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Molecule hydrogen (H2) has been used to suppress tumor growth. To employ the H2 therapy, it is necessary to use a proper agent for continuous generation of H2. As a biodegradable metal, magnesium (Mg) generates H2 in an aqueous environment, but the H2 release rate is still too low. Here, we design a Mg-Al-Ca (AX) alloy that degrades very rapidly due to the presence of a secondary phase Al2Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al2Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al2Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors. This work suggests that the H2 therapy using highly degradable Mg alloys may provide an effective cancer treatment.

Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy. [ABSTRACT FROM AUTHOR]

Molecule hydrogen (H 2) has been used to suppress tumor growth. To employ the H 2 therapy, it is necessary to use a proper agent for continuous generation of H 2. As a biodegradable metal, magnesium (Mg) generates H 2 in an aqueous environment, but the H 2 release rate is still too low. Here, we design a Mg-Al-Ca (AX) alloy that degrades very rapidly due to the presence of a secondary phase Al 2 Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al 2 Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al 2 Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors. This work suggests that the H 2 therapy using highly degradable Mg alloys may provide an effective cancer treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Today, cancer is considered as the second cause of death in the world. Often, the treatment of all types of cancer is very complicated. The discovery of new anti-cancer drugs with high effectiveness, low toxicity, the ability to select normal cells from cancerous cells, and low cost is one of the concerns of the world's pharmaceutical communities. Nowadays, the use of natural compounds based on their synergistic effects has opened a new therapeutic horizon in the management of different types of cancers. The aim of this study was to investigate the synergistic effects of peiminine and hyperthermia therapy on the induction of apoptosis in MCF-7 cell line. Materials and methods: In the present experimental-laboratory study, after culturing MCF-7 cells in 96-well plates, they were treated with peiminine (5.12 µg/ml for 24 h) and hyperthermia (410C for 1 h) independently and simultaneously. Then the cell viability rate, apoptosis percentage, ROS production rate, LDH release rate, and caspase 8 and 9 activity level were measured. Results: The results of the present study showed that peiminine and hyperthermia therapy caused a significant decrease in cell viability as well as a significant increase in the percentage of apoptosis, ROS production, and LDH release compared with the control group. By measuring the activity of caspase 8 and 9, it was determined that peiminine induced apoptosis through both mitochondrial and extracellular pathways. It was also found that peiminine and hyperthermia therapy, in combination, had synergistic antiproliferative effects. Conclusion: According to the results of the present study, it seems that peiminine, as a natural product, when used in combination with hyperthermia therapy has synergistic antiproliferative and apoptosis-inducing effects. This suggests that it can be used as a complementary method in cancer treatment.

Background and purpose: Today, cancer is considered as the second cause of death in the world. Often, the treatment of all types of cancer is very complicated. The discovery of new anti-cancer drugs with high effectiveness, low toxicity, the ability to select normal cells from cancerous cells, and low cost is one of the concerns of the world's pharmaceutical communities. Nowadays, the use of natural compounds based on their synergistic effects has opened a new therapeutic horizon in the management of different types of cancers. The aim of this study was to investigate the synergistic effects of peiminine and hyperthermia therapy on the induction of apoptosis in MCF-7 cell line. Materials and methods: In the present experimental-laboratory study, after culturing MCF-7 cells in 96-well plates, they were treated with peiminine (5.12 µg/ml for 24 h) and hyperthermia (410C for 1 h) independently and simultaneously. Then the cell viability rate, apoptosis percentage, ROS production rate, LDH release rate, and caspase 8 and 9 activity level were measured. Results: The results of the present study showed that peiminine and hyperthermia therapy caused a significant decrease in cell viability as well as a significant increase in the percentage of apoptosis, ROS production, and LDH release compared with the control group. By measuring the activity of caspase 8 and 9, it was determined that peiminine induced apoptosis through both mitochondrial and extracellular pathways. It was also found that peiminine and hyperthermia therapy, in combination, had synergistic antiproliferative effects. Conclusion: According to the results of the present study, it seems that peiminine, as a natural product, when used in combination with hyperthermia therapy has synergistic antiproliferative and apoptosisinducing effects. This suggests that it can be used as a complementary method in cancer treatment. [ABSTRACT FROM AUTHOR]

Histone proteins, building blocks of chromatins, participate in enzymatic reactions in cells heated at around 45°C though in vitro the denaturation of histones significantly proceeds at a similar temperature. It implies that unidentified mechanisms prevent thermal denaturation of histones in vivo. However, studies on the histone structures in the heated cells have been scarce. Here, we analyzed the secondary structures of histone H2A‐H2B proteins originating from the heated cells using circular dichroism spectroscopy. The secondary structure contents of the H2A‐H2B extracted from the heated cells differed from those of H2A‐H2B both native and denatured in vitro but reverted to the native structures by incubating the heated cells at 37°C within 2 h. Such structural flexibility may play a role in protecting genomic functions governed by chromatin structures from heat stresses. [ABSTRACT FROM AUTHOR]

The characterization of nanoparticles is crucial in several medical applications, such as hyperthermic therapy, which heats superparamagnetic nanoparticles with an external electromagnetic field. The knowledge of heating ability (magnetic losses) in AC magnetic field frequency function allows for selecting the optimal excitation. A hybrid system for the characterization of superparamagnetic nanoparticles was designed and tested. The proposed setup consists of an excitation coil and two sensing probes: calorimetric and magnetic. The measurements of the imaginary part of the complex magnetic susceptibility of superparamagnetic nanoparticles are possible in the kilohertz range. The system was verified using a set of nanoparticles with different diameters. The measurement procedure was described and verified. The results confirmed that an elaborated sensor system and measuring procedures could properly characterize the magnetic characteristics of nanoparticles. The main advantage of this system is the ability to compare both characteristics and confirm the selection of optimal excitation parameters. [ABSTRACT FROM AUTHOR]

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) biofilm-associated bacterial infection is the primary cause of nosocomial infection and has long been an ongoing threat to public health. MRSA biofilms are often resistant to multiple antimicrobial strategies, mainly due to the existence of a compact protective barrier; thus, protecting themselves from the innate immune system and antibiotic treatment via limited drug penetration. Results A hierarchically structured hydrogen sulfide (H2S)-releasing nano-disinfectant was presented, which was composed of a zinc sulfide (ZnS) core as a H2S generator and indocyanine green (ICG) as a photosensitizer. This nano-disinfectant (ICG-ZnS NPs) sensitively responded to the biofilm microenvironment and demonstrated efficient eradication of MRSA biofilms via a synergistic effect of Zn2+, gas molecule-mediated therapy, and hyperthermia. Physically boosted by released H2S and a near-infrared spectroscopy-induced hyperthermia effect, ICG-ZnS NPs destroyed the compactness of MRSA biofilms showing remarkable deep-penetration capability. Moreover, on-site generation of H2S gas adequately ameliorated excessive inflammation, suppressed secretion of inflammatory cytokines, and expedited angiogenesis, therefore markedly accelerating the in vivo healing process of cutaneous wounds infected with MRSA biofilms. Conclusion ICG-ZnS NPs combined with NIR laser irradiation exhibited significant anti-biofilm activity in MRSA biofilms, can accelerate the healing process through deep-penetration and anti-inflammatory effectuation. The proposed strategy has great potential as an alternative to antibiotic treatment when combating multidrug-resistant bacterial biofilms. Graphical Abstract

This review article presents an overview of the role of magnetic nanoparticles (MNPs) in various biomedical applications. Various synthesis techniques of magnetic nanoparticles have been discussed in compliance with their suitability in biological applications. Utilizing the magnetic property of the nanoparticles, several biomedical technology applications have been developed such as magnetic resonance imaging (MRI), separation of biomolecules, biosensing, bacteria inhibition, magnetic field stimulated drug delivery, magnetic hyperthermia therapy etc. Among the various applications, this article comprises a detailed review mainly focused on the potentiality of the MNPs in magnetic field stimulated drug delivery technique and hyperthermia therapy. The present difficulties/limitations and remaining challenges of these techniques have also been outlined in this article. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia is now well established to improve neurodevelopmental outcomes after hypoxic-ischemic encephalopathy (HIE). Although the overall principles of treatment are now well established, many smaller questions are unclear. The potential impact of reversal of hypothermia therapy and the effect of high temperatures on recovery of the neurovascular unit after therapeutic hypothermia for HIE has received relatively little attention. This article will address the effects of hypoxia-ischemia and rewarming and increased temperatures on the neurovascular unit in preclinical and clinical models., Competing Interests: Disclosure Nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The development of an evidence-based algorithm for the clinical management of deviations in maternal temperature during labour and childbirth., Population: Pregnant women at any stage of labour, with singleton, term (37-42 weeks) pregnancies at low risk of developing complications., Setting: Health facilities in low- and middle-income countries., Search Strategy: We searched for international guidelines and prioritised WHO guidelines. In addition, we searched for other sources of evidence in the Cochrane Database of Systematic Reviews, EMBASE, MEDLINE and CINAHL until June 2020. Studies were prioritised according to the hierarchy of evidence., Case Scenarios: Two case scenarios were identified: maternal hyperthermia and hypothermia. We developed a single algorithm including both, due to commonalities in diagnosis, monitoring and management of underlying causes. The underlying conditions covered in the pathway include maternal sepsis and infection, chorioamnionitis, pyelonephritis, lower urinary tract and respiratory infections. Key decision points in the algorithm are suspicion of condition, definition, differential diagnosis, monitoring and management., Conclusions: We present an evidence-based algorithm to assist healthcare professionals in making decisions about appropriate clinical management of deviations in maternal temperature. Research is needed to assess the views of healthcare professionals and women accessing healthcare on the feasibility of implementing the algorithm., Tweetable Abstract: An evidence-based intrapartum care algorithm to support management of deviations in maternal temperature in labour and childbirth. #sepsis #maternitycare., (© 2022 John Wiley & Sons Ltd. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Bone tumors are deadly and incurable diseases that invade large areas of bone, resulting in bone defects. Traditional therapies combining surgery, chemotherapy, and radiation have reached their limit of efficacy, motivating efforts to develop new therapeutic methods. Fortunately, the development of biomaterials provides innovative options for bone tumor treatment. Suitable biomaterials are capable of simultaneously providing tumor therapy and promoting bone regeneration. This review summarizes recent progress in the effort to achieve new strategies for bone tumor treatment using biomaterials, focusing on the innovative scaffold design. It also discusses the development of nanocarrier-based drug delivery systems and hyperthermia therapy for bone tumor treatment. In the future, biomaterial-based strategies are likely to become the most effective and reliable options for treating bone tumors, and they have the potential to greatly improve the prognosis and quality of life for patients.

Many efforts have recently concentrated on constructing and developing nanoparticles (NPs) as promising thermal agent for optical hyperthermia and photothermal therapy. However, thermal energy transfer in biological tissue is a complex process involving different mechanisms such as conduction, convection, radiation. Therefore, having information about thermal properties of tissue especially when NPs are embedded in is a necessity for predicting the heat transfer during hyperthermia. In this work, the thermal properties of solid phantom based on agar in the presence of three different nanoparticles (BPSi, tNAs, GNRs) and alone were measured and reported as a function of temperature (ranging from 22 to 62 °C). The thermal response of these NPs to an 808 nm laser beam with three different powers were studied in the water comparatively. Agar and tNAs have almost constant thermal properties in the considered range. Among the three NPs, gold has the highest conductivity and diffusivity. At 62 °C BPSi NPs have the similar amount of increase for the diffusivity. The thermal parameters reported in this paper can be useful for the mathematical modeling. Irradiation of the NPs-loaded water phantom displayed the highest radiosensitivity of gold among the three mentioned NPs. However, for the higher power of irradiation, BPSi and tNAs NPs showed the increased absorption of heat during shorter time and the increased temperature gradient slope for the initial 15 s after the irradiation started. The three NPs showed different thermal and irradiation response behavior; however, this comparison study notes the worth of having information about thermal parameters of NPs-loaded tissue for pre-clinical planning. [ABSTRACT FROM AUTHOR]

Background: Methicillin-resistant Staphylococcus aureus (MRSA) biofilm-associated bacterial infection is the primary cause of nosocomial infection and has long been an ongoing threat to public health. MRSA biofilms are often resistant to multiple antimicrobial strategies, mainly due to the existence of a compact protective barrier; thus, protecting themselves from the innate immune system and antibiotic treatment via limited drug penetration. Results: A hierarchically structured hydrogen sulfide (H2S)-releasing nano-disinfectant was presented, which was composed of a zinc sulfide (ZnS) core as a H2S generator and indocyanine green (ICG) as a photosensitizer. This nano-disinfectant (ICG-ZnS NPs) sensitively responded to the biofilm microenvironment and demonstrated efficient eradication of MRSA biofilms via a synergistic effect of Zn2+, gas molecule-mediated therapy, and hyperthermia. Physically boosted by released H2S and a near-infrared spectroscopy-induced hyperthermia effect, ICG-ZnS NPs destroyed the compactness of MRSA biofilms showing remarkable deep-penetration capability. Moreover, on-site generation of H2S gas adequately ameliorated excessive inflammation, suppressed secretion of inflammatory cytokines, and expedited angiogenesis, therefore markedly accelerating the in vivo healing process of cutaneous wounds infected with MRSA biofilms. Conclusion: ICG-ZnS NPs combined with NIR laser irradiation exhibited significant anti-biofilm activity in MRSA biofilms, can accelerate the healing process through deep-penetration and anti-inflammatory effectuation. The proposed strategy has great potential as an alternative to antibiotic treatment when combating multidrug-resistant bacterial biofilms. [ABSTRACT FROM AUTHOR]

Hyperthermia therapy (HT) of cancer is a well-known treatment approach. With the advent of new technologies, HT approaches are now important for the treatment of brain tumors. We review current clinical applications of HT in neuro-oncology and ongoing preclinical research aiming to advance HT approaches to clinical practice. Laser interstitial thermal therapy (LITT) is currently the most widely utilized thermal ablation approach in clinical practice mainly for the treatment of recurrent or deep-seated tumors in the brain. Magnetic hyperthermia therapy (MHT), which relies on the use of magnetic nanoparticles (MNPs) and alternating magnetic fields (AMFs), is a new quite promising HT treatment approach for brain tumors. Initial MHT clinical studies in combination with fractionated radiation therapy (RT) in patients have been completed in Europe with encouraging results. Another combination treatment with HT that warrants further investigation is immunotherapy. HT approaches for brain tumors will continue to a play an important role in neuro-oncology.

Mild whole-body hyperthermia has been shown to have anti-tumor effects through an immune-modulating mechanism. Before it is widely applied in the clinic, tremendous mechanistic research in animals is necessary to adhere to evidence-based principles. The radio frequency electromagnetic field (RF-EMF) based heating facility could be a good choice for hyperthermia treatment, but the heating characteristics of a facility, including structure design, electromagnetic and thermal dosimetry, and the biologic effects of hyperthermia, need to be well elucidated. Here, we reported the heating characteristic study on a resonant chamber (RC) excited by a 1800 MHz solid source. The EMF in the RC was stirred by 24 static reflectors, which resulted in the standard deviation of electric field intensity being below 3 dB in the EM homogeneity evaluation. For the exposure scenario, six free-moving mice were loaded into separate cases and exposed simultaneously in the RC. The EMF energy absorption and distribution in exposed mice were calculated with the 12-plane-waves method of numerical simulation. Different levels of core body temperature increment in exposed mice were achieved through regulation of the source output power. Overexpression of heat shock proteins (HSPs) was detected in the liver, lung and muscle, but not in the brain of the exposed mice. The levels of representative inflammatory cytokines in the serum, TNF-α and IL-10 increased post RC exposure. Based on the heating characteristic study and validation, the applied RC would be a qualified heating system for mild whole-body hyperthermia effect research in mice.

The characterization of nanoparticles is crucial in several medical applications, such as hyperthermic therapy, which heats superparamagnetic nanoparticles with an external electromagnetic field. The knowledge of heating ability (magnetic losses) in AC magnetic field frequency function allows for selecting the optimal excitation. A hybrid system for the characterization of superparamagnetic nanoparticles was designed and tested. The proposed setup consists of an excitation coil and two sensing probes: calorimetric and magnetic. The measurements of the imaginary part of the complex magnetic susceptibility of superparamagnetic nanoparticles are possible in the kilohertz range. The system was verified using a set of nanoparticles with different diameters. The measurement procedure was described and verified. The results confirmed that an elaborated sensor system and measuring procedures could properly characterize the magnetic characteristics of nanoparticles. The main advantage of this system is the ability to compare both characteristics and confirm the selection of optimal excitation parameters.

Cancer stem cells (CSCs) are thought to be responsible for the recurrence of liver cancer, highlighting the urgent need for the development of effective treatment regimens. In this study, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and thermosensitive magnetoliposomes (TMs) conjugated to anti-CD90 (CD90@17-AAG/TMs) were developed for temperature-responsive CD90-targeted synergetic chemo-/magnetic hyperthermia therapy and simultaneous imaging in vivo. The targeting ability of CD90@DiR/TMs was studied with near-infrared (NIR) resonance imaging and magnetic resonance imaging (MRI), and the antitumor effect of CD90@17-AAG/TM-mediated magnetic thermotherapy was evaluated in vivo. After treatment, the tumors were analyzed with Western blotting, hematoxylin and eosin staining, and immunohistochemical (IHC) staining. The relative intensity of fluorescence was approximately twofold higher in the targeted group than in the non-targeted group, while the T2 relaxation time was significantly lower in the targeted group than in the non-targeted group. The combined treatment of chemotherapy, thermotherapy, and targeting therapy exhibited the most significant antitumor effect as compared to any of the treatments alone. The anti-CD90 monoclonal antibody (mAb)-targeted delivery system, CD90@17-AAG/TMs, exhibited powerful targeting and antitumor efficacies against CD90+ liver cancer stem cells in vivo.

• Impacts of reduced vessel radius and flow velocity on LIPU-induced thermal effect was studied. • In vivo ischemia model constructed by artery ligation to narrow vessel and reduce flow velocity. • FEM study showed reduced flow velocity enhancing LIPU heating by impairing heat dissipation. • Exponential relationship was fitted between LIPU-induced temperature rise and blood flow rate. • Findings enable prediction of LIPU thermal effect in ischemic tissues to ensure safe therapy. Ischemic diseases due to arterial stenosis or occlusion are common and can have serious consequences if untreated. Therapeutic ultrasound like high-intensity focused ultrasound (HIFU) ablates tissues while low-intensity pulsed ultrasound (LIPU) promotes healing at relatively low temperatures. However, blood vessel cooling effect and reduced flow in ischemia impact temperature distribution and ultrasonic treatment efficacy. This work established a rabbit limb ischemia model by ligating the femoral artery, measuring vascular changes and temperature rise during LIPU exposures. Results showed the artery diameter was narrowed by 46.2% and the downstream velocity was reduced by 51.3% after ligation. Finite element simulations verified that the reduced flow velocity impaired heat dissipation, enhancing LIPU-induced heating. Simulation results also suggested the temperature rise was almost related linearly to vessel diameter but decayed exponentially with the increasing flow velocity. Findings indicate that the proposed model could be used as an effectively tool to model the heating effects in ischemic tissues during LIPU treatment. This research on relating varied ischemic flow to LIPU-induced thermal effects is significant for developing safe and efficacious clinical ultrasound hyperthermia treatment protocols for the patients with ischemic diseases. [ABSTRACT FROM AUTHOR]

Recent advances in the field of magnetic materials emphasize that the development of new and useful magnetic nanoparticles (NPs) requires an accurate and fundamental understanding of their collective magnetic behavior. Studies show that the magnetic properties are strongly affected by the magnetic anisotropy of NPs and by interparticle interactions that are the result of the collective magnetic behavior of NPs. Here we study these effects in more detail. For this purpose, we prepared CoxFe3−xO4 NPs, with x = 0–1 in steps of 0.2, from soft magnetic (Fe3O4) to hard magnetic (CoFe2O4) ferrite, with a significant variation of the magnetic anisotropy. The phase purity and the formation of crystalline NPs with a spinel structure were confirmed through Rietveld refinement. The effect of Co doping on structure, morphology and magnetic properties of CoxFe3−xO4 samples was investigated. In particular, we examined the interparticle interactions in the samples by δm graphs and Henkel plots that have not been reported before in literature. Finally, we studied the hyperthermia properties and observed that the heat efficiency of soft Fe3O4 is about 4 times larger than that of hard CoFe2O4 ferrite, which was attributed to the high coercive field of samples compared with the external field amplitude.

Hyperthermia is the most ancient cancer treatment modality used much before even the discoveries of conventional therapeutic modalities such as radiotherapy. Since then, as a cancer therapeutic modality, hyperthermia has seen several advancements, but an upsetting decline in its recognition in last few decades. Currently, majority of the laboratories working in the research field are engaged in developing combinatorial strategies for hyperthermia along with radiation/anticancer agents. For the targeted delivery of therapeutic agents, several nano-formulations have been developed. In recent years, magnetic nanoparticle-based “nanothermotherapy” is getting the attention of researchers. Unfortunately, despite several successful clinical studies, hyperthermia could not get its due acclaim in cancer therapeutics. In the last few decades, mechanistic insights achieved using cutting-edge technologies opened several therapeutic avenues of many diseases including cancer. However, for many reasons, hyperthermia scientists could not match the pace to tap the knowledge for deeper mechanistic insights. Key questions, such as epigenetic changes, role of immune cells/abscopal effects in hyperthermia, and thermo resistance, still needs to be addressed in depth. It is noteworthy to mention that a deeper mechanistic insight shall contribute immensely in hyperthermia-based cancer therapy not only through overcoming thermoresistance but also through assisting in developing novel thermosensitizers and thermotherapy protocols.

Many efforts have recently concentrated on constructing and developing nanoparticles (NPs) as promising thermal agent for optical hyperthermia and photothermal therapy. However, thermal energy transfer in biological tissue is a complex process involving different mechanisms such as conduction, convection, radiation. Therefore, having information about thermal properties of tissue especially when NPs are embedded in is a necessity for predicting the heat transfer during hyperthermia. In this work, the thermal properties of solid phantom based on agar in the presence of three different nanoparticles (BPSi, tNAs, GNRs) and alone were measured and reported as a function of temperature (ranging from 22 to 62 °C). The thermal response of these NPs to an 808 nm laser beam with three different powers were studied in the water comparatively. Agar and tNAs have almost constant thermal properties in the considered range. Among the three NPs, gold has the highest conductivity and diffusivity. At 62 °C BPSi NPs have the similar amount of increase for the diffusivity. The thermal parameters reported in this paper can be useful for the mathematical modeling. Irradiation of the NPs-loaded water phantom displayed the highest radiosensitivity of gold among the three mentioned NPs. However, for the higher power of irradiation, BPSi and tNAs NPs showed the increased absorption of heat during shorter time and the increased temperature gradient slope for the initial 15 s after the irradiation started. The three NPs showed different thermal and irradiation response behavior; however, this comparison study notes the worth of having information about thermal parameters of NPs-loaded tissue for pre-clinical planning.

• Pointwise antenna design in hyperthermia therapy. • Sensitivity analysis of coupled multiphysics system. • First and second order antenna design algorithms. • Capability in selectively heating several targets simultaneously. • Numerical validation in a full transient analysis. This work deals with pointwise antennas design in hyperthermia treatment. Hyperthermia is a non-invasive therapy usually combined with chemotherapy and/or radiotherapy, which consists in heating the diseased tissue in an attempt to kill the cancerous cells. In particular, we want to find the optimal values of current densities passing through each antenna to selectively heat a specified target. The forward problem is governed by the steady-state heat equation in living tissues which is coupled with the Helmholtz problem modeling the electromagnetism phenomenon. An objective functional measuring the difference between the target temperature and the solution to the model problem is minimized with respect to the current densities by using the topological derivative method. The resulting sensitivities are used to devise first and second order antenna design algorithms as well as a third one that combines both the previous algorithms. Numerical experiments are presented showing different features of the proposed methodology, including its capability in selectively heating the target up to the desired temperature. Finally, a selected result is used in a full transient analysis, where the hot spots are keeping over the diseased tissues during the whole heating process. [ABSTRACT FROM AUTHOR]

Exercise is a common trigger of heat-related illness (HRI) events in dogs, accounting for 74% of canine HRI cases treated under primary veterinary care in the United Kingdom. However, few empirical studies have evaluated the effectiveness of differing cooling methods for dogs with exertional hyperthermia or HRI. This study aimed to prospectively evaluate effects of ambient conditions and post-exercise management practices (cooling methods and vehicular confinement) on the post-exercise temperature change of dogs participating in UK canicross events. Canine temperature was recorded at three intervals post-exercise: as close as possible to 0- (immediately post-exercise), 5-, and 15-min post-exercise. Ambient conditions and post-exercise management were recorded for 115 cooling profiles from 52 dogs. In 28/115 (24.4%) profiles, the dog's temperature increased during the first 5-min post-exercise. Overall, 68/115 (59.1%) profiles included passive cooling (stood or walked outside), 35 (30.4%) active cooling (cold-water immersion or application of a cooling coat), and 12 (10.4%) involved no cooling and were immediately housed in vehicles. No dogs developed hypothermia during the study and no adverse effects were observed from any cooling method. In hyperthermic dogs, overall post-exercise body temperature change was significantly negatively associated (i.e. the dogs cooled more) with 0-min post-exercise body temperature (β = -0.93, p < 0.001), and not being housed in a vehicle (β = -0.43, p = 0.013). This study provides evidence cold-water immersion (in water at 0.1-15.0 °C) can be used to effectively and safely cool dogs with exertional hyperthermia. Progressive temperature increases in many dogs - even after exercise has terminated - supports the message to "cool first, transport second" when managing dogs with HRI. When transporting dogs post-exercise or with HRI even after active cooling, care should be taken to cool the vehicle before entry and promote air movement around the dog during transport to facilitate ongoing cooling and prevent worsening of hyperthermia during travel., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dan O'Neill is a member of the “Dogs Die in Hot Cars” consortium. SB, SG and DB work for veterinary companies providing emergency veterinary care to dogs., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ferroptosis pathway is recognized as an essential strategy for tumor treatment. However, killing tumor cells in deep tumor regions with ferroptosis agents is still challenging because of distinct size requirements for intratumoral accumulation and deep tumor penetration. Herein, intelligent nanocapsules with size-switchable capability that responds to acid/hyperthermia stimulation to achieve deep tumor ferroptosis are developed. These nanocapsules are constructed using poly(lactic-co-glycolic) acid and Pluronic F127 as carrier materials, with Au-Fe 2 C Janus nanoparticles serving as photothermal and ferroptosis agents, and sorafenib (SRF) as the ferroptosis enhancer. The PFP@Au-Fe 2 C-SRF nanocapsules, designed with an appropriate size, exhibit superior intratumoral accumulation compared to free Au-Fe 2 C nanoparticles, as evidenced by photoacoustic and magnetic resonance imaging. These nanocapsules can degrade within the acidic tumor microenvironment when subjected to laser irradiation, releasing free Au-Fe 2 C nanoparticles. This enables them to penetrate deep into tumor regions and disrupt intracellular redox balance. Under the guidance of imaging, these PFP@Au-Fe 2 C-SRF nanocapsules effectively inhibit tumor growth when exposed to laser irradiation, capitalizing on the synergistic photothermal and ferroptosis effects. This study presents an intelligent formulation based on iron carbide for achieving deep tumor ferroptosis through size-switchable cascade delivery, thereby advancing the comprehension of ferroptosis in the context of tumor theranostics., (© 2023 Wiley-VCH GmbH.)

Nowadays, magnetic nanoparticles (MNPs) are applied in numerous fields, especially in biomedical applications. Since biofluidic samples and biological tissues are nonmagnetic, negligible background signals can interfere with the magnetic signals from MNPs in magnetic biosensing and imaging applications. In addition, the MNPs can be remotely controlled by magnetic fields, which make it possible for magnetic separation and targeted drug delivery. Furthermore, due to the unique dynamic magnetizations of MNPs when subjected to alternating magnetic fields, MNPs are also proposed as a key tool in cancer treatment, an example is magnetic hyperthermia therapy. Due to their distinct surface chemistry, good biocompatibility, and inducible magnetic moments, the material and morphological structure design of MNPs has attracted enormous interest from a variety of scientific domains. Herein, a thorough review of the chemical synthesis strategies of MNPs, the methodologies to modify the MNPs surface for better biocompatibility, the physicochemical characterization techniques for MNPs, as well as some representative applications of MNPs in disease diagnosis and treatment are provided. Further portions of the review go into the diagnostic and therapeutic uses of composite MNPs with core/shell structures as well as a deeper analysis of MNP properties to learn about potential biomedical applications., (© 2023 Wiley-VCH GmbH.)

Hyperthermia therapy (HT) of cancer is a well-known treatment approach. With the advent of new technologies, HT approaches are now important for the treatment of brain tumors. We review current clinical applications of HT in neuro-oncology and ongoing preclinical research aiming to advance HT approaches to clinical practice. Laser interstitial thermal therapy (LITT) is currently the most widely utilized thermal ablation approach in clinical practice mainly for the treatment of recurrent or deep-seated tumors in the brain. Magnetic hyperthermia therapy (MHT), which relies on the use of magnetic nanoparticles (MNPs) and alternating magnetic fields (AMFs), is a new quite promising HT treatment approach for brain tumors. Initial MHT clinical studies in combination with fractionated radiation therapy (RT) in patients have been completed in Europe with encouraging results. Another combination treatment with HT that warrants further investigation is immunotherapy. HT approaches for brain tumors will continue to a play an important role in neuro-oncology. [ABSTRACT FROM AUTHOR]

Treatment for different diseases has been revolutionized dramatically due to the advancements in the medical sciences, such as the practice of capped nanoparticles to treat carcinoma could be a promising strategy for future. For the first time we show that capping agents enhance the magnetization power while simultaneously reduce the particles size as well. Different capped iron oxide nanoparticles (Fe 3 O 4 -NPs) were synthesized using different organic ligands viz. citric acid and malic acid through co-precipitation method. Compared with un-capped particles, the capped-NPs exhibited reduction in size and cubic spinal structure as confirmed by TEM images and XRD peaks. Moreover, SEM images revealed that the organic acid functionalized NPs had irregular geometries in comparison with uncapped NPs. The presence of -OH -CH 2 and –COOH groups were confirmed by FTIR and variations in magnetic field were recorded using VSM. For in vivo bioassay, capped magnetic NPs were injected inside tumor cells followed by exposure to alternating magnetic fields. Exposure to alternating magnetic field of 15 mT and frequency 100 kHz for 1 h caused rise in temperature from 37 to 48 °C and also resulted in cellular damage and subsequent apoptotic cell death. In an overall assessment, functionalized Fe 3 O 4 -NPs exhibited reduction in particle size, increased magnetization properties and enhanced efficacy for carcinoma treatments by hyperthermia. Image 1 • Narrow range particles size (less than 5 nm). • Enhance the magnetization power with capping agents (CA). • Non-uniform size control the heating effect inside the tumor. • Reduce the tumor after each treatment using hyperthermia therapy. • Apoptotic cell death (due to temperature). [ABSTRACT FROM AUTHOR]

• Ni 0.5 Zn 0.4 Cu 0.1 Fe 2 O 4 ferrite nanoparticles were prepared and incorporated in the titanium dioxide matrix. • Structural and morphological insvestigations were carried out. • Investigation of the magnetic and Mössbauer spectra revealed the presence of superparamagnetic phenomena. • The microwave reflection loss enhances significantly in the incorporated sample. • Considerable specific absorption rate was observed during inductive heating study of the samples. Ni 0.5 Zn 0.4 Cu 0.1 Fe 2 O 4 ferrite nanoparticles (NZCUFO) were prepared using a conventional co-precipitation method. The NZCUFO nanoparticles were then combined with titanium dioxide matrix to make the nanocomposite of [TiO 2 ] 0.2 [Ni 0.5 Zn 0.4 Cu 0.1 Fe 2 O 4 ] 0.8 (TNZCUFO). The formation of the appropriate crystallographic phase was confirmed by analyzing the X-ray diffraction pattern of the samples. Investigations extracted from the X-ray fluorescence spectroscopy, high-resolution transmission electron microscopy, and Raman spectroscopy imply the successful association of ferrite nanoparticles into the TiO 2 matrix. At 300 K, the saturation magnetization of NZCUFO and TNZCUFO reaches 34.6 and 23.4 emu/g, respectively. Mössbauer spectra recorded at 77 and 300 K indicate the presence of superparamagnetic behavior. These results were in agreement with the data obtained from magnetic hysteresis loop, zero field cooled, and field-cooled magnetization measurements. Both the samples were exposed to alternating current inductive heating and the extracted results successfully satisfy the condition of hyperthermia therapy for cancer treatment. The electromagnetic wave absorption capabilities of the samples were measured in the microwave region (8–18 GHz). The microwave reflection loss reaches −13.6 dB at 11.6 GHz and −29.7 dB at 11 GHz for the 2 mm thick samples of NZCUFO and TNZCUFO, respectively. The balanced matching of magnetic and dielectric loss, high magnetization, and specific absorption rate of the samples would be extremely useful for diverse soft magnetic applications. [ABSTRACT FROM AUTHOR]

This article discussed a numerical study of dual-phase-lag (DPL) bioheat transfer model with nonlocal impact on skin tissue during hyperthermia therapy when Gaussian type heat device is applied to the skin's outer surface. With the aid of a sufficient value of the parameters η , Q ro and r p for a heating device of the Gaussian type, the temperature distribution at the targeted location is controlled and maintained. These parameters are employed to destroy a significant number of cancer cells in the targeted location while protecting the surrounding healthy tissue. The temperature profile at the targeted location decreases as lagging time τ q and τ T increases, and increases as spatial lagging λ q increases. The blood perfusion effect can be shown when the value of α increases or when blood temperature decreases then it is seen that the temperature profile decreases. The numerical results obtained by the Finite element Legendre wavelet Galerkin (FELWG) approach are compared with the analytical results obtained in the specific situation to evaluate the precision. The obtained numerical results logically relate to the analytical results when we utilized the operational matrix of order M − 1 (where M = 100). All impacts of problem parameters are graphically represented during hyperthermia treatment. [ABSTRACT FROM AUTHOR]

Purpose: Passive Acoustic Thermometer (PAT) is a safe method for internal temperature estimation that works based on acoustic radiation of materials with a specific temperature. Several experimental studies have been carried out so far in the field of PAT. While, to the best of our knowledge, there is no simulation-based research reported yet. Materials and Methods: In this article (for the first time) we proposed a simulation framework for evaluating the PAT methodologies. This framework supports the generation of acoustic radiation, signal processing, parameter estimation, and temperature reconstruction processes. At the moment, the proposed framework estimates the temperature in the frequency domain and uses the frequency spectrum of the acquired ultrasound signals captured by a single transducer. Results: Using the proposed framework, we tried to implement previously practical experiments and the results of the simulation are consistent with those of the practical experiment. The mean error of temperature estimation was below 0.45 °C. The results show that it is possible to use this framework to evaluate the PAT in different scenarios. Conclusion: Therefore, this method enhances the possibility of examination of different conditions and algorithms. It also reduces the cost of practical experiment.

Magnetic hyperthermia regulates the therapeutic temperature within a specific range to damage malignant cells after exposing the magnetic nanoparticles inside tumor tissue to an alternating magnetic field. The therapeutic temperature of living tissues can be generally predicted using Pennes' bio-heat equation after ignoring both the inhomogeneity of biological structure and the microstructural responses. Although various of the bio-heat transfer models proposed in literature fix these shortages, there is still a lack of a comprehensive report on investigating the discrepancy for different models when applied in the magnetic hyperthermia context. This study compares four different bio-heat equations in terms of the therapeutic temperature distribution and the heat-induced damage situation for a proposed geometric model, which is established based on computed tomography images of a tumor bearing mouse. The therapeutic temperature is also used as an index to evaluate the effect of two key relaxation times for the phase lag behavior on bio-heat transfer. Moreover, this work evaluates the effects of two blood perfusion rates on both the treatment temperature and the cumulative equivalent heating minutes at 43 °C. Numerical analysis results reveal that relaxation times for phase-lag behavior as well as the porosity for living tissues directly affect the therapeutic temperature variation and ultimately the thermal damage for the malignant tissue during magnetic hyperthermia. The dual-phase-lag equation can be converted into Pennes' equation and simple-phase-lag equation when relaxation times meet specific conditions during the process of heat transfer. In addition, different blood perfusion rates can result in an amplitude discrepancy for treatment temperature, but this parameter does not change the characteristics of thermal propagation during therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ovarian cancer is one of the most common causes of mortality throughout the world. Unfortunately, chemotherapy has failed to cure advanced cancers developing multidrug resistance (MDR). Moreover, it has critical side effects because of nonspecific toxicity. Thanks to specific silencing of oncogenes and MDR-associated genes, nano-siRNA drugs can be a great help address the limitations of chemotherapy. Here, we review the current advances in nanoparticle-mediated siRNA delivery strategies such as polymeric- and lipid-based systems, rigid nanoparticles and nanoparticles coupled to specific ligand systems. Nanoparticle-based codelivery of anticancer drugs and siRNA targeting various mechanisms of MDR is a cutting-edge strategy for ovarian cancer therapy, which is completely discussed in this review. [ABSTRACT FROM AUTHOR]

Abstract We have reported the synthesis of core-shell nanostructure of mesoporous silica coated lanthanum strontium manganese oxide nanoparticles (MSLN) as a potential candidate for cancer treatment via magnetic hyperthermia. N 2 adsorption-desorption isotherm revealed that mesoporous silica shell coating increased the surface area and pore volume of lanthanum strontium manganese oxide nanoparticles (LSMO). In comparison to LSMO, MSLN showed a stable colloidal dispersion up to 48 h. In-vitro studies using A549 cells demonstrated increased biocompatibility in MSLN as compared to LSMO. Moreover, cells treated with MSLN exhibited high cell survival rate of up to 1 mg/ml concentration. Further, we used different parameters to modulate the heating efficacies of these nanoparticles. The modulation of specific absorption rates (SAR) with different sample concentrations (0.5, 1, 1.5, 2.0 mg/ml) were studied under four different alternating current magnetic field (AMF) amplitudes (10, 11, 12, 13 kA/m) at a constant frequency of 335 KHz for magnetic hyperthermia experiments. Under the application of AMF, MSLN exhibited faster Néel and Brownian relaxation compared to their LSMO counterparts. SAR value of 295 W/g and intrinsic loss power (ILP) of 5.22 nHm2/kg, at a low sample concentration of MSLN (0.5 mg/ml) were obtained, which was within the clinical limit. Interestingly, our results showed 45% improvement in terms of the heating efficiency over the commercially available products (Table 3). Hence, we conclude that MSLN with high SAR and ILP values, good colloidal dispersion ability and low cytotoxicity could be a potential candidate for magnetic hyperthermia therapy in cancer and warrant further testing in both in-vitro and in-vivo studies. Further, due to their mesoporous nature, MSLN could be considered for target-specific drug delivery applications in clinical therapy. Highlights • Mesoporous silica-coated lanthanum strontium manganese oxide nanoparticles (MSLN) were synthesized. • Structural parameters of lanthanum strontium manganese oxide (LSMO) were calculated using Rietveld refinement software. • MSLN showed a larger surface area and pore volume as compared to LSMO. • MSLN exhibited better colloidal dispersion and enhanced biocompatibility than LSMO nanoparticles. • MSLN showed high specific absorption rate (SAR; 295W/g) as well as high intrinsic loss power (ILP; 5.22 nHm2kg−1). [ABSTRACT FROM AUTHOR]

Highlights • Cobalt Ferrite magnetic nanoparticles were synthesized on DNA scaffold, in different batches. • Changes in different properties for the different batches of particles were observed by different methods, which affirms the binding of the MNP with the DNA. • Change in magnetic properties helped us to choose the suitable particle for magnetic hyperthermia therapy. Abstract In this work, we report that tuning of magnetic properties of cobalt ferrite magnetic nanoparticles (CFMNPs) is possible by combining them with some suitable organic molecules like DNA for hyperthermia therapy. Different batches of CFMNPs were synthesized on DNA scaffold (with varying the DNA concentrations for different batches) by wet chemical co-precipitation method. Final product was characterized by Fourier transform infrared spectroscopy (FT-IR), Scanning electron microscope (SEM) for biological samples, Transmission electron microscope (TEM), Superconducting quantum interference device (SQUID), X-ray diffraction (XRD), Isothermal Titration Calorimetry (ITC) etc. From XRD data it was confirmed that the above mentioned nanoparticles are cobalt ferrite in pure phase and from FT-IR, SEM and TEM analyses, it was observed that cobalt ferrite nanoparticles were properly attached with DNA. Changes in magnetic properties with change of DNA amount for different batches were investigated by SQUID magnetometer. Heating ability under alternating current (AC) magnetic field for different batches of particles was investigated. It was observed that heating property was changing with change in DNA concentration. So it can be concluded that we have synthesized particles where DNA plays a very important role in tuning the magnetic properties which may give us opportunity to customize the particles for hyperthermia therapy. [ABSTRACT FROM AUTHOR]

Abstract This work reports a new approach of synthesis of FePt nanoparticles in aqueous medium using cetyl trimethylammonium bromide (CTAB) surfactant as a capping agent and the influence of change of its concentration on the size of the particles. Tuning of magnetic properties has also been done by changing the CTAB concentrations. Here at higher CTAB concentration, particles formed are of smaller size compared to the size prepared in lower micellar concentration. The ordering parameter of the particles after annealing at 550 °C with the variation of particle size is also studied. The magnetic properties of these particles are studied and the effect of particle phase and size on magnetic property is also investigated. The particles are prepared in aqueous medium because water soluble particles are useful for hyperthermia therapy. Heating abilities of the particles under AC magnetic field are also checked with change in their size. The studies on interaction of particles with cancer cell line was also performed with probing the cell by fluorescence imaging technique after bio-functionalization of the particles by sodium oleate and fluorescent dye rhodamine-B-isothiocyanate (RITC). All these preliminary studies indicate a promising applicability of the particles for localized cancer treatment by magnetic field induced hyperthermia therapy. [ABSTRACT FROM AUTHOR]

Lung cancer is the largest cause of cancer-induced deaths. Non-small cell lung cancer (NSCLC) is the most frequently observed subtype of lung cancer. Although recent studies have provided many therapeutic options, there is still a need for effective and safe treatments. This paper reports the combined effects of cinnamaldehyde (CNM), a flavonoid from cinnamon, together with hyperthermia, a therapeutic option for cancer treatment, on the A549 NSCLC cell line. A hyperthermia treatment of 43 °C potentiated the cytotoxicity of CNM in A549 cells. This was attributed to an increase in the apoptosis markers and suppression of the survival/protective factors, as confirmed by Western blot assays. Flow cytometry supported this result because the apoptotic profile, cell health profile, and cell cycle profile were regulated by CNM and hyperthermia combination therapy. The changes in reactive oxygen species (ROS) and its downstream target pathway, mitogen-activated protein kinases (MAPK), were evaluated. The CNM and hyperthermia combination increased the generation of ROS and MAPK phosphorylation. N-acetylcysteine (NAC), a ROS inhibitor, abolished the apoptotic events caused by CNM and hyperthermia co-treatment, suggesting that the cytotoxic effect was dependent of ROS signaling. Therefore, we suggest CNM and hyperthermia combination as an effective therapeutic option for the NSCLC treatment.

Objective:Human induced pluripotent stem (iPS) cells exhibit great potential for generating functional human cells for medical therapies. In this paper, we report for use of human iPS cells labeled with fluorescent magnetic nanoparticles (FMNPs) for targeted imaging and synergistic therapy of gastric cancer cells in vivo.Methods:Human iPS cells were prepared and cultured for 72 h. The culture medium was collected, and then was coincubated with MGC803 cells. Cell viability was analyzed by the MTT method. FMNP-labeled human iPS cells were prepared and injected into gastric cancer-bearing nude mice. The mouse model was observed using a small-animal imaging system. The nude mice were irradiated under an external alternating magnetic field and evaluated using an infrared thermal mapping instrument. Tumor sizes were measured weekly.Results:iPS cells and the collected culture medium inhibited the growth of MGC803 cells. FMNP-labeled human iPS cells targeted and imaged gastric cancer cells in vivo, as well as inhibited cancer growth in vivo through the external magnetic field.Conclusion:FMNP-labeled human iPS cells exhibit considerable potential in applications such as targeted dual-mode imaging and synergistic therapy for early gastric cancer.

Chemothermal brachytherapy seeds have been developed using a combination of polymeric dual drug chemotherapy and alternating magnetic field induced hyperthermia. The synergistic effect of chemotherapy and hyperthermia brachytherapy has been investigated in a way that has never been performed before, with an in-depth analysis of the cancer cell inhibition property of the new system. A comprehensive in vivo study on athymic mice model with SCC7 tumor has been conducted to determine optimal arrays and specifications of the chemothermal seeds. Dual drug chemotherapy has been achieved via surface deposition of polydopamine that carries bortezomib, and also via loading an acidic pH soluble hydrogel that contains 5-Fluorouracil inside the chemothermal seed; this increases the drug loading capacity of the chemothermal seed, and creates dual drug synergism. An external alternating magnetic field has been utilized to induce hyperthermia conditions, using the inherent ferromagnetic property of the nitinol alloy used as the seed casing. The materials used in this study were fully characterized using FESEM, H 1 NMR, FT-IR, and XPS to validate their properties. This new approach to experimental cancer treatment is a pilot study that exhibits the potential of thermal brachytherapy and chemotherapy as a combined treatment modality. [ABSTRACT FROM AUTHOR]

Thermal dose is an important clinical efficacy index for hyperthermia cancer treatment. This paper presents a new direct radial basis function (RBF) neural network controller for high-temperature hyperthermia thermal dose during the therapeutic procedure of cancer tumours by short-time pulses of high-intensity focused ultrasound (HIFU). The developed controller is stabilized and automatically tuned based on Lyapunov functions and ant colony optimization (ACO) algorithm, respectively. In addition, this thermal dose control system has been validated using one-dimensional (1-D) biothermal tissue model. Simulation results showed that the fully tuned RBF neural network controller outperforms other controllers in the previous studies by achieving targeted thermal dose with shortest treatment times less than 13.5 min, avoiding the tissue cavitation during the thermal therapy. Moreover, the maximum value of its mean integral time absolute error (MTAE) is 98.64, which is significantly less than the resulted errors for the manual-tuned controller under the same treatment conditions of all tested cases. In this study, integrated ACO method with robust RBF neural network controller provides a successful and improved performance to deliver accurate thermal dose of hyperthermia cancer tumour treatment using the focused ultrasound transducer without external cooling effect. [ABSTRACT FROM AUTHOR]