Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Translational research of boron neutron capture therapy for spinal cord gliomas using rat model.

Boron neutron capture therapy (BNCT) is a type of targeted particle radiation therapy with potential applications at the cellular level. Spinal cord gliomas (SCGs) present a substantial challenge owing to their poor prognosis and the lack of effective postoperative treatments. This study evaluated the efficacy of BNCT in a rat SCGs model employing the Basso, Beattie, and Bresnahan (BBB) scale to assess postoperative locomotor activity. We confirmed the presence of adequate in vitro boron concentrations in F98 rat glioma and 9L rat gliosarcoma cells exposed to boronophenylalanine (BPA) and in vivo tumor boron concentration 2.5 h after intravenous BPA administration. In vivo neutron irradiation significantly enhanced survival in the BNCT group when compared with that in the untreated group, with a minimal BBB scale reduction in all sham-operated groups. These findings highlight the potential of BNCT as a promising treatment option for SCGs.

Adapting the Number of Questions Based on Detected Psychological Distress for Cognitive Behavioral Therapy With an Embodied Conversational Agent: Comparative Study.

BACKGROUND: The high prevalence of mental illness is a critical social problem. The limited availability of mental health services is a major factor that exacerbates this problem. One solution is to deliver cognitive behavioral therapy (CBT) using an embodied conversational agent (ECA). ECAs make it possible to provide health care without location or time constraints. One of the techniques used in CBT is Socratic questioning, which guides users to correct negative thoughts. The effectiveness of this approach depends on a therapist's skill to adapt to the user's mood or distress level. However, current ECAs do not possess this skill. Therefore, it is essential to implement this adaptation ability to the ECAs. OBJECTIVE: This study aims to develop and evaluate a method that automatically adapts the number of Socratic questions based on the level of detected psychological distress during a CBT session with an ECA. We hypothesize that this adaptive approach to selecting the number of questions will lower psychological distress, reduce negative emotional states, and produce more substantial cognitive changes compared with a random number of questions. METHODS: In this study, which envisions health care support in daily life, we recruited participants aged from 18 to 65 years for an experiment that involved 2 different conditions: an ECA that adapts a number of questions based on psychological distress detection or an ECA that only asked a random number of questions. The participants were assigned to 1 of the 2 conditions, experienced a single CBT session with an ECA, and completed questionnaires before and after the session. RESULTS: The participants completed the experiment. There were slight differences in sex, age, and preexperimental psychological distress levels between the 2 conditions. The adapted number of questions condition showed significantly lower psychological distress than the random number of questions condition after the session. We also found a significant difference in the cognitive change when the number of questions was adapted based on the detected distress level, compared with when the number of questions was fewer than what was appropriate for the level of distress detected. CONCLUSIONS: The results show that an ECA adapting the number of Socratic questions based on detected distress levels increases the effectiveness of CBT. Participants who received an adaptive number of questions experienced greater reductions in distress than those who received a random number of questions. In addition, the participants showed a greater amount of cognitive change when the number of questions matched the detected distress level. This suggests that adapting the question quantity based on distress level detection can improve the results of CBT delivered by an ECA. These results illustrate the advantages of ECAs, paving the way for mental health care that is more tailored and effective.

Utility of Diffusion-weighted MR Imaging for Evaluating the Depth of Invasion in Oral Tongue Squamous Cell Carcinoma.

PURPOSE: The 8th edition of the American Joint Committee on Cancer staging system included the depth of invasion (DOI) for the T classification of oral cancer. However, no standardized method has been established to clinically measure the DOI. This study aimed to investigate the accuracy of MRI-based DOI for oral tongue squamous cell carcinoma (OTSCC) in each MRI sequence. METHODS: We enrolled 49 patients with histologically proven OTSCC, treated surgically between April 2017 and February 2021. We divided the DOI into three groups using 5 and 10 mm, the thresholds for determining the T stage, and retrospectively evaluated the agreement between MRI-based DOI and pathological DOI (pDOI) for each MRI sequence, axial T1-weighted imaging (T1WI), T2-weighted imaging with fat suppression (FS-T2WI), contrast-enhanced T1WI with fat suppression (CE-T1WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. We also divided the DOI into two groups using 3 mm, the threshold for considering elective neck dissection, and evaluated the overestimation rate of MRI-based DOI in lesions with pDOI ≤ 3 mm. RESULTS: With 5-mm and 10-mm divisions, the accuracy of the DOI assessment was highest on DWI (0.82, weighted kappa = 0.85). With a 3-mm division, the accuracy was also highest on DWI (0.87, kappa = 0.73). The overestimation rate of the MRI-based DOI in lesions with pDOI ≤ 3 mm was lowest on DWI (27.8%). CONCLUSION: DOI on DWI exhibits a comparatively higher rate of concordance with pDOI. DWI may be more useful than other MRI sequences in evaluating the DOI of OTSCC.

Lymphatic Endothelial Cells Produce Chemokines in Response to the Lipid Nanoparticles Used in RNA Vaccines.

RNA vaccines based on Lipid nanoparticles (LNP) were put into practical use within only one year after the global outbreak of the coronavirus disease 2019 (COVID-19). This success of RNA vaccine highlights the utility of an mRNA delivery system as a vaccination strategy. Potent immunostimulatory activity of LNPs (i.e., inflammation occurring at the injection site and the production of inflammatory cytokines) have recently been reported. However, we have only limited knowledge concerning which cells are responsible for responding to the LNPs. We report herein on in vitro chemokine production from non-immune cells in response to exposure to LNPs. In this study, SM-102, an ionizable lipid that is used in the approved RNA vaccine for the clinical usage of COVID-19 mRNA vaccine, was used. Immortalized mouse lymphatic endothelial cells (mLECs) or professional antigen presenting cells (APCs) such as RAW 264.7 monocyte/macrophage cells were incubated with LNPs that contained no mRNA. As a result, chemokines involved in the recruitment of monocytes/neutrophils were produced only by the mLECs following the LNP treatment. These findings indicate that LEC appear to serve as the cell that sends out initial signals to response LNPs.

Probiotic-derived ferrichrome induces DDIT3-mediated antitumor effects in esophageal cancer cells.

Esophageal cancer, which is common among the elderly, has the poorest prognosis among gastrointestinal cancers. Previously, we demonstrated that ferrichrome, produced by the probiotic Lactobacillus casei, exhibited anti-tumor effects in various gastrointestinal cancers, including colorectal and gastric cancers, with minimal effects on non-cancerous intestinal cells. However, it remains unclear whether ferrichrome exerts anti-tumor effects in esophageal cancer. A sulforhodamine B assay revealed that ferrichrome suppressed esophageal adenocarcinoma (OE33, OE19) and squamous cell carcinoma (KYSE70) cells. Ki-67 staining indicated that ferrichrome inhibited the proliferation of esophageal cancer cells. Cell cycle analysis showed that ferrichrome inhibited the DNA synthesis. TUNEL staining revealed that ferrichrome-induced DNA fragmentation. We also confirmed the cleavage of caspase-9 and PARP in ferrichrome-treated cells. Reverse transcription polymerase chain reaction demonstrated an increase in the mRNA of DNA damage-inducible transcript 3 (DDIT-3), a key regulator of programmed cell death, in ferrichrome-treated OE33 cells. In an in vivo OE33 xenograft model, intraperitoneal administration of 5-mg/kg ferrichrome for 14 days resulted in an almost complete inhibition of tumor growth. However, 14 days of intraperitoneal administration of 20-mg/kg 5-fluorouracil (5-FU), but not 20-mg/kg ferrichrome, induced weight loss and myelosuppression in both young and aged mice. Our findings indicate that ferrichrome induces DNA damage-inducible transcript-3, thereby producing anti-tumor effects, including cell cycle arrest and apoptosis, with minimal adverse effects in esophageal cancer cells. This illustrates the high potential of ferrichrome as an anti-tumor drug against esophageal carcinoma.

Exploring the Role of Platelets in Virus-Induced Inflammatory Demyelinating Disease and Myocarditis.

Theiler's murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple sclerosis (MS) in humans. TMEV infection can also cause acute myocarditis with viral replication and immune cell infiltration in the heart, leading to cardiac fibrosis. Since platelets have been reported to modulate immune responses, we aimed to determine the role of platelets in TMEV infection. In transcriptome analyses of platelets, distinct sets of immune-related genes, including major histocompatibility complex (MHC) class I, were up- or downregulated in TMEV-infected mice at different time points. We depleted platelets from TMEV-infected mice by injecting them with platelet-specific antibodies. The platelet-depleted mice had significantly fewer viral antigen-positive cells in the CNS. Platelet depletion reduced the severities of TMEV-IDD and myocarditis, although the pathology scores did not reach statistical significance. Immunologically, the platelet-depleted mice had an increase in interferon (IFN)-γ production with a higher anti-TMEV IgG2a/IgG1 ratio. Thus, platelets may play roles in TMEV infection, such as gene expression, viral clearance, and anti-viral antibody isotype responses.

DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation.

The IL-6 amplifier was originally discovered as a mechanism for the enhanced activation of NF-κB in non-immune cells. In the IL-6 amplifier, IL-6-STAT3 and NF-κB stimulation is followed by an excessive production of IL-6, chemokines, and growth factors to develop chronic inflammation preceding the development of inflammatory diseases. Previously, using a shRNA-mediated genome-wide screening, we found that DEAD-Box Helicase 6 (DDX6) is a candidate positive regulator of the amplifier. Here, we investigate whether DDX6 is involved in the pathogenesis of inflammatory diseases via the IL-6 amplifier. We found that DDX6-silencing in non-immune cells suppressed the NF-κB pathway and inhibited activation of the IL-6 amplifier, while the forced expression of DDX6 enhanced NF-κB promoter activity independent of the RNA helicase activity of DDX6. The imiquimod-mediated dermatitis model was suppressed by the siRNA-mediated gene downregulation of DDX6. Furthermore, silencing DDX6 significantly reduced the TNF-α-induced phosphorylation of p65/RelA and IκBα, nuclear localization of p65, and the protein levels of IκBα. Mechanistically, DDX6 is strongly associated with p65 and IκBα, but not TRADD, RIP, or TRAF2, suggesting a novel function of DDX6 as an adaptor protein in the NF-κB pathway. Thus, our findings demonstrate a possible role of DDX6 beyond RNA metabolism and suggest DDX6 is a therapeutic target for inflammatory diseases.

A Case of Primary Aldosteronism Turned Out to Be Adrenocortical Carcinoma With Disorganized Steroidogenesis.

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis, which essentially needs an early diagnosis because surgery is the only hope of a cure. On the other hand, primary aldosteronism (PA) is an overproduction of aldosterone from the adrenal glands and is known as one of the most common causes of secondary hypertension and hypokalemia. It is mostly a benign disease. ACC accompanied by PA is extremely rare, which can result in delayed diagnosis and clinical pitfalls. A 56-year-old woman was diagnosed with PA. Mild, symptomatic PA was clinically diagnosed as a right-sided aldosterone-producing adenoma (APA) with adrenal tumor using adrenal vein sampling (AVS). The tumor imaging findings showed abnormalities on computed tomography (CT) in terms of size and attenuation value compared with typical benign adenomas. Twelve months later, the tumor was confirmed to be an ACC with cortisol hypersecretion. The resected ACC specimen did not clearly show positive findings for CYP11B1 or CYP11B2, and disorganized steroid production was suspected. However, the prevalence and clinical characteristics of adrenocortical carcinomas with disorganized steroid production remain unclear. Steroidogenic enzyme immunostaining analysis is important not only for the diagnosis of adrenal adenoma but also for a better understanding of the clinical course of hormone-producing ACC.

The Effect of Cholesterol Content on the Adjuvant Activity of Nucleic-Acid-Free Lipid Nanoparticles.

RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response. However, the properties of LNPs that contribute to their adjuvant activity continue to require clarification. To characterize the relationships between the lipid composition, particle morphology, and adjuvant activity of LNPs, the nanostructures of LNPs and their antibody production were evaluated. To simply compare the adjuvant activity of LNPs, empty LNPs were subcutaneously injected with recombinant proteins. Consistent with previous research, the presence of ionizable lipids was one of the determinant factors. Adjuvant activity was induced when a tiny cholesterol assembly (cholesterol-induced phase, ChiP) was formed according to the amount of cholesterol present. Moreover, adjuvant activity was diminished when the content of cholesterol was excessive. Thus, it is plausible that an intermediate structure of cholesterol (not in a crystalline-like state) in an intra-particle space could be closely related to the immunogenicity of LNPs.

Monte Carlo fluorescence ray tracing simulation for laser cooling of solids.

We propose an approach to evaluate solid-state media for laser cooling by anti-Stokes fluorescence employing a Monte Carlo-based simulation of fluorescence ray tracing. This approach prompted a revisit of the experimental method, laser-induced thermal modulation spectroscopy (LITMoS), showing that the external quantum efficiency and the background absorption coefficient can be retrieved solely from the two wavelengths where neither cooling nor heating is observed. Our simulation can accurately compute two experimentally inaccessible quantities essential to evaluate laser-cooling media: the mean fluorescence wavelength and the fluorescence escape efficiency. These computed quantities in combination with LITMoS results allow us to retrieve the internal quantum efficiency which is a performance indicator independent of various factors such as the sample size and doping level. Using the proposed approach, we thoroughly investigate the impact of doping level, sample geometry, and refractive index on the fluorescence escape efficiency and reveal its temperature dependency for the example of Yb:YLF. Through comprehensive numerical analysis, we demonstrate that the reduction of sample symmetry is crucial in achieving lower cooling temperatures.

Nitroglycerin use and adverse clinical outcomes in elderly patients with acute coronary syndrome.

OBJECTIVE: The primary care for acute coronary syndrome (ACS) includes the administration of nitroglycerin (GTN). This study aimed to investigate the association between the use of GTN before percutaneous coronary intervention (PCI) for ACS and clinical outcomes. METHODS: Nine-hundred and forty-seven patients who underwent PCI for ACS were examined and classified into two groups: those who were treated with GTN before PCI (GTN group) and those who were not (non-GTN group). The incidence of major adverse cardiovascular events (MACE), which consist of all-cause mortality, non-fatal myocardial infarction, stroke and rehospitalisation for heart failure at 1 year, was compared between the two groups. RESULTS: This study identified 289 patients with ACS who used GTN preceding PCI. Pre-PCI systolic blood pressure was significantly lower in the GTN group than in the non-GTN group (median (IQR); 132.0 (110.0-143.5) mm Hg vs 134.0 (112.0-157.0) mm Hg, respectively, p=0.03). Multivariate Cox regression analysis indicated that GTN use preceding PCI showed an independent association with the incidence of MACE (HR 1.57; 95% CI 1.09-2.28; p=0.016). Overall, the incidence of MACE 1 year after PCI for ACS was significantly higher in the GTN group than in the non-GTN group (log-rank test, p=0.024); however, this trend was consistently found in elderly patients aged ≥75 years (p=0.002) but not in non-elderly patients aged <75 years (p=0.773). CONCLUSIONS: GTN use preceding PCI for ACS is associated with lower blood pressure and adverse clinical outcomes in elderly patients.

Genome-wide mapping and cryo-EM structural analyses of the overlapping tri-nucleosome composed of hexasome-hexasome-octasome moieties.

The nucleosome is a fundamental unit of chromatin in which about 150 base pairs of DNA are wrapped around a histone octamer. The overlapping di-nucleosome has been proposed as a product of chromatin remodeling around the transcription start site, and previously found as a chromatin unit, in which about 250 base pairs of DNA continuously bind to the histone core composed of a hexamer and an octamer. In the present study, our genome-wide analysis of human cells suggests another higher nucleosome stacking structure, the overlapping tri-nucleosome, which wraps about 300-350 base-pairs of DNA in the region downstream of certain transcription start sites of actively transcribed genes. We determine the cryo-electron microscopy (cryo-EM) structure of the overlapping tri-nucleosome, in which three subnucleosome moieties, hexasome, hexasome, and octasome, are associated by short connecting DNA segments. Small angle X-ray scattering and coarse-grained molecular dynamics simulation analyses reveal that the cryo-EM structure of the overlapping tri-nucleosome may reflect its structure in solution. Our findings suggest that nucleosome stacking structures composed of hexasome and octasome moieties may be formed by nucleosome remodeling factors around transcription start sites for gene regulation.

Enhanced solid-state phosphorescence of organoplatinum π-systems by ion-pairing assembly.

Anion binding and ion pairing of dipyrrolyldiketone PtII complexes as anion-responsive π-electronic molecules resulted in photophysical modulations, as observed in solid-state phosphorescence properties. Modifications to arylpyridine ligands in the PtII complexes significantly impacted the assembling behaviour and photophysical properties of anion-free and anion-binding (ion-pairing) forms. The PtII complexes, in the presence of guest anions and their countercations, formed various anion-binding modes and ion-pairing assembled structures depending on constituents and forms (solutions and crystals). The PtII complexes emitted strong phosphorescence in deoxygenated solutions but showed extremely weak phosphorescence in the solid state owing to self-association. In contrast, the solid-state ion-pairing assemblies with tetraalkylammonium cations exhibited enhanced phosphorescence owing to the formation of hydrogen-bonding 1D-chain PtII complexes dispersed by stacking with aliphatic cations. Theoretical studies revealed that the enhanced phosphorescence in the solid-state ion-pairing assembly was attributed to preventing the delocalisation of the electron wavefunction over PtII complexes.

Neutron flux evaluation algorithm with a combination of Monte Carlo and removal-diffusion calculation methods for boron neutron capture therapy.

BACKGROUND: In Japan, the clinical treatment of boron neutron capture therapy (BNCT) has been applied to unresectable, locally advanced, and recurrent head and neck carcinomas using an accelerator-based neutron source since June of 2020. Considering the increase in the number of patients receiving BNCT, efficiency of the treatment planning procedure is becoming increasingly important. Therefore, novel and rapid dose calculation algorithms must be developed. We developed a novel algorithm for calculating neutron flux, which comprises of a combination of a Monte Carlo (MC) method and a method based on the removal-diffusion (RD) theory (RD calculation method) for the purpose of dose calculation of BNCT. PURPOSE: We present the details of our novel algorithm and the verification results of the calculation accuracy based on the MC calculation result. METHODS: In this study, the "MC-RD" calculation method was developed, wherein the RD calculation method was used to calculate the thermalization process of neutrons and the MC method was used to calculate the moderation process. The RD parameters were determined by MC calculations in advance. The MC-RD calculation accuracy was verified by comparing the results of the MC-RD and MC calculations with respect to the neutron flux distributions in each of the cubic and head phantoms filled with water. RESULTS: Comparing the MC-RD calculation results with those of MC calculations, it was found that the MC-RD calculation accurately reproduced the thermal neutron flux distribution inside the phantom, with the exception of the region near the surface of the phantom. CONCLUSIONS: The MC-RD calculation method is useful for the evaluation of the neutron flux distribution for the purpose of BNCT dose calculation, except for the region near the surface.

Development of DynamicMC for PHITS Monte Carlo package.

Previously, we have developed DynamicMC for modeling relative movement of Oak Ridge National Laboratory phantom in a radiation field for the Monte Carlo N-Particle package (Health Physics. 2023,124(4):301-309). Using this software, three-dimensional dose distributions in a phantom irradiated by a certain mono-energetic (Mono E) source can be deduced through its graphical user interface. In this study, we extended DynamicMC to be used in combination with the Particle and Heavy Ion Transport code System (PHITS) by providing it with a higher flexibility for dynamic movement for an anthropomorphic phantom. For this purpose, we implemented four new functions into the software, which are (1) to generate not only Mono E sources but also those having an energy spectrum of an arbitrary radioisotope (2) to calculate the absorbed doses for several radiologically important organs (3) to automatically average the calculated absorbed doses along the path of the phantom and (4) to generate user-defined slab shielding materials. The first and third items utilize the PHITS-specific modalities named radioisotope-source and sumtally functions, respectively. The computational cost and complexity can be dramatically reduced with these features. We anticipate that the present work and the developed open-source tools will be in the interest of nuclear radiation physics community for research and teaching purposes.

Development of an event-by-event based Li-ZnS(Ag) neutron imaging detector with selective neutron detection capability.

High sensitivity and high resolution is desired in such technologies as neutron radiography. However, the contamination of gamma photons in neutron images decreases the accuracy of neutron radiography. To solve this problem, we developed an event-by-event based neutron imaging system that can selectively detect neutrons. The developed neutron imaging system consists of an Li-ZnS(Ag) scintillator plate optically coupled to a flat panel photomultiplier tube (FP-PMT) with a light guide. Scintillation light emitted from the Li-ZnS(Ag) by the interaction with neutron-induced particles is used to calculate the position based on the center of mass calculations. The spatial resolution of the neutron imaging detector is ∼2.3 mm FWHM, and the sensitivity for 252Cf at 2 cm from the source with 2-cm-thick polystyrene is 20 cps/MBq. Background count fraction from 60Co gamma photons was 0.2 %. For various types of neutron absorption phantoms, high-contrast and high-resolution neutron images are obtained with the developed neutron imaging detector using a252Cf neutron source.

Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.

Out-of-field dosimetry using a validated PHITS model and computational phantom in clinical BNCT.

BACKGROUND: The out-of-field radiation dose for boron neutron capture therapy (BNCT), which results from both neutrons and γ-rays, has not been extensively evaluated. To safely perform BNCT, the neutron and γ-ray distributions inside the treatment room and the whole-body dose should be evaluated during commissioning. Although, certain previous studies have evaluated the whole-body dose in the clinical research phase, no institution providing BNCT covered by health insurance has yet validated the neutron distribution inside the room and the whole-body dose. PURPOSE: To validate the Monte Carlo model of the BNCT irradiation room extended for the whole-body region and evaluate organ-at-risk (OAR) doses using the validated model with a human-body phantom. METHODS: First, thermal neutron distribution inside the entire treatment room was measured by placing Au samples on the walls of the treatment room. Second, neutron and gamma-ray dose-rate distributions inside a human-body water phantom were measured. Both lying and sitting positions were considered. Bare Au, Au covered by Cd (Au+Cd), In, Al, and thermoluminescent dosimeters were arranged at 11 points corresponding to locations of the OARs inside the phantom. After the irradiation, γ-ray peaks emitted from the samples were measured by a high-purity germanium detector. The measured counts were converted to the reaction rate per unit charge of the sample. These measurements were compared with results of simulations performed with the Particle and Heavy Ion Transport code System (PHITS). A male adult mesh-type reference computational phantom was used to evaluate OAR doses in the whole-body region. The relative biological effectiveness (RBE)-weighted doses and dose-volume histograms (DVHs) for each OAR were evaluated. The median dose (D50% ) and near-maximum dose (D2% ) were evaluated for 14 OARs in a 1-h-irradiation process. The evaluated RBE-weighted doses were converted to equivalent doses in 2 Gy fractions. RESULTS: Experimental results within 60 cm from the irradiation center agreed with simulation results within the error bars except at ±20, 30 cm, and those over 70 cm corresponded within one digit. The experimental results of reaction rates or γ-ray dose rate for lying and sitting positions agreed well with the simulation results within the error bars at 8, 4, 11, 7 and 7, 4, 7, 6, 5, 6 out of 11 points, respectively, for Au, Au+Cd, In, Al, and TLD. Among the detectors, the discrepancies in reaction rates between experiment and simulation were most common for Au+Cd, but were observed randomly for measurement points (brain, lung, etc.). The experimental results of γ-ray dose rates were systematically lower than simulation results at abdomen and waist regions for both positions. Extending the PHITS model to the whole-body region resulted in higher doses for all OARs, especially 0.13 Gy-eq increase for D50% of the left salivary gland. CONCLUSION: The PHITS model for clinical BNCT for the whole-body region was validated, and the OAR doses were then evaluated. Clinicians and medical physicists should know that the out-of-field radiation increases the OAR dose in the whole-body region.

Intranasal immunization with an RBD-hemagglutinin fusion protein harnesses preexisting immunity to enhance antigen-specific responses.

Intranasal vaccines are anticipated to be powerful tools for combating many infectious diseases, including SARS-CoV-2, because they induce not only systemic immunity but also mucosal immunity at the site of initial infection. However, they are generally inefficient in inducing an antigen-specific immune response without adjuvants. Here, we developed an adjuvant-free intranasal vaccine platform that utilizes the preexisting immunity induced by previous infection or vaccination to enhance vaccine effectiveness. We made RBD-HA, a fusion of the receptor-binding domain (RBD) of spike derived from SARS-CoV-2 as a vaccine target with HA derived from influenza A virus (IAV) as a carrier protein. Intranasal immunization of previously IAV-infected mice with RBD-HA without an adjuvant elicited robust production of RBD-specific systemic IgG and mucosal IgA by utilizing both HA-specific preexisting IgG and CD4+ T cells. Consequently, the mice were efficiently protected from SARS-CoV-2 infection. Additionally, we demonstrated the high versatility of this intranasal vaccine platform by assessing various vaccine antigens and preexisting immunity associated with a variety of infectious diseases. The results of this study suggest the promising potential of this intranasal vaccine platform to address problems associated with intranasal vaccines.