Search Results (138)

Boron neutron capture therapy (BNCT) is a specialized cancer treatment that leverages the high absorption cross-section of boron for thermal neutrons. When boron captures neutrons, it undergoes a nuclear reaction that produces alpha particles and lithium ions, which have high linear energy transfer (LET) and can effectively damage nearby cancer cells while minimizing harm to surrounding healthy tissues. This targeted approach makes BNCT particularly advantageous for treating tumors situated in sensitive areas where traditional radiation therapies may pose risks to critical structures. In this study, the deuterium–deuterium (DD) neutron generator, specifically the DD-110 model (neutron yield Y = 1 × 10¹⁰ n/s), served as the neutron source for BNCT. The fast neutrons produced by this generator were thermalized to the epithermal energy range using a beam-shaping assembly (BSA). The BSA was designed with a moderator composed of 32 cm of MgF₂, a reflector made of 76 cm of Pb, and filters including 3 cm of Pb and 1.52 cm of Bi. A collimator, featuring a 10 cm high Pb cone frustum with a 12 cm aperture diameter, was also employed to optimize beam characteristics. The entire system’s performance was modeled and simulated using the MCNPX code, focusing on parameters both in-air and in-phantom to evaluate its efficacy. The findings indicated that the BSA configuration yielded an optimal thermal-to-epithermal flux ratio (${\phi }_{ther}$/${\phi }_{epth}$) of 0.19, a current-to-flux ratio of 0.87, and a gamma dose-to-epithermal flux ratio of 1.71 × 10⁻¹³ Gy/cm², all aligning with IAEA recommendations. The simulated system showed acceptable ratios for ${\phi }_{ther}$/${\phi }_{epth}$, gamma dose to epithermal flux, and beam collimation. Notably, the advantage depth was recorded at 5.5 cm, with an advantage ratio of 2.29 and an advantage depth dose rate of 4.1 × 10⁻⁴ Gy.Eq/min. The epithermal neutron flux of D110 exceeded D109, but D110’s fast neutron contamination increased ~6.6 times. On the other hand, D110’s gamma contamination decreased by 30%. Based on these findings, optimizing neutron source characteristics is crucial for BNCT efficacy. Future research should focus on developing advanced neutron generators that balance these factors, aiming to produce optimal neutron yields for enhanced treatment outcomes and broader applicability. Full article

Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl₄-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl₄-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition. Full article

Bone metastases occur when cancer cells from the primary tumor spread to the bones. The incidence of bone metastases is increasing due to the longer survival of patients with primary tumors, driven by advances in cancer treatments. In patients with multiple bone metastases, care is primarily palliative, aiming to improve their quality of life through pain relief. Bone metastases are strongly associated with pathological fractures, particularly in the femur. In these cases, minimally invasive treatments such as percutaneous cementoplasty and internal fixation with intramedullary nails are growing in popularity. Methods: This manuscript focuses on studying these two therapies by developing virtual models using ANSYS^® software. Thermal and thermomechanical analyses were conducted to evaluate the heat effect resulting from the polymerization of different types of bone cement and to assess the benefits of combining it with internal fixation using intramedullary nails made of different materials. Results: The results highlight the advantages of combining these two techniques compared to cementoplasty alone. Furthermore, the use of Gentamicin Bone Cement (CMW 3^®) with an intramedullary nail made of either material has been shown to provide a more significant functional improvement. Conclusions: The combination of cementoplasty with internal fixation is more effective than cementoplasty alone. The use of CMW 3^® cement with an intramedullary nail made of either material provides greater control over the growth of the metastatic lesion. The chosen injection angle results in an excessive volume of cement, causing a high degree of thermal necrosis. Full article

In the field of ultrasound therapy, the estimation of temperature to monitor treatments is becoming essential. We hypothesize that it is possible to measure temperature directly using a constant acoustic power burst. Under the assumption that the acoustic attenuation does not change significantly with temperature, the thermal strain induced by such bursts presents a linear relation with temperature. A mathematical demonstration is given in the introduction. Then, simulations of ultrasound waves in a canine liver model were conducted at different temperatures (from 20 °C to 90 °C). Finally, experimental measurements on phantom samples were performed over the same temperature range. The simulation and experimental results both showed a linear relation between thermal strain and temperature. This relation may suggest the foundation of a new ultrasound-based thermometry method. The potential and limitations of the method are discussed. Full article

The study of bubble growth and collapse is of great significance in the context of sustainability due to its influence on numerous energy-related processes and technologies. Understanding the dynamics of bubble behavior is vital for optimising heat transfer efficiency, which has an energetic role in improving the performance of sustainable systems such as nuclear reactors, thermal inkjet printing, and nucleate boiling. Indeed, researchers can progress strategies to enhance the efficiency of these technologies by analysing the parameters influencing bubble growth and collapse, which can lead to reduced energy consumption and environmental impact. Although several theoretical models and experimental investigations have been achieved in the past to inspect bubble growth and collapse, a thorough review and critical assessment of the studies conducted have not yet been achieved. This review aims to provide a comprehensive understanding of the relationship between bubble dynamics and sustainability, highlighting the potential for further research and development in this area. Specifically, the scope and limitations of past research on bubble growth and collapse is conducted to fill this gap in the open literature. The review covers both numerical and experimental studies of bubble growth and collapse in a wide set of innovative industrial applications including nuclear reactors, thermal inkjet printing, nucleate boiling, hydrodynamic erosion, and ultrasonic and medicinal therapy. The current review also attempts to illustrate and evaluate the numerical methods used and underlines the most relevant results from the studies that were looked at in order to provide researchers with a clear picture of the growth and collapse of bubbles in different applications. The results give a precise understanding of the dynamics of bubble growth and collapse and the related temperature change and cumulative heat transmission from the thermal boundary layer. Additionally, it has been demonstrated that simulation-based models can effectively predict transport coefficients. However, the review observes a number of limitations of the past research on bubble growth and collapse. Due to numerical instability, very little work with respect to dynamic modelling has been carried out on the mechanisms of bubble collapse. Accordingly, a number of recommendations are made for the improvement of heat transmission during bubble growth and collapse. Specifically, future criteria for the highest heat transmission will demand more precise experimental and numerical approaches. Full article

Fibromyalgia (FM) is a chronic and debilitating condition characterized by diffuse pain, often associated with symptoms such as fatigue, cognitive disturbances, and mood disorders. Metformin, an oral hypoglycemic agent, has recently gained attention for its potential benefits beyond glucose regulation. It has shown promise in alleviating neuropathic and inflammatory pain, suggesting that it could offer a novel approach to managing chronic pain conditions like FM. This study aimed to further explore metformin’s analgesic potential by evaluating its effects in an experimental FM model induced by reserpine in both male and female mice. After the administration of 200 mg/kg metformin to male and female mice, the FM-related symptoms were assessed, including mechanical allodynia, thermal hyperalgesia, and depressive-like behaviors. A histological examination of the thalamus, hippocampus, and spinal cord was conducted using haematoxylin and eosin staining. The neurotransmitter and proinflammatory cytokines levels were measured in the brains and spinal cords. Our results have shown that metformin treatment for seven days significantly reversed these FM-like symptoms, reducing pain sensitivity and improving mood-related behaviors in both the male and female mice. Additionally, metformin exhibited neuroprotective effects, mitigating reserpine-induced damage in the hippocampus, thalamus, and spinal cord. It also significantly lowered the levels of the proinflammatory cytokine interleukin 1-beta (IL-1β) in the brain and spinal cord. Notably, metformin modulated the neurotransmitter levels differently between the sexes, decreasing glutamate and increasing serotonin and norepinephrine in the male mice, but not in the females. These findings underscore metformin’s potential as an alternative therapy for FM, with sex-specific differences suggesting distinct mechanisms of action. Full article

According to a modern view, cancer no longer follows a purely mechanistic model. Rather, a tumor is conceived as a more complex structure, composed of cancer cells, the activities of which may interact and reshape the so-called tumor microenvironment (TME), leading to preservation of specific tumoral niches and promoting the survival of tumoral stem cells. Background/Objective: Therapeutic strategies must deal with this unique cancer architecture in the near future by widening their range of activities outside the cancer cells and rewiring a TME to ensure it is hostile to cancer growth. Therefore, an intratumoral therapeutic strategy may open the door to a new type of anticancer activity, one that directly injures the tumoral structure while also eliciting an influence on the TME through local and systemic immunomodulation. This review would like to assess the current situation of intratumoral strategies and their clinical implications. Methods We analyzed data from phase I, II, and III trials, comprehensive reviews and relevant clinical and preclinical research, from robust databases, like PUBMED, EMBASE, Cochrane Library, and clinicaltrials.gov. Results: Intratumoral strategies can be quite variable. It is possible the injection and inhalation of traditional antiblastic agents or immunomodulant agents, or intrapleural administration. Ablation strategy is available, both thermal and photodynamic method. Moreover, TTfields and NPs are analyzed and also brachytherapy is mentioned. Intratumoral therapy can find space in “adjuvant”/perioperative or metastatic settings. Finally, intratumoral strategies allow to synergize their activities with systemic therapies, guaranteeing better local and systemic disease control. Conclusions: Intratumoral strategies are overall promising. Antiblastic/immunomodulant injection and NPs use are especially interesting and intriguing. But, there is generally a lack of phase II and III trials, in particular NPs use need additional experimentation and clinical studies. Full article

Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats. Methods: Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated. Results: SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group. Conclusions: These results indicate SEMA’s neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects. Full article

Glioblastoma (GBM) is the most common primary brain malignancy in the U.S. with a 5-year overall survival < 5% despite an aggressive standard of care. Laser interstitial thermal therapy (LITT) is a surgical approach to treating GBM that has gained traction, providing a safe option for reducing intracranial tumor burden. LITT is believed to potentially modulate GBM immune responses; however, the biochemical mechanisms underlying the modulation of immune checkpoints in GBM cells have been poorly characterized. The present study aimed to preliminarily evaluate the effects of thermal therapy and radiation on PD-L1 modulation in vitro, as a function of IDH mutational status. U87 cells and their IDH-mutant counterpart (U87^R132H), which was generated using a crispr-cas9 knock-in approach, were utilized for this preliminary evaluation. Cell heating was achieved by harvesting with trypsin centrifugation where the cell pellets were treated on a heat block for the associated time and temperature. Following thermal therapy, cells were resuspended and irradiated using a 37-Cesium irradiator at 0.6 Gy min⁻¹. Immediately following treatment, cells were either plated as single cells to allow colonies to form, and stained with Coomassie blue to be counted approximately 10–14 days later or harvested for Western blot analysis. Cell lysates were analyzed for PD-L1 expression with respect to various iron metabolic parameters (mortalin (HSPA9), transferrin receptor, and ferritin heavy chain) using a Western blotting approach. In both U87 and U87^R132H cell lines, thermal therapy showed a temperature-dependent cell-killing effect, but U87^R132H cells appeared more sensitive to thermal treatment when treated at 43 °C for 10 min. Moreover, thermal therapy had minimal effects on cell responses to 2 Gy irradiation. Treatment with thermal therapy downregulated PD-L1 expression in U87^R132H cells, which was associated with increased expression of the mitochondrial iron metabolic enzyme, HSPA9. Thermal therapy reversed the radiation-induced overexpression of PD-L1, transferrin receptor, and ferritin heavy chain in U87^R132H cells. No effects were observed in wild-type U87 cells. Moreover, Ga(NO₃)₃ depleted mitochondrial iron content which, in turn, significantly enhanced the sensitivity of U87^R132H cells to thermal therapy and 2 Gy irradiation and caused a significant increase in PD-L1 expression. These results suggest that thermal therapy alone can modulate the immune checkpoint PD-L1. This effect was more pronounced when thermal therapy was combined with radiation. Mechanistically, mitochondrial iron trafficking through HSPA9 may coordinate the regulation of PD-L1 in the context of thermal therapy and ionizing radiation, which can be targeted with gallium-based therapy. These novel, preliminary findings warrant further mechanistic investigations in pre-clinical models of LITT. Full article

Monoclonal antibodies (mAbs) are widely used in cancer therapy but often show limited efficacy for solid tumors. Enhancing anti-tumor activity by fusing cytokines to tumor-targeting mAbs, which specifically activate immune cells within the tumor microenvironment, represents a promising strategy. However, the optimal design and therapeutic efficacy of antibody–cytokine fusion formats remain unclear. The epithelial cell adhesion molecule (EpCAM), frequently overexpressed in a variety of carcinomas, serves as the target for immunotherapies. In this study, we identified a fully human mAb targeting EpCAM, designated as m801, from a previously constructed phage-displayed fully human antibody library. By fusing m801 with an IL-2 variant (IL-2v) in two configurations, m801.2 (2 anti-EpCAM Fab + 1 IL-2v) and m801.3 (1 anti-EpCAM Fab + 1 IL-2v), we identified m801.2 as the lead candidate due to its superior biophysical properties, including high thermal stability, homogeneity, and low aggregation. Furthermore, m801.2 showed strong binding affinity to EpCAM, with KD values of 0.6 nM, and an EpCAM-expressing tumor cell line, comparable to the original IgG m801. Additionally, m801.2 exhibited IL-2 receptor β subunit (IL-2Rβ)-biased binding activity, with a KD of 27.3 nM, resulting in superior effective T cell activation. In an SW480 xenograft mice model, m801.2 significantly inhibited tumor growth and demonstrated high tolerability. These findings suggest a valuable framework for the future design of immunocytokine therapies. Full article

Background: Dehydration, a common condition where the amount water lost from the body exceeds intake, disrupts metabolic processes and negatively impacts health and performance. Rehydration, the process of restoring body fluids and electrolytes to normal levels, is crucial for maintaining physiological health. In vivo dehydration models are experimental systems used to study the effects of dehydration on living organisms. However, a comprehensive summary of in vivo models and the application of human rehydration strategies is lacking. Methods: This review provides a comprehensive overview of various in vivo models and rehydration strategies. Results: In vivo models, stimulated by fluid restriction, exercise, thermal exposure, and chemicals, have been used to study dehydration. Importantly, the principles, characteristics, and limitations of the in vivo models are also discussed, along with rehydration administration methods, including oral, intestinal, intravenous, subcutaneous, and intraperitoneal routes. Additionally, rehydration strategies and the application for managing different dehydration conditions both in daily life and clinical settings have been summarized. Conclusions: Overall, this review aims to enhance the understanding of the conditions in which in vivo dehydration models and rehydration strategies are applicable, thereby advancing research into the physiological and pathological mechanisms of dehydration and supporting the development of effective rehydration therapies. Full article

Hand paralysis, caused by conditions such as spinal cord injuries, strokes, and arthritis, significantly hinders daily activities. Wearable exo-gloves and telerehabilitation offer effective hand training solutions to aid the recovery process. This study presents the development of lightweight wearable exo-gloves designed for finger telerehabilitation. The prototype uses NiTi shape memory alloy (SMA) actuators to control five fingers. Specialized end effectors target the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, mimicking human finger tendon actions. A variable structure controller, managed through a web-based Human–Machine Interface (HMI), allows remote adjustments. Thermal behavior, dynamics, and overall performance were modeled in MATLAB Simulink, with experimental validation confirming the model’s efficacy. The phase transformation characteristics of NiTi shape memory wire were studied using the Souza–Auricchio model within COMSOL Multiphysics 6.2 software. Comparing the simulation to trial data showed an average error of 2.76°. The range of motion for the MCP, PIP, and DIP joints was 21°, 65°, and 60.3°, respectively. Additionally, a minimum torque of 0.2 Nm at each finger joint was observed, which is sufficient to overcome resistance and meet the torque requirements. Results demonstrate that integrating SMA actuators with telerehabilitation addresses the need for compact and efficient wearable devices, potentially improving patient outcomes through remote therapy. Full article

In recent years, various drug delivery systems circumventing the blood–brain barrier have emerged for treating brain tumors. This study aimed to improve the efficacy of brain tumor treatment in boron neutron capture therapy (BNCT) using cerebrospinal fluid (CSF) circulation to deliver boronophenylalanine (BPA) to targeted tumors. Previous experiments have demonstrated that boron accumulation in the brain cells of normal rats remains comparable to that after intravenous (IV) administration, despite BPA being administered via CSF at significantly lower doses (approximately 1/90 of IV doses). Based on these findings, BNCT was conducted on glioma model rats at the Kyoto University Research Reactor Institute (KUR), with BPA administered via CSF. This method involved implanting C6 cells into the brains of 8-week-old Wistar rats, followed by administering BPA and neutron irradiation after a 10-day period. In this study, the rats were divided into four groups: one receiving CSF administration, another receiving IV administration, and two control groups without BPA administration, with one subjected to neutron irradiation and the other not. In the CSF administration group, BPA was infused from the cisterna magna at 8 mg/kg/h for 2 h, while in the IV administration group, BPA was intravenously administered at 350 mg/kg via the tail vein over 1.5 h. Thermal neutron irradiation (5 MW) for 20 min, with an average fluence of 3.8 × 10¹²/cm², was conducted at KUR’s heavy water neutron irradiation facility. Subsequently, all of the rats were monitored under identical conditions for 7 days, with pre- and post-irradiation tumor size assessed through MRI and pathological examination. The results indicate a remarkable therapeutic efficacy in both BPA-administered groups (CSF and IV). Notably, the rats treated with CSF administration exhibited diminished BPA accumulation in normal tissue compared to those treated with IV administration, alongside maintaining excellent overall health. Thus, CSF-based BPA administration holds promise as a novel drug delivery mechanism in BNCT. Full article

Background: The possibility of keeping liver grafts viable and functioning until transplantation has been explored since the 1950s. However, the current modalities of Normothermic Machine Perfusion (NMP) have shown several limitations, such as the inability to correct electrolytes and pH derangements efficiently. Combining NMP with continuous kidney replacement therapy (CKRT) might provide a promising new model to overcome these issues. Methods: An NMP that covers the organ perfusion, oxygenation, carbon dioxide removal, and thermal balance was connected to a CKRT circuit to ensure physiological hydro-electrolytes, acid–base balance, and catabolite removal from the perfusate. Results: The integration of NMP and CKRT maintains a neoplastic liver in a perfusion system with physiological perfusate for 100 h. CKRT re-established and maintained the hydro-electrolyte and acid–base status throughout the 100 h of perfusion. Significant limitations were the need for frequent monitoring of electrolytes and acid–base disorders and the loss of low molecular weight nutrients, which have to be replenished by manual infusion into the system. Conclusions: This novel CKRT-NMP integrated system may represent a practical and versatile model to support organs’ perfusion and extend preservation times. Further experiments are needed to fix monitoring and adjusting processes. Full article

Glioblastoma multiforme (GBM) is the most severe form of brain cancer in adults, characterized by its complex vascular network that contributes to resistance to conventional therapies. Thermal therapies, such as magnetic hyperthermia (MHT), emerge as promising alternatives, using heat to selectively target tumor cells while minimizing damage to healthy tissues. The organ-on-a-chip can replicate this complex vascular network of GBM, allowing for detailed investigations of heat dissipation in MHT, while computational simulations refine treatment parameters. In this in silico study, tumor-on-a-chip models were used to optimize MHT therapy by comparing heat dissipation in normal and abnormal vascular networks, considering geometries, flow rates, and concentrations of magnetic nanoparticles (MNPs). In the high vascular complexity model, the maximum velocity was 19 times lower than in the normal vasculature model and 4 times lower than in the low-complexity tumor model, highlighting the influence of vascular complexity on velocity and temperature distribution. The MHT simulation showed greater heat intensity in the central region, with a flow rate of 1 µL/min and 0.5 mg/mL of MNPs being the best conditions to achieve the therapeutic temperature. The complex vasculature model had the lowest heat dissipation, reaching 44.15 °C, compared to 42.01 °C in the low-complexity model and 37.80 °C in the normal model. These results show that greater vascular complexity improves heat retention, making it essential to consider this heterogeneity to optimize MHT treatment. Therefore, for an efficient MHT process, it is necessary to simulate ideal blood flow and MNP conditions to ensure heat retention at the tumor site, considering its irregular vascularization and heat dissipation for effective destruction. Full article