The role of Hsp90 in cell response to hyperthermia

(1) Preincubation of SKOV3 human ovarian carcinoma cells with a non-toxic dose of Geldanamycin resulted in exacerbation of hyperthermia-induced cytotoxicity and re-distribution of dying cells toward necrosis. (2) Exposure of primary human ovarian carcinoma cells to mild hyperthermia (42 °C for 2 h) led, after a recovery period of 16 h, to several-fold increase in the levels of Hsp90 and ErbB2, to a moderate decrease in the levels of phospho-Erk1/2, whereas the level of β-catenin appeared to be unchanged. (3) The inhibitors of Hsp90 (Geldanamycin and Novobiocin) significantly affected the cell signaling of heat-pretreated cultures. (4) The results suggest that Hsp90 plays a pivotal role in cell response to hyperthermia. (5) A combination of Hsp90 inhibitors with hyperthermia may considerably increase the efficacy of thermotherapy.     

Force variability depends on core and muscle temperature

The aim of this study was to investigate if voluntary activation and force variability during maximal voluntary contraction (MVC) depends more on muscle (local) or body (core) temperature. Ten volunteers performed a 2-min MVC of the knee extensors under the control (CON) conditions (ambient temperature (21 °C), relative humidity (30%), and air velocity (∼0.1 m/s)) as well as after heating (HT) and cooling (CL) of the lower body. During water manipulation procedure lower body was immersed up to the waist in a water bath at ∼44 °C for 45 min for HT experiment, and ∼15 °C for 30 min for CL experiment. Peak torque, torque variability, muscle voluntary activation and half-relaxation time were assessed during the exercise. HT increased muscle (2.8±0.2 °C) and rectal (1.9±0.1 °C) temperatures while CL lowered muscle (2.2±0.2 °C) temperature, but did not affect rectal temperature. During 2-min MVC, peak torque decreased (P<0.05; SP>90%) and to a lower level in HT compared to CON and CL experiments (52.6±2.3% versus 69.0±2.3% and 65.6±1.9% MVC, respectively, P<0.05; SP>90%). Torque variability increased significantly during exercise and was significantly larger in HT and lower in CL compared to CON experiment. Voluntary activation of exercising muscle was more depressed in HT (i.e. greater central fatigue) and the smallest effect was found in CL compared to CON. In conclusion increased core and muscle temperature impairs voluntary activation and increases force variability of the exercising muscles while a local muscle cooling decrease force variability but has a small effect on central fatigue.     

Quasi-total-body exposure to an oxygen-ozone mixture in a sauna cabin

We have investigated the effects of quasi-total-body exposure of healthy volunteers to either an oxygen-ozone mixture (O(2)-O(3)) or to oxygen (O(2)) alone during a short period in a sauna cabin. The subjects underwent both an experimental and a control examination, separated by a 3.5-month interval. Body mass, blood pressure, body temperature changes, electrocardiograms, venous blood gas and haemocytometric analyses, total antioxidant status and plasma levels of protein thiol groups, thiobarbituric acid reactive substances (TBARS), plasma cytokine, hepatic enzymes and creatine were determined before, immediately after the 20-min period in the cabin and then 0.5, 1.0 and 24 h afterwards. We observed statistically significant variations of body temperature, venous partial pressure of O(2) values, TBARS and plasma levels of interleukin 8, particularly after O(2)-O(3) exposure. The increase in TBARS plasma levels concomitant with protein oxidation has been tentatively interpreted as being attributable to the transcutaneous passage of some reactive O(2) species, which should be considered if this approach is to be used as a biological response modifier. However, in the present study no adverse effects were noted after one session.     

Repeated hyperthermia exposure increases circulating Brain Derived Neurotrophic Factor levels which is associated with improved quality of life,and reduced anxiety: A randomized controlled trial

ContextHyperthermia is known to be beneficial to patients affected by various diseases. Brain Derived Neurotrophic Factor (BDNF) is a marker of neuroplasticity usually increased as response to acute exposure to human body stressors. Little is known about BDNF changes after repeated exposure to hyperthermia.ObjectiveTo investigate the effect of a repeated hyperthermia exposure programme (HTC) on serum BDNF in healthy humans.Design, setting, participantsRandomized, single-blind, controlled trial in healthy humans conducted at Sechenov University Physiology Laboratory between December 2016 and November 2018. The treatment period was 10 weeks. Researchers analysing serum BDNF and questionnaires data were blinded to participants allocation.ParticipantsWere 34 healthy male (age 20.2 ± 1.6 years).InterventionRepeated Hyperthermia exposure programme, HTC, versus Light Intermittent Exercise, LIE, programme as control (10 weeks).Main outcome measureChange in BDNF from baseline to final visit three days after treatment completion.Results25 participants were analyzed. One participant withdrew before signing the informed consent and 8 participants (n = 3 in HTC and n = 5 in LIE) could not undertake the first assessment and were excluded. Mean change in BDNF was higher in HTC group vs LIE after both time points (after 12 and after 24 sessions). After 24 sessions BDNF was 30170 (SD 5268) pg/ml in HTC group a value that was significantly higher than 24104 (SD 2876) pg/ml measured in LIE group. BDNF concentrations were significantly higher than baseline values in HTC group only, 30170 (SD 5268) vs 26710 (SD 5437) pg/ml.ConclusionA 10-week programme consisting of repeated exposure to hyperthermia resulted in a significantly higher increase of circulating BDNF compared to a programme consisting of intermittent light intensity exercise.     

The efficacy of antibiotics in reducing morbidity and mortality from heatstroke – A systematic review

Severe hyperthermia, for example, classical heatstroke or exertional heatstroke from heatwaves or exercise respectively, or from drug ingestion or other non-infective pyrogens, is associated with a high mortality and morbidity, which may be chronic or permanent. Abolition of lipopolysaccharide, from gram-negative intestinal bacteria translocating into the systemic circulation via an intestinal wall rendered permeable from the hyperthermia, reduces the adverse effects, suggesting that antibiotics against the intestinal bacteria may have a similar effect. A systematic review searching Embase, MEDLINE and PubMed from the earliest date available until 2019 was conducted, according to PRISMA guidelines. Two papers were found which fit the criteria. In one, non-absorbable oral antibiotics were administered prior to the onset of heat stress, which reduced the cardiovascular dysfunction and rise in endotoxaemia, but animals succumbed at a lower temperature. In the second, non-absorbable oral antibiotics, in combination with a laxative and enema, given prior to the onset of heat stress, improved mortality; antibiotics administered after the heat stress did not, but the antibiotics used may have limited action against intestinal bacteria. Only two papers were found; both suggest an improvement in organ dysfunction or mortality after an episode of heat stress. No papers were found that investigate the sole use of antibiotics effective against intestinal bacteria given after the onset of heat stress, although biological plausibility suggest they warrant further research.     

3D in silico study of magnetic fluid hyperthermia of breast tumor using Fe3O4 magnetic nanoparticles

Modeling and simulation of the temperature distribution, the mass concentration, and the heat transfer in the breast tissue are hot issues in magnetic fluid hyperthermia treatment of cancer. The breast tissue can be visualized as a porous matrix with saturated blood. In this paper, 3D in silico study of breast cancer hyperthermia using magnetic nanoparticles (MNPs) is conducted. The 3D FEM models are incorporated to investigate the infusion and backflow of nanofluid in the breast tumor, the diffusion of nanofluid, temperature distribution during the treatment, and prediction of the fraction of tumor necrosis while dealing with the thermal therapy. All the hyperthermia procedures are simulated and analyzed on COMSOL Multiphysics. The sensitivity of frequency and amplitude of the applied magnetic field (AMF) is investigated on the heating effect of the tumor. The mesh dependent solution of Penne's bioheat model is also analyzed. The simulated results demonstrate successful breast cancer treatment using MNPs with minimum side effects. Validation of current simulations results with experimental studies existing in literature advocates the success of our therapy. The increase in the amplitude and frequency of the AMF increases of the temperature in the tumor. The variation of mesh from coarser to finer increased the temperature through small fractions. We have also simulated the magnetic induction problem where the magnetic field is generated by current-carrying coil conductors induce heat in nearby breast tumors due to excitation of MNPs by magnetic flux. This research will aid treatment protocols and real-time clinical breast cancer treatments.     

The capacity of lysosomes of cultured mammalian cells to accumulate acridine orange is destroyed by hyperthermia

Summary Lysosomes of cultured mammalian cells, derived from a transplantable murine mammary adenocarcinoma, irreversibly lose their capacity to accumulate the fluorescent dye acridine orange after hyperthermia. As acridine orange may be regarded as a fluorescent probe of the internal pH of the lysosomes, we may conclude that the ability of lysosomes to maintain a low internal pH is destroyed by hyperthermia.The effects of hyperthermia on lysosome fluorescence and on cell survival show several similarities: in both cases hyperthermia is more effective at low pH, below pH 7.0, and CCP (carbonylcyanide-m-chlorophenylhydrazone) enhances effects at low pH, but has no clear effect at pH 8.0. This leads to the conclusion that effects on lysosomes are an important and early event in cellular injury caused by hyperthermia. The activation energy, however, obtained for the effects of hyperthermia on lysosome fluorescence is about a factor of two lower than the activation energy reported for cell survival after hyperthermia. This suggests that the effect on lysosomes is not directly caused by hyperthermia but is triggered by some other hyperthermia-induced cellular damage.Abbreviations CCP carbonylcyanide-m-chlorophenylhydrazone - MES 2-(N-morpholino)ethanesulfonic acid - MOPS 2-(N-morpholino)propanesulfonic acid - Tricine N-tris(hydroxymethyl)methylglycine Supported in part by grants from the KWF (Koningin Wilhelmina Fonds) and the IRS (Interuniversitair Instituut voor Radiopathologie en Stralenbescherming)     

Brain temperature and limits on transcranial cooling in humans: quantitative modeling results

Selective brain cooling (SBC) of varying strengths has been demonstrated in a number of mammals and appears to play a role in systemic thermoregulation. Although primates lack obvious specialization for SBC, the possibility of brain cooling in humans has been debated for many years. This paper reports on the use of mathematical modeling to explore whether surface cooling can control effectively the temperature of the human cerebrum. The brain was modeled as a hemisphere with a volume of 1.33 1 and overlying layers of cerebrospinal fluid, skull, and scalp. Each component was assigned appropriate dimensions, physical properties and physiological characteristics that were determined from the literature. The effects of blood flow and of thermal conduction were modeled using the steady-state form of the bio-heat equation. Input parameters included core (arterial) temperature: normal (37°C) or hyperthermic (40°C), air temperature: warm (30°C) or hot (40°C), and sweat evaporation rate: 0, 0.25, or 0.50 l · m⁻² · h⁻¹. The resulting skin temperatures of the model ranged from 31.8°C to 40.2°C, values which are consistent with data obtained from the literature. Cerebral temperatures were generally insensitive to surface conditions (air temperature and evaporation rate), which affected only the most superficial level of the cerebrum (≤1.5 mm) The remaining parenchymal temperatures were 0.2–0.3°C above arterial temperatures, regardless of surface conditions. This held true even for the worst-case conditions combining core hyperthermia in a hot environment with zero evaporative cooling. Modeling showed that the low surface-to-volume ratio, low tissue conductivity, and high rate of cerebral perfusion combine to minimize the potential impact of surface cooling, whether by transcranial venous flow or by conduction through intervening layers to the skin or mucosal surfaces. The dense capillary network in the brain assures that its temperature closely follows arterial temperature and is controlled through systemic thermoregulation independent of head surface temperature. A review of the literature reveals several independent lines of evidence which support these findings and indicate the absence of functionally significant transcranial venous flow in either direction. Given the fact that humans sometimes work under conditions which produce face and scalp temperatures that are above core temperature, a transcranial thermal link would not necessarily protect the brain, but might instead increase its vulnerability to environmentally induced thermal injury. Accepted: 11 March 1998