Development of small molecule-drug conjugates based on derivatives of natural proteasome inhibitors that exhibit selectivity for PSMA-expressing cancer cells.

In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.

Attenuated polyethylene glycol immunogenicity and overcoming accelerated blood clearance of a fully PEGylated dendrimer.

Polyethylene glycol (PEG) is a popular biocompatible polymer and PEGylated nanoparticles passively accumulate in tumor tissues because of their enhanced permeability and retention effects. Recently, the anti-PEG immunity of PEGylated nanoparticles has become an issue that needs to be solved for their clinical applications. Dendrimers are highly branched and well-defined polymers with many terminal groups, which act as potent drug carriers. In this study, we examined the pharmacokinetics, biodistribution, anti-PEG immunity, and tumor accumulation of a fully PEGylated polyamidoamine (PAMAM) dendrimer after the first and second injections and compared them to those of a PEGylated liposome with the same lipid component as Doxil®. The PEGylated dendrimer showed greater blood circulation than that of the PEGylated liposome after the first and second injections in rats. In mice injected with the PEGylated dendrimer, much less anti-PEG immunoglobulin M (IgM) was generated than that in mice injected with the PEGylated liposome. The PEGylated dendrimer accumulated in the tumor after both the first and second injections. Our results indicated that the PEGylated dendrimer with a small size and high PEG density showed attenuated anti-PEG immunity and overcame the accelerated blood clearance phenomenon, which is useful for drug delivery systems for cancer treatment.

Embedding Bifurcations into Pneumatic Artificial Muscle.

Harnessing complex body dynamics has long been a challenge in robotics, particularly when dealing with soft dynamics, which exhibit high complexity in interacting with the environment. Recent studies indicate that these dynamics can be used as a computational resource, exemplified by the McKibben pneumatic artificial muscle, a common soft actuator. This study demonstrates that bifurcations, including periodic and chaotic dynamics, can be embedded into the pneumatic artificial muscle, with the entire bifurcation structure using the framework of physical reservoir computing. These results suggest that dynamics not present in training data can be embedded through bifurcation embedment, implying the capability to incorporate various qualitatively different patterns into pneumatic artificial muscle without the need to design and learn all required patterns explicitly. Thus, this study introduces a novel approach to simplify robotic devices and control training by reducing reliance on external pattern generators and the amount and types of training data needed for control.

Nonconvulsive status epilepticus in patients with acute subarachnoid hemorrhage is associated with negative arterial spin labeling on peri-ictal magnetic resonance images.

Purpose: Non-convulsive status epilepticus (NCSE) is characterized by repetitive or continuous seizures without convulsions. Arterial spin labeling (ASL) is useful for assessing hyperperfusion due to neurovascular unit coupling in patients with NCSE; subarachnoid hemorrhage (SAH) impairs the neurovascular unit. We hypothesized that the sensitivity of ASL in detecting NCSE is low in patients with SAH during the acute phase. Methods: Based on ASL findings obtained within 48 h after the clinical suspicion of focal-onset NCSE, we divided 34 patients into ASL-negative (no hyperperfusion; n = 10) and ASL-positive (confirmed hyperperfusion; n = 24) groups. We further divided the two groups according to the NCSE etiology: patients who were diagnosed with NCSE within 14 days after SAH onset (acute SAH, n = 11) and patients with NCSE due to factors other acute SAH (n = 23) and compared their characteristics. Results: In 10 of the 34 patients (29.4 %) the ASL findings were normal. The rate of acute SAH was significantly higher in ASL-negative- (n = 8, 80.0 %) than ASL-positive patients (n = 3, 12.5 %). The rate of patients in aphasic status was significantly lower in ASL-negative patients (n = 1, 10 %) than in ASL-positive patients (n = 12, 50.0 %). Conclusion: Normal ASL findings alone should not be used to exclude a diagnosis of NCSE particularly in patients in the acute phase of SAH with deterioration or no improvement in consciousness.

Theoretical Design and Synthesis of Caged Compounds Using X-Ray-Triggered Azo Bond Cleavage.

Caged compounds are frequently used in life science research. However, the light used to activate them is commonly absorbed and scattered by biological materials, limiting their use to basic research in cells or small animals. In contrast, hard X-rays exhibit high bio-permeability due to the difficulty of interacting with biological molecules. With the main goal of developing X-ray activatable caged compounds, azo compounds are designed and synthesized with a positive charge and long π-conjugated system to increase the reaction efficiency with hydrated electrons. The azo bonds in the designed compounds are selectively cleaved by X-ray, and the fluorescent substance Diethyl Rhodamine is released. Based on the results of experiments and quantum chemical calculations, azo bond cleavage is assumed to occur via a two-step process: a two-electron reduction of the azo bond followed by N─N bond cleavage. Cellular experiments also demonstrate that the azo bonds can be cleaved intracellularly. Thus, caged compounds that can be activated by an azo bond cleavage reaction promoted by X-ray are successfully generated.

Differences of Bone Mineral Density by Characteristics of Sports in Amenorrheic Athletes.

Hypothalamic amenorrhea leads to a hypoestrogenic state, causing decreased bone mineral density (BMD), while strong impact loading on bone has been shown to increase BMD. The purpose of this study is to compare BMD in female athletes based on menstrual status and their sports/events by impact loading characteristics. BMD at the lumbar spine was measured by dual-energy X-ray absorptiometry and hormone level. The subjects were classified into four groups and BMD and hormone levels were compared among the four groups, which were divided into amenorrheic athletes (AAs) and eumenorrheic athletes (EAs). This study recruited 410 female athletes (164 in the AAs and 246 in the EAs), 55 athletes in non-impact sports, 123 in low-impact sports, 141 in multidirectional sports, and 91 in high-impact sports. In the AAs group, BMD Z-score was lowest in low-impact sports (Z-score: -1.53 [-1.76, -1.30]), and was highest in high-impact sports (Z-score: 0.02 [-0.34, 0.38]). In multidirectional and high-impact sports, BMD Z-score in the AAs group did not show results lower than the average for non-athletes. When screening female athletes for low BMD, it is important to evaluate the risk of low BMD based on the impact loading characteristics of their sports/events, in addition to the menstrual state.

Near-infrared photoimmunotherapy and anti-cancer immunity.

The activation of the anti-cancer immune system is an important strategy to control cancer. A new form of cancer phototherapy, near-infrared photoimmunotherapy (NIR-PIT), was approved for clinical use in 2020 and uses IRDye® 700DX (IR700)-conjugated antibodies and NIR light. After irradiation with NIR light, the antibody-IR700 conjugate forms water-insoluble aggregations on the plasma membrane of target cells. This aggregation causes lethal damage to the plasma membrane, and effectively leads to immunogenic cell death (ICD). Subsequently, ICD activates anti-cancer immune cells such as dendritic cells and cytotoxic T cells. Combination therapy with immune-checkpoint blockade has synergistically improved the anti-cancer effects of NIR-PIT. Additionally, NIR-PIT can eliminate immunosuppressive immune cells in light-irradiated tumors by using specific antibodies against regulatory T cells and myeloid-derived suppressor cells. In addition to cancer-cell-targeted NIR-PIT, such immune-cell-targeted NIR-PIT has shown promising results by activating the anti-cancer immune system. Furthermore, NIR-PIT can be used to manipulate the tumor microenvironment by eliminating only targeted cells in the tumor, and thus it also can be used to gain insight into immunity in basic research.

Corrigendum: Investigation of supplement use and knowledge among Japanese elite athletes for the Tokyo 2020 Olympic/Paralympic Games and the Beijing 2022 Winter Olympic/Paralympic Games.

[This corrects the article DOI: 10.3389/fspor.2023.1258542.].

Investigation of supplement use and knowledge among Japanese elite athletes for the Tokyo 2020 Olympic/Paralympic games and the Beijing 2022 winter Olympic/Paralympic games.

Elite athletes frequently invest in the use of supplements to optimize their dietary regimens and enhance their athletic performance. However, unregulated and unplanned use of supplements can lead to adverse consequences, including anti-doping rule violations or health issues. Thus, athletes should verify their diets, consider scientific evidence, and take necessary precautions regarding supplements before use. To date, no study has explored whether athletes check these factors before using supplements. This study aimed to investigate supplement use using a questionnaire administered to 1,392 athletes (including candidate athletes) who participated in the Tokyo 2020 Olympic/Paralympic and Beijing 2022 Winter Olympic/Paralympic Games. Participants were categorized as follows: 1,040 participants in the Tokyo 2020 Olympic Games, 83 in the Tokyo 2020 Paralympic Games, 239 in the Beijing 2022 Winter Olympic Games, and 30 in the Beijing 2022 Winter Paralympic Games. We collected data on supplement use and gained further knowledge through interviews with the athletes. Approximately 70% of Tokyo 2020 Olympic/Paralympic and Beijing 2022 Winter Olympic athletes and approximately 50% of Beijing 2022 Winter Paralympians used supplements. Over 50% of athletes had not received a doctor's diagnosis or a dietitian's evaluation before supplement use. Moreover, only 50% of the athletes who used dietary supplements reviewed the scientific evidence for the dietary supplements before using them and justified their choice based on their own investigation, while those who did not use dietary supplements cited either a lack of need or fear of an anti-doping rule violation. Considering the holistic health and performance of athletes, as well as the risk associated with unregulated use, such as overdose and anti-doping rule violations, there is a need for nutritional education on supplement use for athletes and their entourages.

Magnetic resonance imaging findings related to sacroiliac joint pain in high-performance athletes.

BACKGROUND: Sacroiliac joint (SIJ) dysfunction in athletes affects competitiveness. However, the pathology and imaging features have not been clarified. OBJECTIVE: To clarify the association between SIJ pain and MRI findings in high-performance athletes. METHODS: Fifty-two Japanese high-performance athletes with or without SIJ pain were recruited. MRI short tau inversion recovery (STIR) semi-coronal and semi-axial images of their SIJs were taken. The relationships between high-signal changes in MRI-STIR and SIJ pain and pain duration were investigated. Six athletes with continuous SIJ pain were prospectively followed. RESULTS: The proportion of athletes with high-signal changes in the SIJ was significantly higher among athletes with SIJ pain for one month or more (76.9%, 10/13) than among athletes with SIJ pain for less than one month (18.2%, 2/11) and among athletes without SIJ pain (28.6%, 8/28). High-signal changes on painful SIJs were most often present in the sacrum. In three of the six athletes who were prospectively followed, the high-signal area and intensity on MRI both diminished as their symptoms improved. CONCLUSIONS: High-signal changes of the SIJ on MRI-STIR images in high-performance athletes may reflect their SIJ pain.

Comprehensive inpatient rehabilitation for elite athletes after anterior cruciate ligament reconstruction.

[Purpose] The authors' institute offers a comprehensive inpatient approach to rehabilitation after anterior cruciate ligament reconstruction surgery, providing nutritional and psychological support in addition to exercise and physical therapy. This study aimed to determine the outcomes of athletes undergoing this comprehensive rehabilitation program and to compare the outcomes of bone-patellar tendon-bone and semitendinosus/gracilis autograft recipients. [Participants and Methods] Elite athletes who underwent comprehensive inpatient rehabilitation at the authors' institute for at least two weeks after anterior cruciate ligament reconstruction were mailed a questionnaire. Their recovery levels, which were measured against preinjury performance, and secondary anterior cruciate ligament injury rates, were evaluated and compared according to graft type. [Results] Valid responses from 45 athletes were analyzed (bone-patellar tendon-bone [n=12]; semitendinosus/gracilis [n=33]). The frequency of return to preinjury activity levels and secondary anterior cruciate ligament injury were comparable between bone-patellar tendon-bone and semitendinosus/gracilis graft recipients. A greater proportion of athletes returned to preinjury activity levels, while a lower percentage experienced re-rupture compared to previous studies. [Conclusion] A comprehensive rehabilitative approach after anterior cruciate ligament reconstruction may contribute to improved postoperative performance irrespective of graft type. Objective evaluations are needed in the future to clarify the benefits of specific rehabilitative approaches.

Squamous cell carcinoma invading peripheral cerebral blood vessels and causing repeated cerebral hemorrhage : A case report.

Squamous cell carcinoma (SCC) is known to have less brain metastasis, but the reasons are not well established. Herein, we report the case of an 82-year-old man with recurrent cerebral hemorrhage of unknown cause ; upon brain biopsy, SCC was diagnosed infiltrating peripheral blood vessels of the brain and that it was state of micro-metastasis. It is possible that the blood-brain barrier blocked the infiltration of SCC into the brain parenchyma, and it did not form a mass in the brain parenchyma. In addition, because it did not form a mass, it could not be diagnosed as a metastatic brain tumor by contrast-enhanced magnetic resonance imaging or contrast-enhanced computed tomography. Among cases of recurrent cerebral hemorrhage of unknown cause in a short period, there may be cases of vascular infiltration without crossing the blood-brain barrier. Thus, if similar cases of recurrent cerebral hemorrhage of unknown cause is observed, it is necessary to distinguish metastatic brain tumors even if there is no evidence of suspected tumor on contrast-enhanced magnetic resonance imaging scan. J. Med. Invest. 70 : 276-280, February, 2023.

In vivo imaging of acute physiological responses after treatment of cancer with near-infrared photoimmunotherapy.

PURPOSE: Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer phototherapy using an antibody-photosensitizer conjugate (Ab-IR700). By NIR light irradiation, Ab-IR700 forms a water-insoluble aggregation on the plasma membrane of cancer cells, leading to lethal membrane damage of cancer cells with high selectivity. However, IR700 produces singlet oxygen, which induces non-selective inflammatory responses such as edema in normal tissues around the tumor. Understanding such treatment-emergent responses is important to minimize side effects and improve clinical outcomes. Thus, in this study, we evaluated physiological responses during NIR-PIT by magnetic resonance imaging (MRI) and positron emission tomography (PET). PROCEDURES: Ab-IR700 was intravenously injected into tumor-bearing mice with two tumors on the right and left sides of the dorsum. At 24 h after injection, a tumor was irradiated with NIR light. Edema formation was examined by T1/T2/diffusion-weighted MRI and inflammation was investigated by PET with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). Because inflammation can increase vascular permeability via inflammatory mediators, we evaluated changes in oxygen levels in tumors using a hypoxia imaging probe, [18F]fluoromisonidazole ([18F]FMISO). RESULTS: The uptake of [18F]FDG in the irradiated tumor was significantly decreased compared to the control tumor, indicating the impairment of glucose metabolism induced by NIR-PIT. MRI and [18F]FDG-PET images showed that inflammatory edema with [18F]FDG accumulation was present in the surrounding normal tissues of the irradiated tumor. Furthermore, [18F]FMISO accumulation in the center of the irradiated tumor was relatively low, indicating the enhancement of oxygen supply due to increased vascular permeability. In contrast, high [18F]FMISO accumulation was observed in the peripheral region, indicating enhancement of hypoxia in the region. This could be because inflammatory edema was formed in the surrounding normal tissues, which blocked blood flow to the tumor. CONCLUSIONS: We successfully monitored inflammatory edema and changes in oxygen levels during NIR-PIT. Our findings on the acute physiological responses after light irradiation will help to develop effective measures to minimize the side effects in NIR-PIT.

Computational capability of ecological dynamics.

Ecological dynamics is driven by complex ecological networks. Computational capabilities of artificial networks have been exploited for machine learning purposes, yet whether an ecological network possesses a computational capability and whether/how we can use it remain unclear. Here, we developed two new computational/empirical frameworks based on reservoir computing and show that ecological dynamics can be used as a computational resource. In silico ecological reservoir computing (ERC) reconstructs ecological dynamics from empirical time series and uses simulated system responses for information processing, which can predict near future of chaotic dynamics and emulate nonlinear dynamics. The real-time ERC uses real population dynamics of a unicellular organism, Tetrahymena thermophila. The temperature of the medium is an input signal and population dynamics is used as a computational resource. Intriguingly, the real-time ecological reservoir has necessary conditions for computing (e.g. synchronized dynamics in response to the same input sequences) and can make near-future predictions of empirical time series, showing the first empirical evidence that population-level phenomenon is capable of real-time computations. Our finding that ecological dynamics possess computational capability poses new research questions for computational science and ecology: how can we efficiently use it and how is it actually used, evolved and maintained in an ecosystem?

Input-driven chaotic dynamics in vortex spin-torque oscillator.

A new research topic in spintronics relating to the operation principles of brain-inspired computing is input-driven magnetization dynamics in nanomagnet. In this paper, the magnetization dynamics in a vortex spin-torque oscillator driven by a series of random magnetic field are studied through a numerical simulation of the Thiele equation. It is found that input-driven synchronization occurs in the weak perturbation limit, as found recently. As well, chaotic behavior is newly found to occur in the vortex core dynamics for a wide range of parameters, where synchronized behavior is disrupted by an intermittency. Ordered and chaotic dynamical phases are examined by evaluating the Lyapunov exponent. The relation between the dynamical phase and the computational capability of physical reservoir computing is also studied.

Physical deep learning with biologically inspired training method: gradient-free approach for physical hardware.

Ever-growing demand for artificial intelligence has motivated research on unconventional computation based on physical devices. While such computation devices mimic brain-inspired analog information processing, the learning procedures still rely on methods optimized for digital processing such as backpropagation, which is not suitable for physical implementation. Here, we present physical deep learning by extending a biologically inspired training algorithm called direct feedback alignment. Unlike the original algorithm, the proposed method is based on random projection with alternative nonlinear activation. Thus, we can train a physical neural network without knowledge about the physical system and its gradient. In addition, we can emulate the computation for this training on scalable physical hardware. We demonstrate the proof-of-concept using an optoelectronic recurrent neural network called deep reservoir computer. We confirmed the potential for accelerated computation with competitive performance on benchmarks. Our results provide practical solutions for the training and acceleration of neuromorphic computation.

PD1 blockade alters cell-cycle distribution and affects 3'-deoxy-3'-[18F]fluorothymidine uptake in a mouse CT26 tumor model.

OBJECTIVE: We previously reported that alterations of the tumor microenvironment (TME) by programmed death receptor-1 (PD1) blockade affected tumor glucose metabolism and tumor 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake. In cancer cells, high glycolysis allows cells to sustain rapid proliferation since glycolysis is closely related to the proliferation of cancer cells. Therefore, imaging of cellular proliferation may provide more detail of TME alterations. In this study, we investigated how TME alterations by PD1 blockade affects the uptake of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), which is a 18F-radiolabeled thymidine derivative and is taken up by proliferating cells. METHODS: Mice inoculated with murine colon carcinoma CT26 cells were intraperitoneally administered an anti-PD1 antibody on Day 0, when the tumor volume exceeded 50 mm3, and Day 5. [18F]FLT-PET imaging was performed pre-treatment (Day 0) and post treatment (Day 7). Tumor infiltrating lymphocytes (TILs) were identified by flow cytometry. [18F]FLT accumulation and localization in tumor tissue was evaluated by autoradiography and immunohistochemistry. The cell-cycle distribution of tumors and CT26 cells exposed to cytokines (interleukin-2, interferon [INF]-γ, and tumor necrosis factor [TNF]-α) was analyzed by flow cytometry. RESULTS: PD1 blockade increased CD8+ and CD4+ T cells in tumor tissue and significantly suppressed tumor proliferation; however, tumor [18F]FLT uptake remained unchanged. Autoradiography and immunohistochemistry showed that [18F]FLT was mainly taken up by cancer cells, but not TILs. Flow cytometric analysis demonstrated that the population of cells in G2/M phase increased after PD1 blockade. Moreover, INF-γ and TNF-α significantly increased cells in G2/M phase in vitro. CONCLUSION: PD1 blockade-induced alteration of the TME increased CT26 tumor cells in the G2/M phase, which have high thymidine kinase 1 activity. Therefore, [18F]FLT is taken up by tumor cells even if tumor proliferation is suppressed. This observation may be useful for evaluating the response to immunotherapy.

Ligand release from silicon phthalocyanine dyes triggered by X-ray irradiation.

Ligand release from silicon phthalocyanine (SiPc) dyes triggered by near-infrared (NIR) light is a key photochemical reaction involving caged compounds based on SiPc. Although NIR light is relatively permeable compared with visible light, this light can be attenuated by tissue absorption and scattering; therefore, using light to induce photochemical reactions deep inside the body is difficult. Herein, because X-rays are highly permeable and can produce radicals through the radiolysis of water, we investigated whether the axial ligands of SiPcs can be cleaved using X-ray irradiation. SiPcs with different axial ligands (alkoxy, siloxy, oxycarbonyl, and phenoxy groups) were irradiated with X-rays under hypoxic conditions. We found that the axial ligands were cleaved via reactions with hydrated electrons (e-aq), not OH radicals, generated from water in response to X-ray irradiation, and SiPc with alkoxy groups exhibited the highest cleavage efficiency. A quantitative investigation revealed that X-ray-induced axial ligand cleavage proceeds via a radical chain reaction. The reaction is expected to be applicable to the molecular design of X-ray-activatable functional molecules in the future.

Cerebral Tufted Angioma with Gradually Developing Peritumoral Edema: A Case Report.

Tufted angioma is a benign vascular tumor in which immature endothelial and pericyte cells and lymphatic vascular endothelium grow. It manifests as a flat, painful erythema that gradually expands mainly on the trunk and extremities. Although tufted angiomas can also occur in other areas of the body and may be more locally invasive, they rarely occur intracranially. A 63-year-old man underwent magnetic resonance imaging (MRI) for a brain check-up 8 years before his visit to our institute, which detected a mass lesion with surrounding cerebral edema in the left frontal lobe. The patient was followed up with annual MRI analysis, which indicated slow tumor growth and gradual development of peritumoral edema. The tumor was treated by gross-total resection. Histological analysis showed a slightly dilated microvascular core surrounded by many capillary aggregates in the brain parenchyma. Immunohistochemical findings indicated that the vascular endothelial cells were positive for CD34 and Brahma-related gene-1 and were surrounded by smooth muscle actin-positive pericytes. These findings were consistent with tufted angioma. Intracranial tufted angioma is uncommon, but it should be considered in the differential diagnosis for intracranial tumorous lesions. Long-term follow-up is necessary to unravel the natural history of the disease.

Whole-genome sequencing analysis of an atypical teratoid/rhabdoid tumor in a patient with Phelan-McDermid syndrome: a case report and systematic review.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare pediatric brain tumor with abnormalities in SMARCB1 located in 22q11.2. We report a case of AT/RT associated with Phelan-McDermid syndrome (PMS) characterized by congenital developmental disorder, mental retardation, and ring chromosome 22 with 22q13.3-qter depletion, for which we performed whole-genome sequencing (WGS). A 4-year-old girl with a developmental disability was referred to our hospital due to dysphoria. Brain magnetic resonance imaging showed a 5-cm well-demarcated mass that extended bilaterally in the frontal lobes. G-banding was performed preoperatively due to a history of developmental retardation. Ring chromosome 22 and deletion of 22q13.3-qter were observed, and she was diagnosed with PMS. She underwent gross total resection of the tumor, and the pathological diagnosis was AT/RT. WGS showed somatic SMARCB1 mutation (p.R201X) and somatic loss of the entire chromosome 22 in the tumor, but not in the blood sample. WGS confirmed previously unreported BRCA2 mutations, 6q loss, and 14q acquisition during tumor progression, but no other significant findings associated with tumor progression. The present case is discussed with reference to a systematic review of previous reports of AT/RT associated with PMS. PMS patients with ring chromosome 22 should be carefully followed up for AT/RT occurrence.