Browsing by Subject "Hyperthermia"

Now showing 1 - 4 of 4

Heat shock-induced apoptosis
(2013-12) Mahajan, Indra Maria; Wright, Casey Wyatt; Bratton, Shawn B.
Apoptosis is a conserved program of cell death that promotes organism homeostasis in all stages of life. Two main pathways activate caspases, which are cysteinyl-aspartate proteases that execute apoptosis. The extrinsic pathway is initiated by cell surface death receptors, while the intrinsic pathway is initiated by intracellular signals that cause permeabilization of the outer mitochondrial membrane (MOMP). The Bcl-2 protein family regulates MOMP, which causes the release of several pro-apoptotic proteins (such as cytochrome c, Smac) into the cytosol. Bcl-2 proteins share homology in up to four "BH" domains and are subdivided into three subgroups. Pro-apoptotic Bax and Bak catalyze pore formation in the mitochondria, while anti-apoptotic members (Bcl-2, Mcl-1) inhibit MOMP. The third subgroup, termed BH3-only, promotes MOMP by either antagonizing Bcl-2 proteins or by directly activating Bax/Bak, and initiate apoptosis in response to various stressors, including heat shock (HS). Hyperthermia or acute HS reportedly induces apoptosis through caspase-2-mediated cleavage of BID, engaging the intrinsic pathway. However, additional evidence suggests that this pathway could represent an amplification loop. Thus we hypothesized that during HS, another BH3-only protein such as BIM, that does not require cleavage, could engage MOMP. Herein, we report that BIM mediates an alternative HS-induced apoptosis pathway. Cells lacking BIM are resistant to HS and exhibit better short and long-term survival than either Bid[superscript -/-] or Bax[superscript -/-]Bak[superscript -/-]. Moreover, caspase-2 induces apoptosis in Bim[superscript -/-] but not Bid[superscript -/-] cells, implying that caspase-2 kills exclusively through BID. Interestingly, Bim[superscript -/-] and Bax[superscript -/-]Bak[superscript -/-] cells are entirely resistant to MOMP, but the Bax[superscript -/-]Bak[superscript -/-] cells still undergo caspase-3 activation and remain partially sensitive to HS, indicating that BIM triggers caspase-3 activation upstream of mitochondria. Thus, BIM plays an important role in HS-induced apoptosis. Hyperthermia has clinical applications for the treatment of solid tumors. Unfortunately, a practical limitation is the development of thermotolerance, which confers resistance not only to subsequent HS but also to radiotherapy and chemotherapy. Therefore, a better understanding of the molecular mechanisms involved both in heat-induced apoptosis and thermotolerance could lead to new therapeutic interventions. Here we also show evidence for a putative role for the stress kinase JNK signaling pathway in the regulation of thermotolerance.
Impact of intensity and body temperature on cardiovascular responses to exercise
(2009-12) Trinity, Joel Douglas; Coyle, Edward F., 1952-
These studies investigated the impact of intensity and body temperature on performance and cardiovascular regulation during high intensity and prolonged exercise. In study 1, polyphenol antioxidant supplementation proved to have no effect on exercise performance and related variables (gross efficiency, perceived exertion, maximal power) during exercise in the heat. Furthermore, there were no differences between the cardiovascular or thermoregulatory responses between control and antioxidant treatments. Study 2 utilized an integrative approach to investigate a classic topic in exercise physiology, namely, is the cardiac output to oxygen consumption relationship linear across a wide range of exercise intensities? The slope of the CO vs. VO2 relationship was significantly reduced from 70 to 100% of VO2max when compared to the slope from 40 to 70% of VO2max (2.0 ± 0.4 vs. 4.4 ± 0.3 l/min, p = 0.025). This finding, in combination with the plateau and eventual reduction in stroke volume at high intensity exercise compared to moderate intensity exercise (146.0 ± 16.6 vs. 138.5 ± 14.9 ml/beat, p = 0.015), argues in favor of a cardiac limitation to high intensity exercise. This study also showed that the pattern of oxygen extraction at the whole body level (arterial venous O2 difference) and the muscle level (deoxygenated hemoglobin) is not similar and that muscle specific differences exist regarding oxygen extraction. Study 3 determined that hyperthermia (elevation of skin temperature by 4.3°C and core temperature by 0.8°C) did not reduce SV independent of the increase in HR. Even under conditions of moderate hyperthermia the reduction in SV is due to the increase in HR and temporally unrelated to increases in cutaneous blood flow. In summary, antioxidant supplementation had no effect on performance, cardiovascular, or thermoregulatory responses to exercise in the heat in well trained subjects. High intensity exercise is associated with a reduced rate of increase in the CO vs. VO2 relationship. Finally, hyperthermia does not reduce SV during exercise when HR is maintained at normal levels.
Mechanisms of heat stress- and obesity-induced reductions in orthostatic tolerance
(2013-08) Lee, Joshua Floyd; Brothers, Robert Matthew
These studies investigated 1) mechanisms underlying the well-established reduction in orthostatic tolerance (OT) that occurs in humans during heat stress (HS) relative to normothermia (NT) with particular focus on determining factors contributing to the high degree of inter-individual variability in this phenomenon; and 2) influence of obesity on OT, and mechanisms underlying reduced OT, should it exist. In Study #1, OT was assessed during lower body negative pressure (LBNP), and quantified with a cumulative stress index (CSI). Differences in CSI (CSIdiff) between thermal conditions were used to categorize individuals most (LargeDiff) and least (SmallDiff) affected by HS (P<0.001). Cerebral perfusion [indexed as middle cerebral artery blood velocity (MCA Vm̳̳e̳a̳n̳)] was reduced during HS compared to NT (P<0.001); however, the magnitude of reduction did not differ between groups (P=0.51). In the initial stage of LBNP during HS (LBNP20), MCA Vm̳̳e̳a̳n̳ and end-tidal CO₂ (PETC̳O̳₂) were reduced, and heart rate (HR) was higher in the LargeDiff group compared to SmallDiff group (all P<0.05); yet, mean arterial pressure was similar (P=0.23) suggesting impaired mechanisms regulating MCA Vm̳̳e̳a̳n̳ may affect OT. In Study #2, mechanisms of cerebrovascular control were compared in LargeDiff and SmallDiff individuals. Although estimates of cerebral autoregulation (CA) and cerebrovascular reactivity to CO₂ were improved and reduced respectively, during HS compared to NT (all P<0.05), no relationship existed between CA or cerebral reactivity to hypocapnia and CSIdiff (all P>0.05). In Study #3, OT was lower in obese compared to non-obese individuals (P<0.01), and BMI was negatively correlated with CSI (R = -0.47; P < 0.01). HR was elevated at rest and in every level of LBNP (all P<0.05) in obese; yet, peak HR during LBNP was similar between groups (P=0.90). MCA Vm̳̳e̳a̳n̳ and cerebral vascular conductance were similar at rest and during LBNP (both P>0.05), and CA was similar between groups (P>0.05). In summary, a high HR prior to-, and a high HR and reduced MCA Vm̳̳e̳a̳n̳ at the onset of an orthostatic challenge result in reduced OT during HS in healthy individuals; however, reduced OT in obese is related to a higher %peak HR at rest.
RF/microwave absorbing nanoparticles and hyperthermia
(2009-12) Cook, Jason Ray; Emelianov, Stanislav Y.; Pearce, John A.
The primary purpose of this work was to evaluate the capability of nanoparticles to transform electromagnetic energy at microwave frequencies into therapeutic heating. Targeted nanoparticles, in conjunction with microwave irradiation, can increase the temperatures of the targeted area over the peripheral region. Therefore, to become clinically viable, microwave absorbing nanoparticles must first be identified, and a system to monitor the treatment must be developed. In this study, ultrasound temperature imaging was used to monitor the temperature of deep lying structures. First, a material-dependent quantity to correlate the temperature induced changes in ultrasound images (i.e. apparent time shifts) to differential temperatures was gathered for a tissue-mimicking phantom, porcine longissimus dorsi muscle, and porcine fat. Then microwave nanoabsorbers were identified using an infrared radiometer. The determined nanoabsorbers were then injected into ex-vivo porcine longissimus dorsi muscle tissue. Ultrasound imaging frames were gathered during microwave treatment of the inoculated tissue. Finally, the ultrasound frames were analyzed using the correlation between temperature and apparent shifts in ultrasound for porcine muscle tissue. The outcome was depth-resolved temperature profiles of the ex-vivo porcine muscle during treatment. The results of this study show that magnetite is a microwave nanoabsorber that increases the targeted temperature of microwave hyperthermia treatments. Overall, there is clinical potential to use microwave nanoabsorbers to increase the efficiency of microwave hyperthermia treatments.