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International Journal of Molecular... May 2024Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA)...
Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA) compound ([At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [At]PSMA-5 was administered to both normal male ICR mice ( = 85) and cynomolgus monkeys ( = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day ( = 10 per group) and 14 days ( = 5 per group). Monkeys were observed 24 h post-administration of [At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of At using a cyclotron supports its applicability for clinical use.
Topics: Animals; Male; Prostatic Neoplasms; Mice; Tissue Distribution; Mice, Inbred ICR; Astatine; Alpha Particles; Humans; Macaca fascicularis; Glutamate Carboxypeptidase II; Radiopharmaceuticals
PubMed: 38891856
DOI: 10.3390/ijms25115667 -
Journal of Translational Medicine Jun 2024This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous...
BACKGROUND
This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT).
METHODS
The study retrospectively analyzed 232 ESCC patients who underwent pretreatment and post-treatment CT scans. Patients were divided into training (n = 186) and validation (n = 46) sets through fivefold cross-validation. 837 radiomics features were extracted from regions of interest (ROIs) delineations on CT images before and after nCRT to calculate delta values. The LASSO algorithm selected delta-radiomics features (DRF) based on classification performance. Logistic regression constructed a nomogram incorporating DRFs and clinical factors. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses evaluated nomogram performance for predicting pCR.
RESULTS
No significant differences existed between the training and validation datasets. The 4-feature delta-radiomics signature (DRS) demonstrated good predictive accuracy for pCR, with α-binormal-based and empirical AUCs of 0.871 and 0.869. T-stage (p = 0.001) and differentiation degree (p = 0.018) were independent predictors of pCR. The nomogram combined the DRS and clinical factors improved the classification performance in the training dataset (AUC = 0.933 and AUC = 0.941). The validation set showed similar performance with AUCs of 0.958 and 0.962.
CONCLUSIONS
The CT-based delta-radiomics nomogram model with clinical factors provided high predictive accuracy for pCR in ESCC patients after nCRT.
Topics: Humans; Nomograms; Male; Female; Middle Aged; Neoadjuvant Therapy; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Tomography, X-Ray Computed; Chemoradiotherapy; ROC Curve; Treatment Outcome; Aged; Carcinoma, Squamous Cell; Reproducibility of Results; Adult; Area Under Curve; Retrospective Studies; Radiomics
PubMed: 38890720
DOI: 10.1186/s12967-024-05392-4 -
Cell Death & Disease Jun 2024Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs....
Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.
Topics: Alpha Particles; Humans; Tumor Suppressor Protein p53; Animals; Mice; Radiation-Sensitizing Agents; Mutation; Quinuclidines; Cell Line, Tumor; Mice, Nude; Xenograft Model Antitumor Assays; Apoptosis; Neoplasms
PubMed: 38890278
DOI: 10.1038/s41419-024-06830-3 -
Nutrition, Metabolism, and... May 2024Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the...
BACKGROUND AND AIMS
Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the vascular endothelium has been hypothesized to be an initial step in the formation of atherosclerotic plaques, with inflammatory cytokines serving as the signaling mechanism for concomitant macrophage activation. Supplementation with the antioxidative macular xanthophylls (lutein [L], zeaxanthin [Z], and meso-zeaxanthin [MZ]) has been shown to aid in the reduction of inflammatory physiologic responses; therefore, we hypothesized that in our study population, supplementation with these xanthophylls would facilitate a systemic reduction in markers of inflammation and cardiovascular lipid oxidation.
METHODS AND RESULTS
In this double-blind placebo-controlled supplementation study, participants were randomly allocated to receive the active intervention containing L (10 mg) + MZ (10 mg) + Z (2 mg) or placebo (containing sunflower oil). Serum concentrations of carotenoids (assessed by HPLC), inflammatory cytokines (IL-6, IL-1β, TNF-α) and oxidized LDL (OxLDL; by solid-phase sandwich ELISA) were measured at baseline and at 6-months. Results showed that over the supplementation period, compared to placebo, the active group demonstrated statistically significant increases in serum concentrations of L, Z, & MZ (p < 0.05), reductions in inflammatory cytokines IL-1β (p < 0.001) and TNF-α (p = 0.003), as well as a corresponding reduction in serum OxLDL (p = 0.009).
CONCLUSIONS
Our data show that L, Z, & MZ supplementation results in decreased serum IL-1β, TNF-α, and OxLDL. This suggests that these carotenoids are acting systemically to attenuate oxidative lipid products and inflammation, thus reducing their contribution to atherosclerotic plaque formation.
PubMed: 38890092
DOI: 10.1016/j.numecd.2024.05.009 -
Advances in Radiation Oncology Jul 2024Ultrahypofractionated (UHF) radiation therapy (RT) has become a treatment alternative for patients with localized prostate cancer. In more advanced cases, seminal...
Ultrahypofractionated Radiation Therapy for Prostate Cancer Including Seminal Vesicles in the Target Volume: A Treatment-planning Study Based on the HYPO-RT-PC Fractionation Schedule.
PURPOSE
Ultrahypofractionated (UHF) radiation therapy (RT) has become a treatment alternative for patients with localized prostate cancer. In more advanced cases, seminal vesicles (SVs) are routinely included in the target volume. The Scandinavian HYPO-RT-PC trial, which compared 42.7 Gy in 7 fractions (fr) to conventional fractionation (CF), did not include SVs in the clinical target volume. The primary objective of the present work was to implement a ultrahypofractionated-simultaneous integrated boost (UHF-SIB) for prostate cancer RT, incorporating SVs into the target volume based on this fractionation schedule. A secondary objective was to analyze the unintentional dose coverage of SVs from state-of-the-art volumetric modulated arc therapy treatments to the prostate gland only.
METHODS AND MATERIALS
Two different equieffective UHF-SIB treatment schedules to SVs were derived based on the CF clinical schedule (50.0 Gy/25 fr to elective SVs and 70.0 Gy/35 fr to verified SV-invasion (SVI)) using the linear quadric model with α/β = 2 Gy and 3 Gy. The dose to the prostate was 42.7 Gy/7 fr in both schedules, with 31.2 Gy/37.8 Gy (α/β = 2 Gy) and 32.7 Gy/40.1 Gy (α/β = 3 Gy) to elective SV/verified SVI. Volumetric modulated arc therapy plans to the proximal 10 mm and 20 mm were optimized, and dose-volume metrics for target volumes and organs at risk were evaluated.
RESULTS
Dose metrics were overall lower for UHF-SIB compared with CF. QUANTEC-based volume criteria were 2% to 7% lower for the rectum and 2% to 4% lower for the bladder in the UHF-SIB. The D to elective SV was 7 to 12 Gy lower with UHF-SIB, and the corresponding data for verified SVI were approximately 2 to 3 Gy. The SV(10 mm) V for prostate-only treatments (42.7 Gy) were as follows: median (IQR), 99% (87-100) and 78% (58-99) for the clinical target volume and planning target volume, respectively.
CONCLUSIONS
UHF RT based on the HYPO-RT-PC fractionation schedule, with a SIB technique, to the prostate and the base of the SV can be planned with lower doses (EQD2) to organs at risk, compared with CF. The unintentional dose to the proximal parts of SVs in prostate-only treatment can be substantial.
PubMed: 38883997
DOI: 10.1016/j.adro.2024.101531 -
Journal of Materials Chemistry. C Jun 2024Pyroelectricity in a recently developed all-organic composite electret with a polar polynorbornene-based filler and polydimethylsiloxane (PDMS) matrix has been studied...
Pyroelectricity in a recently developed all-organic composite electret with a polar polynorbornene-based filler and polydimethylsiloxane (PDMS) matrix has been studied with the help of thermal and dielectric techniques. Measurement of the pyroelectric coefficient using a quasi-static periodic temperature variation at RT shows a non-linear dependence with the applied poling field, which is uncharacteristic of amorphous materials. Dielectric relaxation spectroscopy (DRS) and the thermally stimulated depolarization current (TSDC) technique reveal that this behaviour can be attributed to Maxwell-Wagner interface (MWI) polarization that occurs at the filler-matrix interface. These charges released during the onset of dipolar and relaxations of the filler particles contribute majorly to the observed pyroelectricity at RT. The saturation of both MWI TSDC shoulders and spontaneous polarization at higher electric fields correlates with the coefficient value reaching a plateau at these applied fields. A maximum coefficient of 0.54 μC m K is calculated for a poling field of 30 V μm.
PubMed: 38882549
DOI: 10.1039/d4tc00791c -
Digital Health 2024Pain is a common adverse event in survivors of breast cancer (sBCs). As there is no gold standard to assess pain experience predominantly related to central...
INTRODUCTION
Pain is a common adverse event in survivors of breast cancer (sBCs). As there is no gold standard to assess pain experience predominantly related to central sensitization (CS) symptoms, we designed the , which includes an algorithm to report whether patients are under predominant CS pain mechanisms.
OBJECTIVE
We aimed to assess the reliability of the to estimate whether sBC pain experience is predominantly related to CS symptoms.
METHODS
An observational, descriptive reliability design was employed to assess the inter- and intrarater reliability of the This app includes an algorithm that considers the number of painful body parts and some questionnaires related to pain, such as the Numeric Pain-Rating Scale the Brief Pain Inventory, the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, and the Central Sensitization Inventory (CSI).
RESULTS
A total of 21 sBCs with persistent pain were recruited. We observe a general trend of close agreement between the paper-based and app-based formats (ICCs ranged between 0.802 and 0.972; Cronbach's alpha ranged between 0.797 and 0.971). Test-retest reliabilities were moderate to excellent (ICCs ranged between 0.510 and 0.941; Cronbach's alpha ranged between 0.499 and 0.938). The agreement between the categorization of the CS algorithm and the CSI (cut-off point ≥ 40 for CS symptoms) was 95.24%.
CONCLUSION
The emerges as a robust tool for evaluating pain experience predominantly related to CS and pain-related symptoms in sBCs. Its demonstrated reliability not only bolsters its utility but also signifies its potential as a valuable asset for healthcare professionals engaged in pain education programs.
PubMed: 38882256
DOI: 10.1177/20552076241260150 -
Translational Cancer Research May 2024Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had...
Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.
PubMed: 38881922
DOI: 10.21037/tcr-23-2104 -
Thoracic Cancer Jun 2024Limited literature exists on the feasibility and effectiveness of integrating stereotactic ablative radiotherapy (SABR) techniques with hyperfractionated regimens for...
BACKGROUND
Limited literature exists on the feasibility and effectiveness of integrating stereotactic ablative radiotherapy (SABR) techniques with hyperfractionated regimens for patients with lung cancer. This study aims to assess whether the SABR technique with hyperfractionation can potentially reduce lung toxicity.
METHODS
We utilized the linear-quadratic model to find the optimal fraction to maximize the tumor biological equivalent dose (BED) to normal-tissue BED ratio. Validation was performed by comparing the SABR plans with 50 Gy/5 fractions and hyperfractionationed plans with 88.8 Gy/74 fractions with the same tumor BED and planning criteria for 10 patients with early-stage lung cancer. Mean lung BED, Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP), critical volume (CV) criteria (volume below BED of 22.92 and 25.65 Gy, and mean BED for lowest 1000 and 1500 cc) and the percentage of the lung receiving 20Gy or more (V20) were compared using the Wilcoxon signed-rank test.
RESULTS
The transition point occurs when the tumor-to-normal tissue ratio (TNR) of the physical dose equals the TNR of α/β in the BED dose-volume histogram of the lung. Compared with the hypofractionated regimen, the hyperfractionated regimen is superior in the dose range above but inferior below the transition point. The hyperfractionated regimen showed a lower mean lung BED (6.40 Gy vs. 7.73 Gy) and NTCP (3.50% vs. 4.21%), with inferior results concerning CV criteria and higher V20 (7.37% vs. 7.03%) in comparison with the hypofractionated regimen (p < 0.01 for all).
CONCLUSIONS
The hyperfractionated regimen has an advantage in the high-dose region of the lung but a disadvantage in the low-dose region. Further research is needed to determine the superiority between hypo- and hyperfractionation.
PubMed: 38881388
DOI: 10.1111/1759-7714.15335 -
Food Chemistry Jun 2024The effect of inhibiting retrogradation and changes in chain length distribution by AG and BE, which are texture-modifying enzymes, has been clarified. To ascertain in...
The effect of inhibiting retrogradation and changes in chain length distribution by AG and BE, which are texture-modifying enzymes, has been clarified. To ascertain in which part of the rice grain retrogradation occurs and which enzymes is most effective, the degree of retrogradation in each part of the rice grain was measured from the surface to the core of the same rice grain using a synchrotron radiation X-ray beam with a beam size of 100 μm. Retrogradation was effectively suppressed at all measurement sites by enzyme addition, although the effect of enzymes was greater at the surface. Rice grain sections were stained with iodine and eosin. A starch layer that does not easily form a complex with iodine was observed inside the protein layer at the surface of cooked rice. A starch layer with a long molecular chain that forms complexes with iodine was observed inside the rice grain.
PubMed: 38878545
DOI: 10.1016/j.foodchem.2024.140049