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Correction to “From Structure to Function: Zn/Mn-Modified Maghemite as an Advanced Nanoplatform for Magnetic Hyperthermia and Radionuclide Therapy”

In the original paper, the acknowledgment contained an error in the attribution of the financial support. The correction is necessary to accurately reflect the source of funding that supported the contributions of the authors from the Institute of Physics Belgrade. The corrected Acknowledgments section is below. Here, this correction pertains solely to the funding acknowledgment and does not affect the scientific content, data, results, or conclusion of the work in any way.

Cancer therapy↗

Temperature controller for hyperthermia devices

Temperature controller monitors and controls temperature in local region of tumor. Medical grade thermocouples are inserted in or near tumor, controller pulse modulates radio frequency diathermy power source to maintain temperature within 0.2 C. System may be extended to control diathermy of more than one tumor or patient.

Couch, R. H.↗

Hyperthermia heating apparatus

Electromagnetic energy is delivered to a localized area of a patient's body in a hyperthermic treatment so that it provides a uniform distribution of electromagnetic flux lines within the localized area of the patient's body and produces a uniform and localized heating gradient. An electrode array includes a number of electrodes which are arranged in pair, with the electrodes in each pair being spaced a particular distance apart. The array is driven by a balanced line system which is electromagnetically coupled to each pair of electrodes and which is shielded by a ground coaxial shield which itself is ground to the body of the patient. Each electrode is embedded in a Teflon stand-off in order to move the region of strong field, from the body, produced by rapidly changing potentials. The two pairs of electrodes forming a cross-like geometry are used with the balanced line systems. The electrical power is either multiplexed among the electrodes or the second pair is driven by a potential which is sinusoidal and which is 90% out of phase with the first balanced line system which is also sinusoidal.

Gammell, P. M.↗

Exercise hyperthermia as a factor limiting physical performance - Temperature effect on muscle metabolism

The effect of trunk cooling on the muscle contents of ATP, ADP, AMP, creatine phosphate (CrP), and creatine, as well as of glycogen, some glycolytic intermediates, pyruvate, and lactate were assessed in 11 fasted dogs exercised at 20 C on treadmill to exhaustion. Without cooling, dogs were able to run 57 min, and their rectal (Tre) and muscle (Tm) temperatures increased to 41.8 and 43.0 C, respectively. Cooling with ice packs prolonged the ability to run by 45 percent, and resulted in lower Tre (by 1.1 C) and Tm (by 1.2 C). Depletion of muscle content of total high-energy phosphates (ATP + CrP) and glycogen, and increases in contents of AMP, pyruvate, and lactate were lower in cooled dogs than in non-cooled dogs. The muscle content of lactiate correlated positively with TM. These results indicate that hypothermia accelerates glycolysis, and shifts the equilibrium between high- and low-energy phosphates in favor of the latter. The adverse effect of hypothermia on muscle metabolism may be relevant to the limitation of endurance.

Kozlowski, S.↗

Magnetic Microspheres for Therapeutical Applications

Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady. The basic obstacle of the present heating methods are non-uniform thermal properties of the tissue. Our approach is to develop a novel class of magnetic fluids which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as a suitable nano-particle material. The objective is to synthesize, characterize and evaluate the efficacy of TRMF for hyperthermia therapy.

Mazuruk, K.↗

Magnetic Microspheres and Tissue Model Studies for Therapeutical Applications

Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia breast therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady for an extended period (2-3 hours). The basic shortcomings of the presently utilized heating methods stem from the non-uniform thermal properties of the tissue and the point heating characteristics of the techniques without any thermal control. Our approach is to develop a novel class of magnetic fluids, which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as suitable nano to micron-size particle material. The objective is to synthesize, characterize and evaluate the efficacy of Thermo Regulating Magnetic Fluids (TRMF) for hyperthermia therapy. The development of a tissue model and testing the fluid dynamics of particle motion, settling, distribution in the tissue matrix and heat generation will be discussed.

Ramachandran, N.↗

Central effects of some peptide and non-peptide opioids and naloxone on thermoregulation in the rabbit

The effects of several peptide and non-peptide opiods and naloxone on induced hyperthermia is studied in rabbits. The effect of tyical mu, kappa, and sigma receptor antagonists (morphine, ketocyclazcine and SKF 10,0 10, 047) and some opioid peptides (Beta-endorphin /BE/, methionine-enkaphalin /ME/, and D-Ala2-methionine-enkaphalin-amide /DAME/ are determined. The role of prostaglandins (PG), cAMP, and norepinephrine (NE) in morphine, BE, and DAME induced hyperthermia is investigated. In addition, the effect of naloxone on pyrogen, arachidonic acid, PGE2, prostacyclin, dibutyryl cAMP, and NE induced hyperthermia is determined. Among other results, it is found that the three receptor antagonists induced hyperthermia in rabbits. BE, ME, and DAME were also found to cause hyperthermia, and it is suggested that they act on the same type of receptor. It is also determined that neither NE nor cAMP is involved in the hyperthermia due to morphine, BE, and DAME. It is suggested that an action of endogenous peptides on naloxone sensitive receptors plays little role in normal thermoregulation or in hyperthermia.

Kandasamy, S. B.↗

Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig

The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl normetazocine and an agonist at both kappa and sigma receptors, pentazocine, was found to induce hyperthermia in guinea pigs. The similar administration of peptide opioids like beta endorphin, methionine endkephalin, leucine endkephaline, and several of their synthetic analogues was also found to cause hyperthermia. Only the liver-like transport system of the three anion transport systems (iodide, hippurate, and liver-like) present in the choroid plexus was determined to be important to the central inactivation of beta-endorphin and two synthetic analogues. Prostaglandins and norepinephrine (NE) as well as cAMP were not involved in peptide and nonpeptide opioid-induced hyperthermia. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine and beta-endorphin, while hyperthermic responses to ketocyclazocine, N-allyl normetazocine, pentazocine, Met-enkephalin, Leu-enkephalin, and two of the synthetic analogues were not antagonized by nalozone. The lack of antagonism of naloxone on pyrogen, arachidonic acid, PGE2, dibutyryl cAMP, and NE-induced hyperthermia shows that endogenous opioid peptides are not likely to be central mediators of the hyperthermia induced by these agents.

Kandasamy, S. B.↗

Muscle metaboreceptor modulation of cutaneous active vasodilation

PURPOSE: Isometric handgrip exercise in hyperthermia has been shown to reduce cutaneous vascular conductance (CVC) by inhibiting the cutaneous active vasodilator system. METHODS: To identify whether this response was initiated by muscle metaboreceptors, in seven subjects two 3-min bouts of isometric handgrip exercise in hyperthermia were performed, followed by 2 min of postexercise ischemia (PEI). An index of forearm skin blood flow (laser-Doppler flowmetry) was measured on the contralateral arm at an unblocked site and at a site at which adrenergic vasoconstrictor function was blocked via bretylium iontophoresis to reveal active cutaneous vasodilator function unambiguously. Sweat rate was measured via capacitance hygrometry, CVC was indexed from the ratio of skin blood flow to mean arterial pressure and was expressed as a percentage of maximal CVC at that site. In normothermia, neither isometric exercise nor PEI affected CVC (P > 0.05). RESULTS: The first bout of isometric handgrip exercise in hyperthermia reduced CVC at control sites and this reduction persisted through PEI (pre-exercise: 59.8 +/- 5.4, exercise: 49.8 +/- 4.9, PEI: 49.7 +/- 5.3% of maximum; both P < 0.05), whereas there were no significant changes in CVC at the bretylium treated sites. The succeeding bout of isometric exercise in hyperthermia significantly reduced CVC at both untreated (pre-exercise: 59.0 +/- 4.8, exercise: 47.3 +/- 4.0, PEI: 50.1 +/- 4.1% of maximum; both P < 0.05) and bretylium treated sites (pre-exercise: 61.4 +/- 7.3, exercise: 50.6 +/- 5.1, PEI: 53.9 +/- 6.0% of maximum, both P < 0.05). At both sites, CVC during PEI was lower than during the pre-exercise period (P < 0.05). Sweat rate rose significantly during both bouts of isometric exercise and remained elevated during PEI. CONCLUSIONS: These data suggest that the reduction in CVC during isometric exercise in hyperthermia, including the inhibition of the active vasodilator system, is primarily mediated by muscle metaboreceptors, whereas central command or muscle mechanoreceptors have less influence.

Non-NASA Center↗

Thermoregulation During Spaceflight

The purpose of this flight proposal is to investigate human thermoregulatory parameters during exercise in microgravity. The hypothesis to be tested is that microgravity-adopted astronauts will exhibit accentuated increases in their core temperature (excess hyperthermia) during exercise because of altered heat loss responses due to reduced sweating and/or accentuated vasodilation. The specific aims are (1) to compare core and skin temperature responses during moderate exercise before flight and inflight; (2) to determine whether the hypothesized inflight excessive hyperthermia is due to increased heat production, reduced, sweating, impaired peripheral vasodilation, or to some combination of these factors; and (3) to determine whether heat production at an exercise load of 60 percent of the maximal working capacity is similar preflight and inflight. It is expected that the astronauts will exhibit excessive hyperthermia during exposure to microgravity which will be caused by decreased sweating and decreased skin blood flow.

Greenleaf, John E.↗

Dual-Responsive Turn-On T 1 Imaging-Guided Mild Photothermia for Precise Apoptotic Cancer Therapy

Apoptosis has gained increasing attention in cancer therapy as an intrinsic signaling pathway, which leads to minimal leakage of waste products from a dying cell to neighboring normal cells. Among various stimuli to trigger apoptosis, mild hyperthermia is attractive but confronts limitations of non-specific heating and acquired resistance from elevated expression of heat shock proteins. Here, a dual-stimulation activated turn-on T 1 imaging-based nanoparticulate system (DAS) is developed for mild photothermia (≈43 °C)-mediated precise apoptotic cancer therapy. In the DAS, a superparamagnetic quencher (ferroferric oxide nanoparticles, Fe 3 O 4 NPs) and a paramagnetic enhancer (Gd-DOTA complexes) are connected via the N6-methyladenine (m 6 A)-caged, Zn 2+ -dependent DNAzyme molecular device. The substrate strand of the DNAzyme contains one segment of Gd-DOTA complex-labeled sequence and another one of HSP70 antisense oligonucleotide. When the DAS is taken up by cancer cells, overexpressed fat mass and obesity-associated protein (FTO) specifically demethylates the m 6</-sup>A group, thereby activating DNAzymes to cleave the substrate strand and simultaneously releasing Gd-DOTA complex-labeled oligonucleotides. The restored T 1 signal from the liberated Gd-DOTA complexes lights up the tumor to guide the location and time of deploying 808 nm laser irradiation. Afterward, locally generated mild photothermia works in concert with HSP70 antisense oligonucleotides to promote apoptosis of tumor cells. This highly integrated design provides an alternative strategy for mild hyperthermia-mediated precise apoptotic cancer therapy.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Photothermal Properties of Nanostructured Black Titanium Dioxide for Targeted Cellular and Microbial Elimination

Heterophase black titanium dioxide (hB-TiO 2 ), characterized by broadened near-infrared (NIR) absorption, has emerged as a promising photothermally active nanomaterial. This study focused on the synthesis of nanoscale hB-TiO 2 and its evaluation as a multifunctional agent for photothermal therapy (PTT). The purity and composition of the mixed-phase nanoscale hB-TiO 2 were demonstrated by X-ray diffraction, and the morphology of nanoparticles was imaged by transmission electron microscopy. Extensive additional characterization was conducted to validate the optoelectronic properties. The material was further evaluated in biological systems using NIH 3T3-GFP fibroblasts and the fungus Candida albicans. Nanoscale hB-TiO 2 exhibited good biocompatibility in the absence of laser irradiation and effectively ablated both NIH 3T3-GFP cells and C. albicans following 20 min of laser exposure. This noninvasive treatment strategy leverages NIR-responsive materials to induce localized hyperthermia. The findings provide grounds for the use of selectively induced hyperthermia, which could be employed for the targeted destruction of cells or fungi with minimal impact on surrounding tissue if the material is functionalized with specific targeting groups and delivered to cells or fungal infections.

Irradiation↗

Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs

It is shown that the intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP) induced hyperthermia in guinea pigs which was not mediated through prostaglandins or norepinephrine since a prostaglandin synthesis inhibitor and an alpha-adrenergic receptor blocking agent did not antagonize the hyperthermia. However, the hyperthermic response to Db-cAMP was attenuated by the central administration of a beta-adrenergic receptor antagonist, which indicates that cAMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production and conservation. The central administration of Db-cGMP produced hypothermia which was not mediated via histamine H1 or H2 receptors and serotonin. The antagonism of hypothermia induced by Db-cGMP and acetylcholine + physostigmine by central administration of a cholinergic muscarine receptor antagonist and not by a cholinergic nicotinic receptor antagonist suggests that cholinoceptive neurons and endogenous cGMP may regulate heat loss through cholinergic muscarine receptors. It is concluded that these results indicate a regulatory role in thermoregulation provided by a balance between opposing actions of cAMP and cGMP in guinea pigs.

Kandasamy, S. B.↗

Hypothermic and antipyretic effects of ACTH (1-24) and alpha-melanotropin in guinea-pigs

Intracerebroventricular administration of adrenocorticotropin (ACTH 1-24) and alpha-melanotropin (alpha-MSH), peptides which occur naturally in brain induced dose-related hypothermia in guinea-pigs at room temperature (21 C) and also produced greater hypothermia at low (10 C) ambient temperature. However, when the experiments were repeated in a warm (30 C) environment, no effect on body temperature was observed. These results indicate that the peptides did not reduce the central set-point of temperature control. The hypothermia induced by ACTH and alpha-MSH was not mediated via histamine H1- or H2-receptors and serotonin since the H1-receptor antagonist, mepyramine, the H2-receptor antagonist, cimetidine, and the serotonin antagonist, methysergide, had no antagonistic effects. The peptides were antipyretic since they reduced pyrogen-induced-fever and hyperthermia due to prostaglandin E2, norepinephrine and dibutyryl cAMP, at a dose which did not affect normal body temperature. The powerful central effects of these peptides on normal body temperature, fever and hyperthermia, together with their presence of the brain regions important to temperature control, suggest that they participate in thermoregulation.

Kandasamy, S. B.↗