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Abstract For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6–77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.

Abstract Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1–3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1–3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0–2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1–2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Abstract Osteoporosis, vertebral fractures, and spinal degenerative diseases are common conditions that often coexist in older adults. This study aimed to determine the factors influencing low back pain and its impact on activities of daily living (ADL) and physical performance in older individuals with multiple comorbidities. This cross-sectional study was part of a large-scale population-based cohort study in Japan, involving 1009 participants who underwent spinal magnetic resonance imaging (MRI) to assess cervical cord compression, radiographic lumbar spinal stenosis, and lumbar disc degeneration. Vertebral fractures in the thoracolumbar spine were evaluated using sagittal MRI with a semi-quantitative method. Bone mineral density was measured using dual-energy X-ray absorptiometry. Low back pain, Oswestry Disability Index (ODI), and physical performance tests, such as one-leg standing time, five times chair-stand time, maximum walking speed, and maximum step length, were assessed. Using clinical conditions as objective variables and image evaluation parameters as explanatory variables, multiple regression analysis showed that vertebral fractures were significantly associated with low back pain and ODI. Vertebral fractures and osteoporosis significantly impacted physical performance, whereas osteoporosis alone did not affect low back pain or ODI. Our findings contribute to new insights into low back pain and its impact on ADL and physical performance.

Abstract This study focused on the heterogeneity in progress notes written by physicians or nurses. A total of 806 days of progress notes written by physicians or nurses from 83 randomly selected patients hospitalized in the Gastroenterology Department at Kagawa University Hospital from January to December 2021 were analyzed. We extracted symptoms as the International Classification of Diseases (ICD) Chapter 18 (R00–R99, hereinafter R codes) from each progress note using MedNER-J natural language processing software and counted the days one or more symptoms were extracted to calculate the extraction rate. The R-code extraction rate was significantly higher from progress notes by nurses than by physicians (physicians 68.5% vs. nurses 75.2%; p = 0.00112), regardless of specialty. By contrast, the R-code subcategory R10–R19 for digestive system symptoms (44.2 vs. 37.5%, respectively; p = 0.00299) and many chapters of ICD codes for disease names, as represented by Chapter 11 K00–K93 (68.4 vs. 30.9%, respectively; p

Abstract Pathogenic variants in WDR45 on chromosome Xp11 cause neurodegenerative disorder beta-propeller protein-associated neurodegeneration (BPAN). Currently, there is no effective therapy for BPAN. Here we report a 17-year-old female patient with BPAN and show that antisense oligonucleotide (ASO) was effective in vitro. The patient had developmental delay and later showed extrapyramidal signs since the age of 15 years. MRI findings showed iron deposition in the globus pallidus and substantia nigra on T2 MRI. Whole genome sequencing and RNA sequencing revealed generation of pseudoexon due to inclusion of intronic sequences triggered by an intronic variant that is remote from the exon–intron junction: WDR45 (OMIM #300526) chrX(GRCh37):g.48935143G > C, (NM_007075.4:c.235 + 159C > G). We recapitulated the exonization of intron sequences by a mini-gene assay and further sought antisense oligonucleotide that induce pseudoexon skipping using our recently developed, a dual fluorescent splicing reporter system that encodes two fluorescent proteins, mCherry, a transfection marker designed to facilitate evaluation of exon skipping and split eGFP, a splicing reaction marker. The results showed that the 24-base ASO was the strongest inducer of pseudoexon skipping. Our data presented here have provided supportive evidence for in vivo preclinical studies.

Abstract Abnormalities in visual exploration affect the daily lives of patients with schizophrenia. For example, scanpath length during free-viewing is shorter in schizophrenia. However, its origin and its relevance to symptoms are unknown. Here we investigate the possibility that abnormalities in eye movements result from abnormalities in visual or visuo-cognitive processing. More specifically, we examined whether such abnormalities reflect visual salience in schizophrenia. Eye movements of 82 patients and 252 healthy individuals viewing natural and/or complex images were examined using saliency maps for static images to determine the contributions of low-level visual features to salience-guided eye movements. The results showed that the mean value for orientation salience at the gazes of the participants with schizophrenia were higher than that of the healthy control subjects. Further analyses revealed that orientation salience defined by the L + M channel of the DKL color space is specifically affected in schizophrenia, suggesting abnormalities in the magnocellular visual pathway. By looking into the computational stages of the visual salience, we found that the difference between schizophrenia and healthy control emerges at the earlier stage, suggesting functional decline in early visual processing. These results suggest that visual salience is affected in schizophrenia, thereby expanding the concept of the aberrant salience hypothesis of psychosis to the visual domain.

Abstract Numerous methods for bulk RNA sequence deconvolution have been developed to identify cellular targets of diseases by understanding the composition of cell types in disease-related tissues. However, issues of heterogeneity in gene expression between subjects and the shortage of reference single-cell RNA sequence data remain to achieve accurate bulk deconvolution. In our study, we investigated whether a new data generative method named sc-CMGAN and benchmarking generative methods (Copula, CTGAN and TVAE) could solve these issues and improve the bulk deconvolutions. We also evaluated the robustness of sc-CMGAN using three deconvolution methods and four public datasets. In almost all conditions, the generative methods contributed to improved deconvolution. Notably, sc-CMGAN outperformed the benchmarking methods and demonstrated higher robustness. This study is the first to examine the impact of data augmentation on bulk deconvolution. The new generative method, sc-CMGAN, is expected to become one of the powerful tools for the preprocessing of bulk deconvolution.

Abstract The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages.

Abstract To develop artificial cell models that mimic living cells, cell-sized lipid vesicles encapsulating cell-free protein synthesis (CFPS) systems are useful for protein expressions or artificial gene circuits for vesicle–vesicle communications. Therefore, investigating the transcriptional and translational properties of CFPS systems in lipid vesicles is important for maximizing the synthesis and functions of proteins. Although transcription and translation using CFPS systems inside lipid vesicles are more important than that outside lipid vesicles, the former processes are not investigated by changing the lipid composition of lipid vesicles. Herein, we investigated changes in transcription and translation using CFPS systems inside giant lipid vesicles (approximately 5–20 μm in diameter) caused by changing the lipid composition of lipid vesicles containing neutral, positively, and negatively charged lipids. After incubating for 30 min, 1 h, 2 h, and 4 h, the transcriptional and translational activities in these lipid vesicles were determined by detecting the fluorescence intensities of the fluorogenic RNA aptamer on the 3′-untranslated region of mRNA (transcription) and the fluorescent protein sfCherry (translation), respectively. The results revealed that transcriptional and translational activities in a lipid vesicle containing positively charged lipids were high when the protein was synthesized using the CFPS system inside the lipid vesicle. Thus, the present study provides an experimental basis for constructing complex artificial cell models using bottom-up approaches.

Abstract This study investigates the application of the Metaheuristic Aided Structural Topology Optimization (MASTO) method as a novel approach to address the multiphysics design challenge of creating a heat sink with both high heat conductivity and minimal Electromagnetic Interference (EMI). A distinctive 2D layout with elongated fins is examined for electromagnetic traits, highlighting resonance-related EMI concerns. MASTO proves to be a valuable tool for navigating the complex design space, yielding thoughtfully optimized solutions that harmonize efficient heat dissipation with effective EMI control. By merging simulation findings with practical observations, this study underscores the potential of the MASTO method in achieving effective designs for intricate multiphysics optimization problems. Specifically, the method's capacity to address the complex interplay of heat transfer with convection and the suppression of electromagnetic emissions is showcased. Moreover, the study demonstrates the feasibility of translating these solutions into tangible outcomes through manufacturing processes.

Abstract The surface of the insect body is covered with a hydrophobic layer called cuticular wax (CW). In addition to functioning as an anti-desiccation agent, CW is critical for chemical communication. It has been reported that in Chrysomelidae, males discriminate between sexes based on the sex-specific CW. However, little is known regarding the underlying sensory basis. Herein, we demonstrate that chemosensory input from mouthparts mediates sexual discrimination in male Galerucella grisescens (Chrysomelidae). Observations of mating behaviour, bioassays for CW, and chemical analyses revealed that G. grisescens possess qualitatively sexually dimorphic CW, and such compositional differences allow males to distinguish between sexes. Using electron microscopy, blocking male chemosensory organs, and electrophysiological experiments, we showed that male mouthparts bear chemosensory sensilla tuned to female CW components, and sensory input from them induces male aedeagal insertion, a common male behavioural response to females. Thus, detecting CW via mouthparts is essential for males to distinguish between sexes, consistent with the fact that males inspect conspecific individuals by licking their body surfaces. To our best knowledge, this is the first report describing the detailed functional roles of mouthparts in sexual discrimination in Coleoptera. We believe that this study will promote further studies on insect chemical communication.

Abstract Time-lapse observation is a popular method for analyzing mammalian preimplantation embryos, but it often requires expensive equipment and skilled techniques. We previously developed a simply and costly embryo-culture system in a sealed tube that does not require a CO2 incubator. In the present study, we developed a new time-lapse observation system using our previous culture method and a glass capillary. Zygotes were placed in a glass capillary and sunk in oil for observation under a stereomicroscope. Warming the capillary using a thermoplate enabled most of the zygotes to develop into blastocysts and produce healthy offspring. This time-lapse observation system captured images every 30 min for up to 5 days, which confirmed that the developmental speed and quality of the embryos were not affected, even with fluorescence. Overall, this new system is a simple time-lapse observation method for preimplantation embryos that does not require dedicated machines and advanced techniques.

Abstract Previous literature has highlighted the importance of maternal behavior during the prenatal period for the upbringing of healthy adults. During pregnancy, fetal health assessments are mainly carried out non-invasively by monitoring fetal growth and heart rate (HR) or RR interval (RRI). Despite this, research entailing prediction of fHRs from mHRs is scarce mainly due to the difficulty in non-invasive measurements of fetal electrocardiogram (fECG). Also, so far, it is unknown how mHRs are associated with fHR over the short term. In this study, we used two machine learning models, support vector regression (SVR) and random forest (RF), for predicting average fetal RRI (fRRI). The predicted fRRI values were compared with actual fRRI values calculated from non-invasive fECG. fRRI was predicted from 13 maternal features that consisted of age, weight, and non-invasive ECG-derived parameters that included HR variability (HRV) and R wave amplitude variability. 156 records were used for training the models and the results showed that the SVR model outperformed the RF model with a root mean square error (RMSE) of 29 ms and an average error percentage (

Abstract Zirconia ceramics have been widely used as dental restorations due to their esthetic appearance and high flexural strength. The bonding of zirconia with resin cement should rely on both mechanical and chemical bonds. This study was performed to investigate the effect of zirconia surface topography and its wettability after surface pretreatments on the microshear bond strength (μSBS) of a resin cement. Zirconia slabs were prepared and randomly divided into 5 groups based on the surface treatment as follows: no treatment (control), air abrasion (AB), etching with hydrofluoric acid (F), the mixture of hydrofluoric acid and nitric acid (FN), or the mixture of hydrochloric acid and nitric acid (CN) for 10 min. The specimens were subjected to investigation of surface roughness characteristics [average roughness (Ra), peak-to-valley average distance (Rpv), skewness (Rsk), and kurtosis (Rku)] using atomic force microscopy (AFM) and measurements of surface contact angle (θ c) and μSBS of a resin cement. In addition, the area % of the nanoscale surface irregularity (nSI%) was calculated from the AFM images. The effects of nSI%, Ra and θ c on the μSBS were analyzed by multiple linear regression analysis (p

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The pathological hallmark of PD is the appearance of intraneuronal cytoplasmic α-synuclein (α-Syn) aggregation, called Lewy bodies. α-Syn aggregation is deeply involved in the pathogenesis of PD. Oxidative stress is also associated with the progression of PD. In the present study, to investigate whether a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitor, FG-4592 (also called roxadustat), has neuroprotective effects against α-Syn-induced neurotoxicity, we employed a novel α-Syn stably expressing cell line (named α-Syn-N2a cells) utilizing a piggyBac transposon system. In α-Syn-N2a cells, oxidative stress and cell death were induced by α-Syn, and FG-4592 showed significant protection against this neurotoxicity. However, FG-4592 did not affect α-Syn protein levels. FG-4592 triggered heme oxygenase-1 (HO-1) expression downstream of HIF-1α in a concentration-dependent manner. In addition, FG-4592 decreased the production of reactive oxygen species possibly via the activation of HO-1 and subsequently suppressed α-Syn-induced neurotoxicity. Moreover, FG-4592 regulated mitochondrial biogenesis and respiration via the induction of the peroxisome proliferator-activated receptor-γ coactivator-1α. As FG-4592 has various neuroprotective effects against α-Syn and is involved in drug repositioning, it may have novel therapeutic potential for PD.

Abstract Bacterial aggregation by mixing with polymers is applied as pretreatment to identify pathogens in patients with infectious diseases. However, the detailed interaction between polymers and bacteria has yet to be fully understood. Here, we investigate the interaction between polyallylamine and Escherichia coli by isothermal titration calorimetry. Aggregation was observed at pH 10 and the binding was driven by favorable enthalpic gain such as the electrostatic interaction. Neither aggregation nor the apparent heat of binding was observed at pH 4.0, despite the strong positive charge of polyallylamine. These results suggest that intermolecular repulsive forces of the abundant positive charge of polyallylamine cause an increased loss of conformational entropy by binding. Non-electrostatic interaction plays a critical role for aggregation.

Abstract Pairs of sense and antisense transcriptions that are adjacent at their 5′ and 3′ regions are called divergent and convergent transcription, respectively. However, the structural properties of divergent/convergent transcription in different species or RNA biotypes are poorly characterized. Here, we developed CCIVR2, a program that facilitates identification of both overlapping and non-overlapping antisense transcripts produced from divergent/convergent transcription whose transcription start sites (TSS) or transcript end sites (TES) are located within a specified region. We used CCIVR2 to analyze antisense transcripts starting around the sense TSS (from divergent transcription) or ending around the sense TES (from convergent transcription) in 11 different species and found species- and RNA biotype-specific features of divergent/convergent transcription. Furthermore, we confirmed that CCIVR2 enables the identification of multiple sense/antisense transcript pairs from divergent transcription, including those with known functions in processes such as embryonic stem cell differentiation and TGFβ stimulation. CCIVR2 is therefore a valuable bioinformatics tool that facilitates the characterization of divergent/convergent transcription in different species and aids the identification of functional sense/antisense transcript pairs from divergent transcription in specified biological processes.

Abstract Low levels of physical activity in individuals with chronic pain can lead to additional functional impairment and disability. This study aims to investigate the predictors of low physical activity levels in individuals with chronic pain, and to determine the accuracy of the artificial neural network used to analyze these predictors. Community-dwelling older adults with chronic pain (n = 103) were surveyed for their physical activity levels and classified into low, moderate, or high physical activity level groups. Chronic pain-related measurements, physical function assessment, and clinical history, which all influence physical activity, were also taken at the same time. Logistic regression analysis and analysis of multilayer perceptron, an artificial neural network algorithm, were performed. Both analyses revealed that history of falls was a predictor of low levels of physical activity in community-dwelling older adults. Multilayer perceptron analysis was shown to have excellent accuracy. Our results emphasize the importance of fall prevention in improving the physical activity levels of community-dwelling older adults with chronic pain. Future cross-sectional studies should compare multiple analysis methods to show results with improved accuracy.

Abstract We aimed to obtain widefield (WF) swept source optical coherence tomography (SS-OCT) data and examine the features of choroidal thickness maps in healthy eyes. The posterior pole choroidal thickness was examined in 127 eyes using enhanced depth imaging of SS-OCT with a viewing angle of 20 (vertical) × 23 (horizontal) mm, and choroidal thickness maps were generated. For SS-OCT image analysis, we developed a grid with inner and outer rings, each divided into superotemporal, inferotemporal, superonasal, and inferonasal quadrants, comprising a total of nine subfields, including the central 3-mm ring. The posterior pole choroidal thicknesses were significantly lower at the periphery than in the central area, in the inferior field than in the superior field, and in the nasal field than in the temporal field (p

Abstract Some older adults with spinal deformity maintain standing posture via pelvic compensation when their center of gravity moves forward. Therefore, evaluations of global alignment should include both pelvic tilt (PT) and seventh cervical vertebra-sagittal vertical axis (C7-SVA). Here, we evaluate standing postures of older adults using C7-SVA with PT and investigate factors related to postural abnormality. This cross-sectional study used an established population-based cohort in Japan wherein 1121 participants underwent sagittal whole-spine radiography in a standing position and bioelectrical impedance analysis for muscle mass measurements. Presence of low back pain (LBP), visual analog scale (VAS) of LBP, and LBP-related disability (Oswestry Disability Index [ODI]) were evaluated. Based on the PT and C7-SVA, the participants were divided into four groups: normal, compensated, non-compensated, and decompensated. We defined the latter three categories as “malalignment” and examined group characteristics and factors. There were significant differences in ODI%, VAS and prevalence of LBP, and sarcopenia among the four groups, although these were non-significant between non-compensated and decompensated groups on stratified analysis. Moreover, the decompensated group was significantly associated with sarcopenia. Individuals with pelvic compensation are at increased risk for LBP and related disorders even with the C7-SVA maintained within normal range.

Abstract Sarcopenia is defined as decreasing in muscle strength and mass, and dynapenia is defined as decreasing in muscle strength and maintained muscle mass. This study elucidated the prevalence and characteristics of sarcopenia and dynapenia and evaluate in elderly spinal disorders patients. 1039 spinal disorders patients aged ≥ 65 years were included. We measured age, grip strength, muscle mass, spinal sagittal alignment parameters, low back pain (LBP) scores and health-related quality of life (HR-QoL) scores. Based on the previous reports, patients were categorised into normal group: NG, pre-sarcopenia group: PG, dynapenia group: DG, and sarcopenia group: SG. Pre-sarcopenia, dynapenia, and sarcopenia were found in 101 (9.7%), 249 (19.2%), and 91 (8.8%) patients, respectively. The spinal sagittal alignment parameters, trunk muscle mass, LBP, and HR-QoL scores were significantly worse in DG and SG compared with those in PG and NG. Spinal alignment, trunk muscle mass, and clinical outcomes, including LBP and HR-QoL scores, were maintained in the PG and poor in the DG and SG. Thus, intervention for muscle strength may be a treatment option for changes of spinal sagittal alignment and low back pain.

Abstract This study aimed to examine the validity of urinary N-terminal titin fragment/creatinine (urinary N-titin/Cr) reflecting muscle damage biomarker in patients with interstitial lung disease. This retrospective study enrolled patients with interstitial lung disease. We measured urinary N-titin/Cr. Furthermore, we measured the cross-sectional areas of the pectoralis muscles above the aortic arch (PMCSA) and erector spinae muscles of the 12th thoracic vertebra muscles (ESMCSA) to assess muscle mass until 1 year. We examined the correlation between urinary N-titin/Cr and the change in muscle mass. We plotted receiver operating characteristic curves to estimate the cut-off points for urinary N-titin/Cr for distinguishing the greater-than-median and smaller-than-median reduction of muscle mass after 1 year. We enrolled 68 patients with interstitial lung disease. The median urinary N-titin/Cr value was 7.0 pmol/mg/dL. We observed significant negative correlations between urinary N-titin/Cr and changes in the PMCSA after 1 year (p

Abstract The objective of this study was to clarify the impact of adverse reactions on immune dynamics. We investigated the pattern of systemic adverse reactions after the second and third coronavirus disease 2019 (COVID-19) vaccinations and their relationship with immunoglobulin G against severe acute respiratory syndrome coronavirus 2 spike 1 protein titers, neutralizing antibody levels, peak cellular responses, and the rate of decrease after the third vaccination in a large-scale community-based cohort in Japan. Participants who received a third vaccination with BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna), had two blood samples, had not had COVID-19, and had information on adverse reactions after the second and third vaccinations (n = 2198) were enrolled. We collected data on sex, age, adverse reactions, comorbidities, and daily medicine using a questionnaire survey. Participants with many systemic adverse reactions after the second and third vaccinations had significantly higher humoral and cellular immunity in the peak phase. Participants with multiple systemic adverse reactions after the third vaccination had small changes in the geometric values of humoral immunity and had the largest geometric mean of cellar immunity in the decay phase. Systemic adverse reactions after the third vaccination helped achieve high peak values and maintain humoral and cellular immunity. This information may help promote uptake of a third vaccination, even among those who hesitate due to adverse reactions.

Abstract Mitochondria, a major source of reactive oxygen species (ROS), are intimately involved in the response to oxidative stress in the body. The production of excessive ROS affects the balance between oxidative responses and antioxidant defense mechanisms thus perturbing mitochondrial function eventually leading to tissue injury. Therefore, antioxidant therapies that target mitochondria can be used to treat such diseases and improve general health. This study reports on an attempt to establish a system for delivering an antioxidant molecule coenzyme Q10 (CoQ10) to mitochondria and the validation of its therapeutic efficacy in a model of acetaminophen (APAP) liver injury caused by oxidative stress in mitochondria. A CoQ10-MITO-Porter, a mitochondrial targeting lipid nanoparticle (LNP) containing encapsulated CoQ10, was prepared using a microfluidic device. It was essential to include polyethylene glycol (PEG) in the lipid composition of this LNP to ensure stability of the CoQ10, since it is relatively insoluble in water. Based on transmission electron microscope (TEM) observations and small angle X-ray scattering (SAXS) measurements, the CoQ10-MITO-Porter was estimated to be a 50 nm spherical particle without a regular layer structure. The use of the CoQ10-MITO-Porter improved liver function and reduced tissue injury, suggesting that it exerted a therapeutic effect on APAP liver injury.

Abstract BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit growth of CML and Ph1-ALL cells showing downregulated expression of BRCA1. Here, we show that PARPi effectively induced cell death in BCR/ABL1 positive cells and suppressed colony forming activity. Prevention of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. The results showed that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. One possible mechanism underlying PARPi-dependent inhibition of leukemogenesis is increased interferon signaling via activation of the cGAS/STING pathway. This is compatible with the use of interferon as a first-line therapy for CML. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, combined use of PARPi and a TKI is an attractive option that may eradicate CML stem cells.

Abstract Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

Abstract The use of artificial intelligence (AI) in the diagnosis of dry eye disease (DED) remains limited due to the lack of standardized image formats and analysis models. To overcome these issues, we used the Smart Eye Camera (SEC), a video-recordable slit-lamp device, and collected videos of the anterior segment of the eye. This study aimed to evaluate the accuracy of the AI algorithm in estimating the tear film breakup time and apply this model for the diagnosis of DED according to the Asia Dry Eye Society (ADES) DED diagnostic criteria. Using the retrospectively corrected DED videos of 158 eyes from 79 patients, 22,172 frames were annotated by the DED specialist to label whether or not the frame had breakup. The AI algorithm was developed using the training dataset and machine learning. The DED criteria of the ADES was used to determine the diagnostic performance. The accuracy of tear film breakup time estimation was 0.789 (95% confidence interval (CI) 0.769–0.809), and the area under the receiver operating characteristic curve of this AI model was 0.877 (95% CI 0.861–0.893). The sensitivity and specificity of this AI model for the diagnosis of DED was 0.778 (95% CI 0.572–0.912) and 0.857 (95% CI 0.564–0.866), respectively. We successfully developed a novel AI-based diagnostic model for DED. Our diagnostic model has the potential to enable ophthalmology examination outside hospitals and clinics.

Abstract Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson’s disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor–derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51–1.44 for clinical assessments and 0.56–1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62–0.80 for scores derived from weekly averages and 0.24–0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings. Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019.

Abstract Allogeneic “off-the-shelf” mesenchymal stem/stromal cell (MSC) therapy requires scalable, quality-controlled cell manufacturing and distribution systems to provide clinical-grade products using cryogenic cell banking. However, previous studies report impaired cell function associated with administering freeze-thawed MSCs as single cell suspensions, potentially compromising reliable therapeutic efficacy. Using long-term culture-adapted clinical-grade clonal human bone marrow MSCs (cBMSCs) in this study, we engineered cBMSC sheets in 24 h to provide rapid preparation. We then sought to determine the influence of cBMSC freeze-thawing on both in vitro production of pro-regenerative factors and in vivo ability to reduce renal fibrosis in a rat model compared to freshly harvested cBMSCs. Sheets from freeze-thawed cBMSCs sheets exhibited comparable in vitro protein production and gene expression of pro-regenerative factors [e.g., hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and interleukin 10 (IL-10)] to freshly harvested cBMSC sheets. Additionally, freeze-thawed cBMSC sheets successfully suppressed renal fibrosis in vivo in an established rat ischemia–reperfusion injury model. Despite previous studies reporting that freeze-thawed MSCs exhibit impaired cell functions compared to fresh MSC single cell suspensions, cell sheets engineered from freeze-thawed cBMSCs do not exhibit impaired cell functions, supporting critical steps toward future clinical translation of cBMSC-based kidney disease treatment.

Abstract We investigated the effect of preoperative therapy for non-small cell lung cancer on programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1), poliovirus receptor (CD155), and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) expression and prognosis with the cases of 28 patients received preoperative concurrent chemo-radiotherapy (cCRT) and 27 received preoperative drug therapy. The post-treatment PD-L1 expression was higher in cCRT group than in the drug therapy (50.0% vs 5.0%, p = 0.000), whereas that of CD155 did not significantly differ (40.0% vs 60.0%, p = 0.131). The PD-1 expression was not significantly different between the cCRT and drug therapy groups (51.1% vs 42.9%, p = 0.076), while the TIGIT was significantly higher in the cCRT group (41.5% vs 34.0%, p = 0.008). The patients who received cCRT resulted in elevated PD-L1and TIGIT values had a worse prognosis (p = 0.008). The PD-L1 and TIGIT expression after cCRT was significantly higher than after drug treatment. The cCRT population with high expression of both had a significantly poorer prognosis, indicating elevation of PD-L1 and TIGIT after cCRT as a negative prognostic factor. Combination therapy with anti-PD-L1 and anti-TIGIT antibodies after cCRT may contribute to an improved prognosis.

Abstract Approximately 10% of patients with colorectal cancer with submucosal invasion have lymph node metastasis. Pathological risk factors for lymph node metastasis have varying sensitivities and specificities. To predict the risk of lymph node metastasis, the identification of new risk factors is vital. Tumor-infiltrating T cells have been reported to improve the prognosis of many solid tumors. Therefore, the purpose of this study was to examine the relationship between lymph node metastasis and tumor-infiltrating T cells in patients with colorectal cancer with submucosal invasion. We examined CD8+ tumor-infiltrating T cells level as a risk factor for lymph node metastasis in patients with colorectal cancer with submucosal invasion. Using immunohistochemical staining, we identified CD8 + T cells in surgically resected specimens from 98 patients with SM-CRC. We showed that low CD8+ tumor-infiltrating T cells levels are positively correlated with lymph node metastasis. Furthermore, by combining the number of CD8+ tumor-infiltrating T cell and the number of CD103+ tumor-infiltrating T cells, the results showed a high positive predictive value for lymph node metastasis in cases with low numbers of both types of tumor-infiltrating T cells and a high negative predictive value in cases with high numbers of both types of tumor-infiltrating T cells.

Abstract Podoplanin (PDPN) is intensely expressed on the podocyte membrane in an evolutionally conserved manner. CLEC-2, the endogenous ligand of PDPN, is highly expressed in platelets and also exists in a soluble form in plasma. Normally, podocytes are sequestered from CLEC-2, but when the glomerular barrier is injured, podocytes gain access to CLEC-2. We tested the effects of CLEC-2 in podocytes in vitro and in vivo. Cultured podocytes treated with Fc-CLEC-2 demonstrated that CLEC-2 induced the dephosphorylation of ezrin, radixin, and moesin (ERM) proteins. Podocytes treated with Fc-CLEC-2 also showed the dissociation of F-actin filaments from PDPN, F-actin degradation, detachment, and round morphology. Next, we perfused normal mouse kidney in vivo with FLAG-CLEC-2. CLEC-2 induced dephosphorylation of ERM and widening of the foot processes of podocytes. Platelets were detected by immunostaining for CD41 in the urine of mice with podocyte injury, indicating that podocytes can encounter platelets when glomeruli are injured. Collectively, these observations suggest that when platelets leak through the injured glomeruli, CLEC-2 from the platelets acts on PDPN in podocytes and induces morphological change and detachment, which may further aggravate podocyte injury. Thus, PDPN on podocytes may work as a leaked-platelet sensor.

Abstract Old age and spinal surgery significantly increase the risk of postoperative hyponatremia. However, detailed analyses of postoperative hyponatremia after spinal surgery in elderly patients are lacking. Therefore, we retrospectively reviewed the records of 582 consecutive patients aged > 60 years who underwent spinal surgery to evaluate the frequency, risk factors, and symptoms of postoperative hyponatremia after spinal surgery in the elderly population. Postoperative hyponatremia was defined as a postoperative blood sodium level

Abstract Mouse cloning by nuclear transfer using freeze-drying (FD) somatic cells is now possible, but the success rate is significantly lower than that of FD spermatozoa. Because spermatozoa, unlike somatic cells, are haploid cells with hardened nuclei due to protamine, the factors responsible for their tolerance to FD treatment remain unclear. In this study, we attempt to produce offspring from FD spermatid, a haploid sperm progenitor cell whose nuclei, like somatic cells, have not yet been replaced by protamine. We developed a method for collecting FD spermatids from testicular suspension. Despite the significantly lower success rate than that of FD spermatozoa, healthy offspring were obtained when FD spermatids were injected into oocytes. Offspring were also obtained from FD spermatids derived from immature male mice that had not yet produced spermatozoa. These results suggest that nuclear protaminization, rather than haploid nuclei, is one of the key processes responsible for tolerance to FD treatment.

Abstract Streptococcus mutans is a major etiological agent for dental caries. We previously demonstrated that S. mutans strains expressing collagen-binding proteins (CBPs) were related to the pathogenesis of systemic diseases. However, their acquisition and colonization remain unknown. Here, we investigated the detection rates of CBP-positive S. mutans strains in children and their guardians to clarify the background for the acquisition and colonization in children. Saliva samples were collected from children and their mothers, and detection of S. mutans and collagen-binding genes (cnm, cbm) was performed by PCR after DNA extraction. The oral status of each child was examined, and their mothers were asked to complete a questionnaire. The isolation rate of Cnm-positive S. mutans was significantly higher in mothers than in children. Notably, the possession rates of CBP-positive strains in children were significantly higher in children whose mothers had CBP-positive strains than in children whose mothers did not have these strains. Furthermore, children with CBP-positive strains had a significantly shorter breastfeeding period than children without these strains. The present results suggest that nutritional feeding habits in infancy are one of the factors involved in the acquisition and colonization of CBP-positive S. mutans strains.

Abstract This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p

Abstract We report clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG). Patient 1 exhibited a unique constellation of clinical features including marked hydrocephalus, spondyloepimetaphyseal dysplasia (SEMD), and thrombocytopenia which is comparable to that of an infant reported by Faye-Peterson et al., whereas patients 2 and 3 showed Camera-Genevieve type SMED with intellectual/developmental disability which is currently known as the sole disease name for NANS-CDG. Molecular studies revealed a maternally inherited likely pathogenic c.207del:p.(Arg69Serfs*57) variant and a paternally derived likely pathogenic c.979_981dup:p.(Ile327dup) variant in patient 1, a homozygous likely pathogenic c.979_981dup:p.(Ile327dup) variant caused by maternal segmental isodisomy involving NANS in patient 2, and a paternally inherited pathogenic c.133−12T>A variant leading to aberrant splicing and a maternally inherited likely pathogenic c.607T>C:p.(Tyr203His) variant in patient 3 (reference mRNA: NM_018946.4). The results, together with previously reported data, imply that (1) NANS plays an important role in postnatal growth and fetal brain development; (2) SMED is recognizable at birth and shows remarkable postnatal evolution; (3) NANS-CDG is associated with low-normal serum sialic acid, obviously elevated urine N-acetylmannosamine, and normal N- and O-glycosylation of serum proteins; and (4) NANS-CDG is divided into Camera-Genevieve type and more severe Faye-Peterson type.

Abstract Cis-natural antisense transcripts (cis-NATs) are transcribed from the same genomic locus as their partner gene but from the opposite DNA strand and overlap with the partner gene transcript. Here, we developed a simple and convenient program termed CCIVR (comprehensive cis-NATs identifier via RNA-seq data) that comprehensively identifies all kinds of cis-NATs based on genome annotation with expression data obtained from RNA-seq. Using CCIVR with genome databases, we demonstrated total cis-NAT pairs from 11 model organisms. CCIVR analysis with RNA-seq data from parthenogenetic and androgenetic embryonic stem cells identified well-known imprinted cis-NAT pair, KCNQ1/KCNQ1OT1, ensuring the availability of CCIVR. Finally, CCIVR identified cis-NAT pairs that demonstrate inversely correlated expression upon TGFβ stimulation including cis-NATs that functionally repress their partner genes by introducing epigenetic alteration in the promoters of partner genes. Thus, CCIVR facilitates the investigation of structural characteristics and functions of cis-NATs in numerous processes in various species.

Abstract There are various interventions of rehabilitation on the bed, but these are time-consuming and cannot be performed for all patients. The purpose of this study was to identify the patients who require early mobilization based on the level of sedation. We retrospectively evaluated the data of patients who underwent physical therapy, ICU admission of > 48 h, and were discharged alive. Sedation was defined as using sedative drugs and a Richmond Agitation–Sedation Scale score of

Abstract This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR

Abstract Virtual thin-slice (VTS) technique is a generative adversarial network-based algorithm that can generate virtual 1-mm-thick CT images from images of 3–10-mm thickness. We evaluated the performance of VTS technique for assessment of the spine. VTS was applied to 4-mm-thick CT images of 73 patients, and the visibility of intervertebral spaces was evaluated on the 4-mm-thick and VTS images. The heights of vertebrae measured on sagittal images reconstructed from the 4-mm-thick images and VTS images were compared with those measured on images reconstructed from 1-mm-thick images. Diagnostic performance for the detection of compression fractures was also compared. The intervertebral spaces were significantly more visible on the VTS images than on the 4-mm-thick images (P

Abstract The clinical usage of induced pluripotent stem cell (iPSC)-derived regenerative medicine products is limited by the possibility of residual undifferentiated cells forming tumours after transplantation. Most of the existing quality control tests involve crushing of cells. As a result, the cells to be transplanted cannot be directly tested, thereby increasing the cost of transplantation. Therefore, we tested a highly sensitive and non-disruptive quality-testing method that involves measuring microRNAs (miRNAs) in culture supernatants released by cells. By measuring miR-302b in the culture supernatant, residual iPSCs were detected with higher sensitivity than by measuring LIN28 (Lin-28 Homolog A) in the cells. To use this method, we also monitored the progression of differentiation. Our novel highly sensitive and non-disruptive method for detecting residual undifferentiated cells will contribute to reducing the manufacturing cost of iPSC-derived products and improving the safety of transplantation.

Abstract Endoscopic duodenal stent (DS) placement for malignant gastric outlet obstruction (GOO) is rapidly increasing in clinical practice; however, the most suitable patient candidates for DS placement have not been determined. One hundred and thirty-five patients with GOO who underwent DS placement in three Japanese referral centers between January 2010 and October 2019 were retrospectively evaluated. Overall survival (OS) after DS placement, technical/clinical success rates, adverse events, and predictive factors affecting OS after DS placement were also analyzed. The median OS after DS placement of all patients was 81 (7–901) days. Technical and clinical success rates were 99.3% and 83.7%, respectively. The GOO Scoring System score significantly increased before and after DS placement (0.9 vs. 2.7, P

Abstract In our previous studies, we found that blue light has a lethal effect on various insect species and demonstrated that the most effective wavelength to control the hygiene pest, the mosquito, Culex pipiens form molestus (Diptera: Culicidae), is ~ 420 nm through all developmental stages. The genera Aedes and Culex include many globally crucial hygiene pest species that transmit serious diseases to humans and animals. However, effective lethal wavelengths have been shown to differ among insect species. In this study, we investigated the lethal effects of blue light on the Asian tiger mosquito, Aedes albopictus, using light-emitting diodes. Blue-light irradiation had a lethal effect on the larvae, pupae, and adults of Ae. albopictus. In particular, the 417-nm blue-light wavelength had a strong lethal effect on the larvae, showing 100% mortality before pupation at the photon flux density of 10 × 1018 photons·m−2·s−1. In contrast, no blue-light wavelength had a lethal effect on the eggs. Moreover, the 417-nm wavelength had the strongest effect on the pupae among the tested blue-light wavelengths. Our findings indicate that ~ 420 nm is the most promising blue-light wavelength to control populations of Ae. albopictus and C. pipiens f. molestus.

Abstract The streptavidin–biotin system is known to have a very high affinity and specificity and is widely used in biochemical immunoassays and diagnostics. However, this method is affected by endogenous D-biotin in serum sample measurements (biotin interference). While several efforts using alternative high-affinity binding systems (e.g., genetically modified streptavidin and biotin derivatives) have been attempted, these efforts have all led to reduction in affinity. To solve this interference issue, the enantiomer of streptavidin was synthesized, which enabled specific binding to L-biotin. We successfully obtained a functional streptavidin molecule by peptide synthesis using D-amino acids and an in vitro folding technique. Several characterizations, including size exclusion chromatography (SEC), circular dichroism spectra (CD), and heat denaturation experiments collectively confirmed the higher-order enantiomer of natural streptavidin had been formed with comparable stability to the natural protein. L-biotin specific binding of this novel molecule enabled us to avoid biotin interference in affinity measurements using the Biacore system and enzyme-linked immunosorbent assay (ELISA). We propose the enantiomer of streptavidin as a potential candidate to replace the natural streptavidin–biotin system, even for in vivo use.

Abstract This study aimed to construct a prediction model for small-for-gestational-age (SGA) infants in Japan by creating a risk score during pregnancy. A total of 17,073 subjects were included in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study. A multiple logistic regression model was used to construct risk scores during early and mid-gestational periods (11–17 and 18–21 weeks of gestation, respectively). The risk score during early gestation comprised the maternal age, height, body mass index (BMI) during early gestation, parity, assisted reproductive technology (ART) with frozen-thawed embryo transfer (FET), smoking status, blood pressure (BP) during early gestation, and maternal birth weight. The risk score during mid-gestation also consisted of the maternal age, height, BMI during mid-gestation, weight gain, parity, ART with FET, smoking status, BP level during mid-gestation, maternal birth weight, and estimated fetal weight during mid-gestation. The C-statistics of the risk scores during early- and mid-gestation were 0.658 (95% confidence interval [CI]: 0.642–0.675) and 0.725 (95% CI: 0.710–0.740), respectively. In conclusion, the predictive ability of the risk scores during mid-gestation for SGA infants was acceptable and better than that of the risk score during early gestation.

Abstract Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

Abstract We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2–22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495–2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p

Abstract Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.