pilot trial.

OBJECTIVES: To describe changes in balance, walking speed, functional mobility, and eye movements following an activity-oriented physiotherapy (AOPT) or its combination with eye movement training (AOPT-E) in patients with Parkinson's disease (PD). To explore the feasibility of a full-scale randomised controlled trial (RCT). METHODS: Using an assessor-blinded pilot RCT, 25 patients with PD were allocated to either AOPT or AOPT-E. Supervised interventions were performed 30 minutes, 4x/weekly, for 4 weeks, alongside inpatient rehabilitation. Outcomes were assessed at baseline and post-intervention, including dynamic balance, walking speed, functional and dual-task mobility, ability to safely balance, health-related quality of life (HRQoL), depression, and eye movements (number/duration of fixations) using a mobile eye tracker. Freezing of gait (FOG), and falls-related self-efficacy were assessed at baseline, post-intervention, and 4-week follow-up. Effect sizes of 0.10 were considered weak, 0.30 moderate, and ≥0.50 strong. Feasibility was assessed using predefined criteria: recruitment, retention and adherence rates, adverse events, falls, and post-intervention acceptability using qualitative interviews. RESULTS: Improvements were observed in dynamic balance (effect size r = 0.216-0.427), walking speed (r = 0.165), functional and dual-task mobility (r = 0.306-0.413), ability to safely balance (r = 0.247), HRQoL (r = 0.024-0.650), and depression (r = 0.403). Falls-related self-efficacy (r = 0.621) and FOG (r = 0.248) showed varied improvements, partly sustained at follow-up. Eye movement improvements were observed after AOPT-E only. Feasibility analysis revealed that recruitment was below target, with less than two patients recruited per month due to COVID-19 restrictions. Feasibility targets were met, with a retention rate of 96% (95% confidence interval [CI]: 77.68-99.79) and a 98.18% (95% CI: 96.12-99.20) adherence rate, exceeding the targets of 80% and 75%, respectively. One adverse event unrelated to the study intervention confirmed intervention safety, and interview data indicated high intervention acceptability. CONCLUSIONS: AOPT-E and AOPT appeared to be effective in patients with PD. Feasibility of a larger RCT was confirmed and is needed to validate results.

Weight Loss and Fat Metabolism during Multi-Day High-Altitude Sojourns: A Hypothesis Based on Adipocyte Signaling.

Several publications and random observations have reported weight loss in high-altitude sojourners of both sexes. This could be a result of multiple adaptations, which hypoxia and mountaineering provoke on a cellular and organic level. Several publications have discussed the effect on appetite-regulating hormones to be one of the main contributing factors. We aimed to review the available data and show the current state of knowledge regarding nutritional aspects in high altitude with a special focus on fatty dietary forms. To reach this aim we conducted a literature search via PubMed according to the PRISMA 2020 protocol to identify relevant studies. We found that very few studies cover this field with scientifically satisfying evidence. For final analysis, reviews as well as papers that were not clearly related to the topic were excluded. Six articles were included discussing hormonal influences and the impact of exercise on appetite regulation as well as genetic factors altering metabolic processes at altitude. Leptin expression seems to be the biggest contributor to appetite reduction at altitude with an initial increase followed by a decrease in the course of time at high altitude. Its expression is greatly dependent on the amount of white adipose tissue. Since the expression of leptin is associated with an increased ß-oxidation of fatty acids, a high-fat diet could be advantageous at a certain time point in the course of high-altitude sojourns.

Expiratory Peak Flow and Minute Ventilation Are Significantly Increased at High Altitude versus Simulated Altitude in Normobaria.

Simulated altitude (normobaric hypoxia, NH) is used to study physiologic hypoxia responses of altitude. However, several publications show differences in physiological responses between NH and hypobaric conditions at altitude (hypobaric hypoxia, HH). The causality for these differences is controversially discussed. One theory is that the lower air density and environmental pressure in HH compared to NH lead to lower alveolar pressure and therefore lower oxygen diffusion in the lung. We hypothesized that, if this theory is correct, due to physical laws (Hagen-Poiseuille, Boyle), resistance respectively air compression (Boyle) at expiration should be lower, expiratory flow higher, and therefore peak flow and maximum expiratory flow (MEF) 75-50 increased in hypobaric hypoxia (HH) vs. normobaric hypoxia (NH). To prove the hypothesis of differences in respiratory flow as a result of lower alveolar pressure between HH and NH, we performed spirography in NH at different simulated altitudes and the corresponding altitudes in HH. In a cross over study, 6 healthy subjects (2 f/4 m, 28.3 ± 8.2 years, BMI: 23.2 ± 1.9) performed spirography as part of spiroergometry in a normobaric hypoxic room at a simulated altitude of 2800 m and after a seven-hour hike on a treadmill (average incline 14%, average walking speed 1.6 km/h) to the simulated summit of Mauna Kea at 4200 m. After a two-month washout, we repeated the spirometry in HH on the start and top of the Mauna Kea hiking trail, HI/USA. Comparison of NH (simulated 4200 m) and HH at 4200 m resulted in increased pulmonary ventilation during exercise (VE) (11.5%, p < 0.01), breathing-frequency (7.8%, p < 0.01), peak expiratory flow PEF (13.4%, p = 0.028), and MEF50 (15.9%, p = 0.028) in HH compared to NH, whereas VO2max decreased by 2%. At 2800 m, differences were only trendy, and at no altitude were differences in volume parameters. Spirography expresses higher mid expiratory flows and peak flows in HH vs. NH. This supports the theory of lower alveolar and small airway pressure due to a lower air density resulting in a lower resistance.

Effects of Acute Hypoxia on Lactate Thresholds and High-Intensity Endurance Performance-A Pilot Study.

The present project compared acute hypoxia-induced changes in lactate thresholds (methods according to Mader, Dickhuth and Cheng) with changes in high-intensity endurance performance. Six healthy and well-trained volunteers conducted graded cycle ergometer tests in normoxia and in acute normobaric hypoxia (simulated altitude 3000 m) to determine power output at three lactate thresholds (PMader, PDickhuth, PCheng). Subsequently, participants performed two maximal 30-min cycling time trials in normoxia (test 1 for habituation) and one in normobaric hypoxia to determine mean power output (Pmean). PMader, PDickhuth and PCheng decreased significantly from normoxia to hypoxia by 18.9 ± 9.6%, 18.4 ± 7.3%, and 11.5 ± 6.0%, whereas Pmean decreased by only 8.3 ± 1.6%. Correlation analyses revealed strong and significant correlations between Pmean and PMader (r = 0.935), PDickhuth (r = 0.931) and PCheng (r = 0.977) in normoxia and partly weaker significant correlations between Pmean and PMader (r = 0.941), PDickhuth (r = 0.869) and PCheng (r = 0.887) in hypoxia. PMader and PCheng did not significantly differ from Pmean (p = 0.867 and p = 0.784) in normoxia, whereas this was only the case for PCheng (p = 0.284) in hypoxia. Although investigated in a small and select sample, the results suggest a cautious application of lactate thresholds for exercise intensity prescription in hypoxia.

Cardiorespiratory and Metabolic Responses During Graded Exercise in Normobaric and Hypobaric Hypoxia.

Background: The study investigated submaximal exercise responses during an acute exposure to normobaric hypoxia (NH) versus hypobaric hypoxia (HH) focusing on different exercise intensities. Methods: Eight recreationally trained male subjects (age 23 ± 3 years) performed submaximal cycling exercise at three different intensity levels (100, 150, and 200 W) in NH (simulated altitude 3150 m) and HH (terrestrial high altitude, 3150 m) in a cross-over study design. Cardiorespiratory parameter, blood lactate concentration, and ratings of perceived exertion were determined at each intensity level. Results: Cardiorespiratory parameters, arterial oxygen saturation, and ratings of perceived exertion did not differ between NH and HH except for the higher ventilatory equivalent for oxygen in HH compared to NH (25.9 ± 1.3 vs. 24.6 ± 1.0 at 100 W, 28.0 ± 1.6 vs. 27.1 ± 1.6 at 150 W, 32.1 ± 3.9 vs. 31.3 ± 3.6 at 200 W, p = 0.03). Blood lactate concentration tended to be higher in HH compared to NH (1.8 ± 0.9 mmol/L vs. 1.7 ± 0.8 mmol/L at 100 W, 3.2 ± 1.8 mmol/L vs. 2.8 ± 1.6 mmol/L at 150 W, 6.0 ± 3.1 mmol/L vs. 5.5 ± 3.0 mmol/L at 200 W, p = 0.08) with a significant interaction effect for exercise intensity (p = 0.02). Conclusions: Cycling during acute exposure to NH appears to result in equivalent cardiorespiratory responses to HH. The more pronounced lactate accumulation in HH should be a topic of future research.

Adiponectin, Leptin and Visfatin in Hypoxia and its Effect for Weight Loss in Obesity.

Rationale: Hypoxia induces leptin gene expression in human adipocytes via hypoxia-inducible factors (HIF-α/ß). Under ambient moderate hypoxia, leptin in adipocytes is elevated for at least 14 days. Leptin is supposedly involved in the reduced food intake, increased utilization of fatty acids for energy production and possible weight loss observed at high altitudes. Literature on adiponectin and visfatin in high altitude is inconsistent with reports of elevated levels and non-elevated levels. Exercise in hypoxia studies in obese subjects have shown a significant weight loss after up to 3 weeks, but it is unclear if this effect holds up for longer time periods. Therefore, we aimed to investigate 32 obese subjects completing 52 exercise and rest sessions within 8 months at either moderate or sham hypoxia and to analyze leptin, adiponectin, and visfatin mRNA-expression at different time points of exposure. Methods: Abdominal subcutaneous fat biopsies were taken from 32 obese subjects before, after 3 months and after 8 months of intervention. Subjects were randomly divided into two groups and exercised at moderate intensity at two different study sites twice a week. The IG was exposed to normobaric hypoxia (FiO2: 14.0 ± 0.2%,) at exercise and at rest (FiO2: 12.0 ± 0.2%) and the CG to sham hypoxia. Quantitative real-time polymerase chain reaction (qPCR) was used in order to determine mRNA-levels of leptin, adiponectin, and visfatin. Results: No differences in leptin levels after 3 and 8 months compared to baseline and between groups were found. There was no significant difference regarding adiponectin or visfatin at any time point compared to baseline in the hypoxia group, but an increase after 3 months was seen in the control group at normoxia compared to the hypoxia group (adiponectin: p = 0.029 and visfatin: p = 0.014). Conclusion: In this first several months' duration randomized sham controlled hypoxia exercise and rest study with obese subjects, we found no time extended leptin mRNA-expression in subjects under hypoxia after 3 and 8 months compared to baseline levels. Moderate exercise in normoxia not in hypoxia leads to elevated adiponectin and visfatin levels after 3 months.

Evaluation of chemopreventive agents for genotoxic activity.

We conducted genetic toxicity evaluations of 11 candidate chemopreventive agents with the potential for inhibiting carcinogenesis in humans at increased risk of cancer. The compounds were evaluated for bacterial mutagenesis in the Salmonella-E. coli assay, for mammalian mutagenesis in mouse lymphoma cells, for chromosome aberrations in Chinese Hamster Ovary (CHO) cells, and for micronucleus induction in mouse bone marrow. Tested agents were indole 3-carbinol (I3C), bowman-birk inhibitor concentrate (BBIC), black tea polyphenols (BTP), farnesol, geraniol, l-Se-methylselenocysteine (SeMC), 5,6-dihydro-4H-cyclopenta[1,2]-dithiol-3-thione(DC-D3T), 4'-bromoflavone, 2,5,7,8-tetramethyl-(2R-[4R,8R,12-trimethyltridecyl] chroman-6-yloxy) acetic acid (alpha-TEA), SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo[2,3-b] carbazole and SR16157 (3-O-sulfamoyloxy-7alpha-methyl-21-(2-N,N-diethylaminoethoxy)-19-norpregna-1,3,5(10)-triene). All these agents, except I3C and BTP, were negative in the Salmonella-E. coli assay in the presence and absence of metabolic activation (S9). I3C and BTP induced a weak mutagenic response in the presence and absence of S9 with strains TA100 and TA98, respectively. Of the three compounds tested in the mouse lymphoma assay (I3C, BBIC, and BTP), only BTP was mutagenic in the presence of S9. In the chromosomal aberration assay, of the 8 compounds that were tested, 4'-bromoflavone elicited a positive response in the absence of S9 only, while SR16157 was positive in the presence of S9. The results with geraniol remain inconclusive. I3C, BBIC and BTP were not tested in the chromosomal aberration assay. None of the 11 agents induced micronuclei in mouse bone marrow erythrocytes.

The Linkage between Breast Cancer, Hypoxia, and Adipose Tissue.

OBJECTIVE: The development of breast cancer cells is linked to hypoxia. The hypoxia-induced factor HIF-1α influences metastasis through neovascularization. Hypoxia seems to decrease the responsiveness to hormonal treatment due to loss of estrogen receptors (ERs). Obesity is discussed to increase hypoxia in adipocytes, which promotes a favorable environment for tumor cells in mammary fat tissue, whereas, tumor cells profit from good oxygen supply and are influenced by its deprivation as target regions within tumors show. This review gives an overview of the current state on research of hypoxia and breast cancer in human adipose tissue. METHODS: A systematic literature search was conducted on PubMed (2000-2016) by applying hypoxia and/or adipocytes and breast cancer as keywords. Review articles were excluded as well as languages other than English or German. There was no restriction regarding the study design or type of breast cancer. A total of 35 papers were found. Eight studies were excluded due to missing at least two of the three keywords. One paper was removed due to Russian language, and one was dismissed due to lack of adherence. Seven papers were identified as reviews. After applying exclusion criteria, 18 articles were eligible for inclusion. RESULTS: Two articles describe the impairment of mammary epithelial cell polarization through hypoxic preconditioning. A high amount of adipocytes enhances cancer progression due to the increased expression of HIF-1α which causes the loss of ER α protein as stated in four articles. Four articles analyzed that increased activation of HIF's induces a series of transcriptions resulting in tumor angiogenesis. HIF inhibition, especially when combined with cytotoxic chemotherapy, holds strong potential for tumor suppression as stated in further four articles. In two articles there is evidence of a strong connection between hypoxia, oxidative stress and a poor prognosis for breast cancer via HIF regulated pathways. Acute hypoxia seems to normalize the microenvironment in breast cancer tissue and has proven to affect tumor growth positively as covered in two articles. CONCLUSION: This review indicates that the development of breast cancer is influenced by hypoxia. A high amount of adipocytes enhances cancer progression due to the increased expression of HIF-1α.

Endurance Training in Normobaric Hypoxia Imposes Less Physical Stress for Geriatric Rehabilitation.

Rationale: Evidence suggests that training in hypoxia can be very effective even while requiring less physical effort. We therefore aimed to measure the effect of endurance training under hypoxic conditions on pulmonary and cardiovascular parameters in an elderly population undergoing inpatient rehabilitation. Methods: Forty patients over age 65 years with multiple co-morbid conditions were recruited during a 3-week stay in a geriatric rehabilitation center. Using a randomized, single-blinded, placebo-controlled design, patients were assigned to a hypoxic (HG) or normoxic (NG) group. HG patients completed seven training sessions of 30 min duration on a treadmill in a normobaric chamber with inspired oxygen fraction (FiO2) of 15.27%, with 10-30 min active training. Training was conducted with target heart rate at 80% of peak oxygen consumption (VO2-peak). NG group performed similar training in sham hypoxia (room air or FiO2 = 20.94%). At pre- and post-test completion, measures included: (1) cycle ergometry with ECG monitoring and measurement of VO2-peak, and (2) echocardiography for ejection fraction. Results: The physical effort required of patients to reach target heart rate was reduced significantly (-28%, p = 0.043) in the HG compared to NG. Cardiopulmonary parameters showed no differences between groups. Conclusion: Endurance training at 3,000 meters elevation imposes less stress on the locomotor systems while resulting in a similar physiological strain (i.e., heart rate). Hypoxic training holds promise for successful geriatric rehabilitation by being more accommodating to physical limitations in geriatric patients. Trial registration: Registration at DRKS. (Approval No. 359/12, Trial No. DRKS00005241).

SpO2 and Heart Rate During a Real Hike at Altitude Are Significantly Different than at Its Simulation in Normobaric Hypoxia.

Rationale: Exposures to simulated altitude (normobaric hypoxia, NH) are frequently used in preparation for mountaineering activities at real altitude (hypobaric hypoxia, HH). However, physiological responses to exercise in NH and HH may differ. Unfortunately clinically useful information on such differences is largely lacking. This study therefore compared exercise responses between a simulated hike on a treadmill in NH and a similar field hike in HH. Methods: Six subjects (four men) participated in two trials, one in a NH chamber and a second in HH at an altitude of 4,205 m on the mountain Mauna Kea. Subjects hiked in each setting for 7 h including breaks. In NH, hiking was simulated by walking on a treadmill. To achieve maximal similarity between hikes, subjects used the same nutrition, clothes, and gear weight. Measurements of peripheral oxygen saturation (SpO2), heart rate (HR) and barometrical pressure (PB)/inspired oxygen fraction (FiO2) were taken every 15 min. Acute mountain sickness (AMS) symptoms were assessed using the Lake-Louise-Score at altitudes of 2,800, 3,500, and 4,200 m. Results: Mean SpO2 values of 85.8% in NH were significantly higher compared to those of 80.2% in HH (p = 0.027). Mean HR values of 103 bpm in NH were significantly lower than those of 121 bpm in HH (p = 0.029). AMS scores did not differ significantly between the two conditions. Conclusion: Physiological responses to exercise recorded in NH are different from those provoked by HH. These findings are of clinical importance for subjects using simulated altitude to prepare for activity at real altitude. Trial registration: Registration at DRKS. (Approval No. 359/12, Trial No. DRKS00005241).

Preclinical pharmacokinetic, toxicological and biomarker evaluation of SR16157, a novel dual-acting steroid sulfatase inhibitor and selective estrogen receptor modulator.

PURPOSE: SR16157 is a novel dual-acting inhibitor of estrogen action that irreversibly inhibits the estrogen biosynthetic enzyme steroid sulfatase (STS) and releases the selective estrogen receptor modulator SR16137, which blocks the estrogen receptor. SR16157 is a promising agent for the endocrine therapy of breast cancer. We conducted preclinical in vivo toxicity evaluations to determine the maximum-tolerated dose (MTD), target organ(s) of toxicity, reversibility, dose-limiting toxicity, no observable adverse effect level (NOAEL), and toxicokinetics (TK) and to investigate a potential biomarker for use in SR16157 clinical trials. METHODS: SR16157 was administered to female Fischer 344 rats or beagle dogs by oral gavage (po) or capsule. Intravenous (iv) groups were included for the determination of bioavailability. Endpoints evaluated included clinical observations, body weights, hematology, serum chemistry, pharmacokinetics, TK, pathology of tissues, and STS activity in liver, or peripheral blood mononuclear cells (PBMCs). RESULTS: For rats, the MTD (i.e., the highest dose that did not cause lethality but produced toxicity) was 33 mg/kg/day (198 mg/m(2)/day), and the NOAEL was <10 mg/kg/day (60 mg/m(2)/day). For dogs, the MTD was estimated to exceed 10 mg/kg/day (200 mg/m(2)/day), and the NOAEL was estimated to be at or above 2.5 mg/kg/day (50 mg/m(2)/day). CONCLUSIONS: Our studies demonstrate that SR16157 has excellent pharmacokinetic properties and an acceptable toxicological profile. Modulation of STS activity in PBMCs appeared to be a possible biomarker for use in future clinical trials of SR16157.