The use of new radiopharmaceuticals labeled with lutetium-177 represents a successful translation of experimental results into clinical practice. Recent experimental data suggests that terbium-161 might well follow the example of lutetium-177 regarding applicability in nuclear medicine. Similarly to lutetium-177, the terbium-161 emits beta particles and gamma-radiation, although terbium-161 emits short-ranged conversion and Auger electrons, creating an effect that may eliminate smaller tumor metastases more effectively than lutetium-177. Terbium-161 may exert a higher radiobiological effect in the target tissues in comparison with lutetium-177, a difference which makes possible a reduction in the doses of radioactivity administered. Further, due to the similar chemical properties of lutetium-177 and terbium-161, similar radiolabeling techniques can be used. The differences found in preclinical experiments on radiotoxicity of the counterparts seem to be minor. Despite intensive progress, the number of preclinical studies on 161Tb-labeled agents is still not comparable to studies on lutetium-177. Clinical trials with 161Tb-labeled radiopharmaceuticals focused on the treatment of prostate cancer and selected neuroendocrine tumors have already begun, although none of them have been completed yet.
- MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Lutetium * therapeutic use adverse effects chemistry MeSH
- Nuclear Medicine * methods MeSH
- Radiopharmaceuticals therapeutic use MeSH
- Radioisotopes * therapeutic use adverse effects MeSH
- Terbium * therapeutic use chemistry adverse effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Comparative Study MeSH
Medulloblastoma, the most prevalent brain tumor among children, requires a comprehensive understanding of its cellular characteristics for effective research and treatment. In this study, we focused on DAOY, a permanent cell line of medulloblastoma, and investigated the unique properties of DAOY cells when cultured as floating multicellular aggregates called spheres, as opposed to adherent monolayers. Through our comprehensive analysis, we identified distinct characteristics associated with DAOY spheres. Our findings demonstrate that DAOY spheres express markers for both neural stem cells, such as CD133 (PROM1), and differentiated neurons, exemplified by MAP2. Additionally, our investigation revealed that spheres-derived cells exhibit heightened resistance to ionizing radiation compared to adherent cells. Consequently, our results indicate that caution is advised when interpreting experimental results obtained from adherent cell cultures and extrapolating them to in vivo situations.
- Publication type
- Journal Article MeSH
PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.
- MeSH
- CD8-Positive T-Lymphocytes * immunology drug effects MeSH
- Tertiary Lymphoid Structures * immunology pathology MeSH
- Hepatocyte Nuclear Factor 1-alpha * genetics metabolism MeSH
- Immune Checkpoint Inhibitors * therapeutic use pharmacology MeSH
- Carboplatin administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Tumor Microenvironment * immunology drug effects MeSH
- Ovarian Neoplasms * drug therapy immunology pathology MeSH
- Neoadjuvant Therapy methods MeSH
- Paclitaxel administration & dosage therapeutic use pharmacology MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use pharmacology MeSH
- Cystadenocarcinoma, Serous drug therapy pathology immunology MeSH
- Endoplasmic Reticulum Stress drug effects immunology MeSH
- Lymphocytes, Tumor-Infiltrating immunology drug effects metabolism MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Radiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear. METHODS: We established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments. RESULTS: In this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression. CONCLUSIONS: These findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII.
- MeSH
- Ataxia Telangiectasia Mutated Proteins * metabolism genetics MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- DNA Damage * MeSH
- Radiation Injuries metabolism genetics MeSH
- Ubiquitin-Specific Proteases * metabolism genetics MeSH
- Intestines radiation effects pathology MeSH
- Ubiquitination * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Ultra high dose rate (UHDR) radiotherapy using ridge filter is a new treatment modality known as conformal FLASH that, when optimized for dose, dose rate (DR), and linear energy transfer (LET), has the potential to reduce damage to healthy tissue without sacrificing tumor killing efficacy via the FLASH effect. PURPOSE: Clinical implementation of conformal FLASH proton therapy has been limited by quality assurance (QA) challenges, which include direct measurement of UHDR and LET. Voxel DR distributions and LET spectra at planning target margins are paramount to the DR/LET-related sparing of organs at risk. We hereby present a methodology to achieve experimental validation of these parameters. METHODS: Dose, DR, and LET were measured for a conformal FLASH treatment plan involving a 250-MeV proton beam and a 3D-printed ridge filter designed to uniformly irradiate a spherical target. We measured dose and DR simultaneously using a 4D multi-layer strip ionization chamber (MLSIC) under UHDR conditions. Additionally, we developed an "under-sample and recover (USRe)" technique for a high-resolution pixelated semiconductor detector, Timepix3, to avoid event pile-up and to correct measured LET at high-proton-flux locations without undesirable beam modifications. Confirmation of these measurements was done using a MatriXX PT detector and by Monte Carlo (MC) simulations. RESULTS: MC conformal FLASH computed doses had gamma passing rates of >95% (3 mm/3% criteria) when compared to MatriXX PT and MLSIC data. At the lateral margin, DR showed average agreement values within 0.3% of simulation at 100 Gy/s and fluctuations ∼10% at 15 Gy/s. LET spectra in the proximal, lateral, and distal margins had Bhattacharyya distances of <1.3%. CONCLUSION: Our measurements with the MLSIC and Timepix3 detectors shown that the DR distributions for UHDR scenarios and LET spectra using USRe are in agreement with simulations. These results demonstrate that the methodology presented here can be used effectively for the experimental validation and QA of FLASH treatment plans.
Effects of pre/postnatal 2.45 GHz continuous wave (CW), Wireless-Fidelity (Wi-Fi) Microwave (MW) irradiation on bone have yet to be well defined. The present study used biochemical and histological methods to investigate effects on bone formation and resorption in the serum and the tibia bone tissues of growing rats exposed to MW irradiation during the pre/postnatal period. Six groups were created: one control group and five experimental groups subjected to low-level different electromagnetic fields (EMF) of growing male rats born from pregnant rats. During the experiment, the bodies of all five groups were exposed to 2.45 GHz CW-MW for one hour/day. EMF exposure started after fertilization in the experimental group. When the growing male rats were 45 days old in the postnatal period, the control and five experimental groups' growing male and maternal rats were sacrificed, and their tibia tissues were removed. Maternal rats were not included in the study. No differences were observed between the control and five experimental groups in Receptor Activator Nuclear factor-kB (RANK) biochemical results. In contrast, there was a statistically significant increase in soluble Receptor Activator of Nuclear factor-kB Ligand (sRANKL) and Osteoprotegerin (OPG) for 10 V/m and 15 V/m EMF values. Histologically, changes in the same groups supported biochemical results. These results indicate that pre/postnatal exposure to 2.45 GHz EMF at 10 and 15 V/m potentially affects bone development.
- MeSH
- Electromagnetic Fields * adverse effects MeSH
- Rats MeSH
- Microwaves * adverse effects MeSH
- Rats, Sprague-Dawley MeSH
- Pregnancy MeSH
- Bone Development MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cíl: Cílem pilotní studie bylo zjistit vliv dynamického sedu na míru bolesti v oblasti zad a pánve v těhotenství a na mobilitu a kvalitu života v těhotenství. Soubor a metodika: Výzkumu se zúčastnilo 22 těhotných žen, které byly rozděleny do experimentální a kontrolní skupiny. Experimentální skupina (n = 11) ve věku 32,55 ± 5,5 roku a se vstupním body mass indexem (BMI) 24,81 ± 3,26 a kontrolní skupina (n = 11) ve věku 31,64 ± 5,12 roku se vstupním body mass indexem 24,27 ± 2,4. Ženy v experimentální skupině používaly při sezení dynamickou podložku po dobu 20 minut denně, celkově po dobu 2 měsíců. K hodnocení efektu byla použita zkrácená verze McGillova dotazníku bolesti a dotazník Pregnancy mobility index hodnotící mobilitu a kvalitu života žen v těhotenství. Výsledky: Dle zkrácené verze McGillova dotazníku bolesti došlo v části bodového skóre preskriptorů bolesti u experimentální skupiny ke zlepšení a u kontrolní skupiny ke zhoršení bolesti. V porovnání mezi skupinami nebyla změna statisticky významná. Dle dotazníku hodnotícího mobilitu a kvalitu života žen v těhotenství došlo ke zhoršení u kontrolní skupiny. Rozdíl mezi skupinami nebyl statisticky významný. Závěry: Dynamickou podložku jako prevenci bolestí zad a prevenci zhoršení mobility a kvality života v těhotenství nelze jednoznačně doporučit. Přesto parciální výsledky pilotní studie ukazují, že má význam se touto problematikou dále zabývat a provést další výzkumy především s větším počtem probandek.
Objective: The aim of this pilot study was to investigate the impact of dynamic sitting on the level of back and pelvic pain during pregnancy, as well as on mobility and quality of life during pregnancy. Participants and methods: The study included 22 pregnant women who were divided into an experimental and a control group. The experimental group (N = 11), with an average age of 32.55 ± 5.5 years and an initial body mass index (BMI) of 24.81 ± 3.26, used a dynamic cushion while sitting for 20 minutes daily over a period of two months. The control group (N = 11), with an average age of 31.64 ± 5.12 years and an initial BMI of 24.27 ± 2.4, did not use the dynamic cushion. The effect was assessed using a shortened version of the McGill pain questionnaire and a questionnaire evaluating the mobility and quality of life of pregnant women, known as the Pregnancy mobility index. Results: According to the shortened version of the McGill pain questionnaire, there was improvement in part of the pain assessment score in the experimental group and a deterioration of pain in the control group. The difference between the groups was not statistically significant. According to the questionnaire evaluating mobility and quality of life during pregnancy, there was a deterioration in the control group. The difference between the groups was not statistically significant. Conclusions: The use of a dynamic cushion cannot be unequivocally recommended as a preventive measure for back pain or for preserving mobility and quality of life during pregnancy. However, partial results from the pilot study suggest that further exploration of this issue is warranted, and additional research should be conducted, particularly with a larger sample size.
- Keywords
- dynamický sed, dotazník SF-MPQ,
- MeSH
- Back Pain * prevention & control MeSH
- Adult MeSH
- Pregnancy Complications MeSH
- Quality of Life MeSH
- Humans MeSH
- Pelvic Pain * prevention & control MeSH
- Pilot Projects MeSH
- Sitting Position * MeSH
- Surveys and Questionnaires statistics & numerical data MeSH
- Exercise Movement Techniques methods MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
Východiska: Mnohé experimentální a klinické studie jsou prováděny s cílem prozkoumat účinky různých aplikací botulotoxinu (BTx) při léčbě nežádoucích účinků radioterapie. Neexistují žádné studie, které by ukazovaly jasné výsledky ohledně jeho pozitivních a negativních účinků při aktivním klinickém využití v dlouhodobém měřítku a na toto téma probíhají diskuze. Navíc je třeba prozkoumat, jakým způsobem a jak dlouho lze BTx používat a jaké může vyvolat nežádoucí účinky. Účinnou a bezpečnou možností při léčbě nežádoucích účinků vyvolaných radioterapií je BTx-A. Aplikace injekce BTx do správného místa určitým způsobem vpichu zvyšuje účinnost a bezpečnost léčby. Cíl: Bylo zkoumáno, zda BTx bude potenciálním nástrojem pro dosažení dokonalých estetických a funkčních výsledků při snižování chronických nežádoucích účinků vyvolaných radioterapií.
Background: Many experimental and clinical studies are conducted to investigate the effects of various applications of botulinum toxin (BTx) in the treatment of radiation related side effects. There are no studies that show clear results about the positive and negative effects of its active clinical use in the long run, and discussions are ongoing. In addition, there is a need for various researches about how BTx can be used and how long it can be used, and the side effects it may cause. BTx-A, which is one of the options in the treatment of side effects that will occur due to radiotherapy, is an effective and safe option. Applying BTx injection to the right place with specific injection methods increases the effectiveness and safety of the treatment. Purpose: It has been investigated whether BTx will be a potential tool to perfect the esthetic and functional results in reducing the chronic side effects associated with radiotherapy.
- MeSH
- Botulinum Toxins * therapeutic use MeSH
- Humans MeSH
- Radiotherapy * adverse effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
After large-scale radiation accidents where many individuals are suspected to be exposed to ionizing radiation, biological and physical retrospective dosimetry assays are important tools to aid clinical decision making by categorizing individuals into unexposed/minimally, moderately or highly exposed groups. Quality-controlled inter-laboratory comparisons of simulated accident scenarios are regularly performed in the frame of the European legal association RENEB (Running the European Network of Biological and Physical retrospective Dosimetry) to optimize international networking and emergency readiness in case of large-scale radiation events. In total 33 laboratories from 22 countries around the world participated in the current RENEB inter-laboratory comparison 2021 for the dicentric chromosome assay. Blood was irradiated in vitro with X rays (240 kVp, 13 mA, ∼75 keV, 1 Gy/min) to simulate an acute, homogeneous whole-body exposure. Three blood samples (no. 1: 0 Gy, no. 2: 1.2 Gy, no. 3: 3.5 Gy) were sent to each participant and the task was to culture samples, to prepare slides and to assess radiation doses based on the observed dicentric yields from 50 manually or 150 semi-automatically scored metaphases (triage mode scoring). Approximately two-thirds of the participants applied calibration curves from irradiations with γ rays and about 1/3 from irradiations with X rays with varying energies. The categorization of the samples in clinically relevant groups corresponding to individuals that were unexposed/minimally (0-1 Gy), moderately (1-2 Gy) or highly exposed (>2 Gy) was successfully performed by all participants for sample no. 1 and no. 3 and by ≥74% for sample no. 2. However, while most participants estimated a dose of exactly 0 Gy for the sham-irradiated sample, the precise dose estimates of the samples irradiated with doses >0 Gy were systematically higher than the corresponding reference doses and showed a median deviation of 0.5 Gy (sample no. 2) and 0.95 Gy (sample no. 3) for manual scoring. By converting doses estimated based on γ-ray calibration curves to X-ray doses of a comparable mean photon energy as used in this exercise, the median deviation decreased to 0.27 Gy (sample no. 2) and 0.6 Gy (sample no. 3). The main aim of biological dosimetry in the case of a large-scale event is the categorization of individuals into clinically relevant groups, to aid clinical decision making. This task was successfully performed by all participants for the 0 Gy and 3.5 Gy samples and by 74% (manual scoring) and 80% (semiautomatic scoring) for the 1.2 Gy sample. Due to the accuracy of the dicentric chromosome assay and the high number of participating laboratories, a systematic shift of the dose estimates could be revealed. Differences in radiation quality (X ray vs. γ ray) between the test samples and the applied dose effect curves can partly explain the systematic shift. There might be several additional reasons for the observed bias (e.g., donor effects, transport, experimental conditions or the irradiation setup) and the analysis of these reasons provides great opportunities for future research. The participation of laboratories from countries around the world gave the opportunity to compare the results on an international level.
- MeSH
- Biological Assay methods MeSH
- Chromosome Aberrations * MeSH
- Chromosomes MeSH
- Humans MeSH
- Radiometry methods MeSH
- Retrospective Studies MeSH
- Radioactive Hazard Release * MeSH
- Dose-Response Relationship, Radiation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Dramatically increased levels of electromagnetic radiation in the environment have raised concerns over the potential health hazards of electromagnetic fields. Various biological effects of magnetic fields have been proposed. Despite decades of intensive research, the molecular mechanisms procuring cellular responses remain largely unknown. The current literature is conflicting with regards to evidence that magnetic fields affect functionality directly at the cellular level. Therefore, a search for potential direct cellular effects of magnetic fields represents a cornerstone that may propose an explanation for potential health hazards associated with magnetic fields. It has been proposed that autofluorescence of HeLa cells is magnetic field sensitive, relying on single-cell imaging kinetic measurements. Here, we investigate the magnetic field sensitivity of an endogenous autofluorescence in HeLa cells. Under the experimental conditions used, magnetic field sensitivity of an endogenous autofluorescence was not observed in HeLa cells. We present a number of arguments indicating why this is the case in the analysis of magnetic field effects based on the imaging of cellular autofluorescence decay. Our work indicates that new methods are required to elucidate the effects of magnetic fields at the cellular level.
- MeSH
- Electromagnetic Fields * MeSH
- HeLa Cells MeSH
- Humans MeSH
- Magnetic Fields * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
