Publications by authors named "Ayako Suzuki"

226 Publications

Application of long-read sequencing to the detection of structural variants in human cancer genomes.

Comput Struct Biotechnol J 2021 28;19:4207-4216. Epub 2021 Jul 28.

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561, Japan.

In recent years, the so-called long-read sequencing technology has had a substantial impact on various aspects of genome sciences. Here, we introduce recent studies of cancerous structural variants (SVs) using long-read sequencing technologies, namely Pacific Biosciences (PacBio) sequencers, Oxford Nanopore Technologies (ONT) sequencers, and linked-read methods. By taking advantage of long-read lengths, these technologies have enabled the precise detection of SVs, including long insertions by transposable elements, such as LINE-1. In addition to SV detection, the epigenome status (including DNA methylation and haplotype information) surrounding SV loci has also been unveiled by long-read sequencing technologies, to identify the effects of SVs. Among the various research fields in which long-read sequencing has been applied, cancer genomics has shown the most remarkable advances. In fact, many studies are beginning to shed light on the detection of SVs and the elucidation of their complex structures in various types of cancer. In the particular case of cancers, we summarize the technical limitations of the application of this technology to the analysis of clinical samples. We will introduce recent achievements from this viewpoint. However, a similar approach will be started for other applications in the near future. Therefore, by complementing the current short-read sequencing analysis, long-read sequencing should reveal the complex nature of human genomes in their healthy and disease states, which will open a new opportunity for a better understanding of disease development and for a novel strategy for drug development.
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http://dx.doi.org/10.1016/j.csbj.2021.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350331PMC
July 2021

Lip-closing strength in children is enhanced by lip and facial muscle training.

Clin Exp Dent Res 2021 Sep 9. Epub 2021 Sep 9.

Department of Dental Hygiene, Ogaki Women's College, Ogaki, Japan.

Objectives: Weakening of lip-closing strength (LCS) associated with an incompetent lip seal (ILS) may affect the oral balance between the lip and tongue pressures. The purpose of this study was to evaluate the effects of lip-closing training in children with lower LCS and/or abnormal habits across different age groups and to compare its effects on increasing LCS in children with malocclusion and/or oral habits.

Material And Methods: Lip-closing training was performed by 154 Japanese children aged 3-12 years using a specialized training device at home for 3 months. Children with oral habits and/or exhibiting less than standard LCS were included. LCS was measured using a digital strain force gauge at a dental clinic at the beginning (T0) and after each month (after 3 months: T3).

Results: Children had higher LCS responses after lip-closing training. The first month of lip-closing training was more effective than the subsequent months. With lip-closing training, the LCS increased from an average of 6.2 N (T0) to 11.4 N (T3) in Group I, 7.9 N (T0) to 12.8 N (T3) in Group II, and 6.8 N to 11.4 N in Group III. Anterior cross bite, including reverse bite, open bite, and tongue thrusting, significantly reduced training effects.

Conclusion: Our findings showed that lower LCS in children with ILS resulted in greater responses to lip-closing training in a short period, but oral dysfunction, such as abnormal habits, inhibited the positive effects of training. Our results suggest that less detrimental effects of malocclusion and abnormal oral habits lip-closing training enhances LCS in younger children.
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http://dx.doi.org/10.1002/cre2.490DOI Listing
September 2021

COVID-19-Associated Mortality in US Veterans with and without SARS-CoV-2 Infection.

Int J Environ Res Public Health 2021 08 11;18(16). Epub 2021 Aug 11.

Division of Gastroenterology, Duke University, Durham, NC 27710, USA.

Background: We performed an observational Veterans Health Administration cohort analysis to assess how risk factors affect 30-day mortality in SARS-CoV-2-infected subjects relative to those uninfected. While the risk factors for coronavirus disease 2019 (COVID-19) have been extensively studied, these have been seldom compared with uninfected referents.

Methods: We analyzed 341,166 White/Black male veterans tested for SARS-CoV-2 from March 1 to September 10, 2020. The relative risk of 30-day mortality was computed for age, race, ethnicity, BMI, smoking status, and alcohol use disorder in infected and uninfected subjects separately. The difference in relative risk was then evaluated between infected and uninfected subjects. All the analyses were performed considering clinical confounders.

Results: In this cohort, 7% were SARS-CoV-2-positive. Age >60 and overweight/obesity were associated with a dose-related increased mortality risk among infected patients relative to those uninfected. In contrast, relative to never smoking, current smoking was associated with a decreased mortality among infected and an increased mortality in uninfected, yielding a reduced mortality risk among infected relative to uninfected. Alcohol use disorder was also associated with decreased mortality risk in infected relative to the uninfected.

Conclusions: Age, BMI, smoking, and alcohol use disorder affect 30-day mortality in SARS-CoV-2-infected subjects differently from uninfected referents. Advanced age and overweight/obesity were associated with increased mortality risk among infected men, while current smoking and alcohol use disorder were associated with lower mortality risk among infected men, when compared with those uninfected.
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http://dx.doi.org/10.3390/ijerph18168486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394601PMC
August 2021

Chronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma.

Nat Commun 2021 08 10;12(1):4821. Epub 2021 Aug 10.

Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

Subclonal genetic heterogeneity and their diverse gene expression impose serious problems in understanding the behavior of cancers and contemplating therapeutic strategies. Here we develop and utilize a capture-based sequencing panel, which covers host hotspot genes and the full-length genome of human T-cell leukemia virus type-1 (HTLV-1), to investigate the clonal architecture of adult T-cell leukemia-lymphoma (ATL). For chronologically collected specimens from patients with ATL or pre-onset individuals, we integrate deep DNA sequencing and single-cell RNA sequencing to detect the somatic mutations and virus directly and characterize the transcriptional readouts in respective subclones. Characteristic genomic and transcriptomic patterns are associated with subclonal expansion and switches during the clinical timeline. Multistep mutations in the T-cell receptor (TCR), STAT3, and NOTCH pathways establish clone-specific transcriptomic abnormalities and further accelerate their proliferative potential to develop highly malignant clones, leading to disease onset and progression. Early detection and characterization of newly expanded subclones through the integrative analytical platform will be valuable for the development of an in-depth understanding of this disease.
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http://dx.doi.org/10.1038/s41467-021-25101-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355240PMC
August 2021

Hepatic mitochondrial SAB deletion or knockdown alleviates diet induced metabolic syndrome, steatohepatitis and hepatic fibrosis.

Hepatology 2021 Jul 31. Epub 2021 Jul 31.

USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

The hepatic MAPK cascade leading to JNK activation has been implicated in the pathogenesis of nonalcoholic fatty liver /non-alcoholic steatohepatitis (NAFL/NASH). In acute hepatotoxicity we previously identified a pivotal role for mitochondrial SH3BP5 (SAB) as a target of JNK which sustains its activation through promotion of reactive oxygen species (ROS) production.

Aim: Assess the role of hepatic SAB in experimental NASH and metabolic syndrome.

Results: In mice fed high-fat, high-calorie, high-fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK/ATF2 activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8 weeks followed by decreased body fat at 16 weeks of HFHC diet. After 30 weeks mice treated with control-ASO developed steatohepatitis and fibrosis which was prevented by Sab-ASO treatment. P-JNK and P-ATF2 were markedly attenuated by Sab-ASO treatment. After 52 weeks of HFHC feeding control N-acetylgalactosamine antisense oligonucleotide (GalNAc-Ctl-ASO) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis but GalNAc-Sab-ASO treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, P-ATF2, and P-JNK to chow fed levels.

Conclusions: Hepatic SAB expression increases in HFHC diet fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte Sab is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte targeted GalNAc-Sab-ASO treatment reversed steatohepatitis and fibrosis.
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http://dx.doi.org/10.1002/hep.32083DOI Listing
July 2021

Clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis.

Lung Cancer 2021 09 16;159:74-83. Epub 2021 Jul 16.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. Electronic address:

Objectives: The purpose of this study was to investigate the clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis.

Methods: We retrospectively reviewed 521 cases with pathologic stage I lung adenocarcinoma resected by lobectomy and lymph node dissection. We calculated the ratio of tumor necrotic area by digital image analysis and investigated the relationship between tumor necrosis and prognosis. Furthermore, we analyzed the differentially expressed genes between cases with and without necrosis using The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset. Using whole exon sequencing data (n = 97), we examined whether tumor necrosis correlates with single nucleotide variants (SNVs) and driver mutations.

Results: Eighty four (16%) cases of the study cohort had tumor necrosis. The presence of necrosis significantly correlated with poorer prognosis (5-year overall survival: 91.9% vs. 75.4%, p < 0.001; 5-year recurrence-free survival: 86.0% vs. 59.0%, p < 0.001); however, the ratio of necrotic area did not correlate with prognosis. In multivariable analysis, invasive component size, vascular invasion, and tumor necrosis were independently associated with a higher risk of recurrence (hazard ratio, 1.652; 95% confidence interval, 1.033-2.641; p = 0.036). Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as cell cycle and response to hypoxia, in cases with necrosis. The cases with tumor necrosis had more SNVs than those without tumor necrosis (p = 0.027), especially in smokers.

Conclusion: Stage I lung adenocarcinoma with tumor necrosis has worse prognosis than that without, and has distinctclinicopathological features in terms of gene expression and genetic features.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.001DOI Listing
September 2021

Safety of vancomycin in patients with moderate and severe renal dysfunction.

Clin Nephrol 2021 Jul 26. Epub 2021 Jul 26.

Aim: The new guidelines in Japan do not recommend a vancomycin (VCM) loading dose for patients with an estimated glomerular filtration rate (eGFR) 30 < and ≤ 80 mL×min×1.73m (moderate renal dysfunction) or administration to those with the eGFR < 30 mL×min×1.73m (severe renal dysfunction). We investigated the safety and efficiency of VCM in patients with moderate and severe renal dysfunction based on the new guidelines.

Materials And Methods: The study involved patients admitted to our hospital between April 2014 and March 2018 with an eGFR < 80 mL×min×1.73m and treated with VCM. VCM trough concentration and pre- and post-administration renal function were investigated retrospectively. The primary endpoints were the proportion of patients who achieved an effective trough concentration of 10 - 20 µg/mL and rate of acute kidney injury (AKI).

Results: We included 64 patients (32 moderate, 32 severe). The mean VCM trough concentration achieved for the first time was 9.3 and 11.6 µg/mL in the moderate and severe renal dysfunction groups, respectively (p = 0.91). The effective trough concentration endpoint was achieved by 50% and 43% of the patients in the severe and moderate renal dysfunction groups, respectively, and no significant difference was found in the AKI rate. The serum creatinine change was significantly different between the groups - the moderate group showed a slight deterioration and the severe renal dysfunction group an improvement.

Conclusion: It may be necessary to increase the dose for these patients with severe renal dysfunction while implementing a VCM loading dose and monitoring trough concentrations and adverse effects.
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http://dx.doi.org/10.5414/CN110475DOI Listing
July 2021

Single-cell and spatial analyses of cancer cells: toward elucidating the molecular mechanisms of clonal evolution and drug resistance acquisition.

Inflamm Regen 2021 Jul 16;41(1):22. Epub 2021 Jul 16.

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa-shi, Chiba, 277-8561, Japan.

Even within a single type of cancer, cells of various types exist and play interrelated roles. Each of the individual cells resides in a distinct microenvironment and behaves differently. Such heterogeneity is the most cumbersome nature of cancers, which is occasionally uncountable when effective prevention or total elimination of cancers is attempted. To understand the heterogeneous nature of each cell, the use of conventional methods for the analysis of "bulk" cells is insufficient. Although some methods are high-throughput and compressive regarding the genes being detected, the obtained data would be from the cell mass, and the average of a large number of the component cells would no longer be measured. Single-cell analysis, which has developed rapidly in recent years, is causing a drastic change. Genome, transcriptome, and epigenome analyses at single-cell resolution currently target cancer cells, cancer-associated fibroblasts, endothelial cells of vessels, and circulating and infiltrating immune cells. In fact, surprisingly diverse features of clonal evolution of cancer cells, during the development of cancer or acquisition of drug resistance, accompanied by corresponding gene expression changes in the circumstantial stromal cells, appeared in recent single-cell analyses. Based on the obtained novel insights, better optimal drug selection and new drug administration sequences were started. Even a remaining concern of the single cell analyses is being addressed. Until very recently, it was impossible to obtain positional information of cells in cancer via single-cell analysis because such information is lost during preparation of single-cell suspensions. A new method, collectively called spatial transcriptome (ST) analysis, has been developed and rapidly applied to various clinical specimens. In this review, we first outline the recent achievements of single-cell cancer analysis in analyzing the molecular basis underlying the acquisition of drug resistance, particularly focusing on the latest anti-epidermal growth factor receptor tyrosine kinase inhibitor, osimertinib. Further, we review the currently available ST analysis methods and introduce our recent attempts regarding the respective topics.
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http://dx.doi.org/10.1186/s41232-021-00170-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283950PMC
July 2021

Single-Cell Analyses Reveal Diverse Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer.

Cancer Res 2021 Sep 9;81(18):4835-4848. Epub 2021 Jul 9.

Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.

Tumor heterogeneity underlies resistance to tyrosine kinase inhibitors (TKI) in lung cancers harboring mutations. Previous evidence suggested that subsets of preexisting resistant cells are selected by EGFR-TKI treatment, or alternatively, that diverse acquired resistance mechanisms emerge from drug-tolerant persister (DTP) cells. Many studies have used bulk tumor specimens or subcloned resistant cell lines to identify resistance mechanism. However, intratumoral heterogeneity can result in divergent responses to therapies, requiring additional approaches to reveal the complete spectrum of resistance mechanisms. Using EGFR-TKI-resistant cell models and clinical specimens, we performed single-cell RNA-seq and single-cell ATAC-seq analyses to define the transcriptional and epigenetic landscape of parental cells, DTPs, and tumor cells in a fully resistant state. In addition to , , and , which are all known to induce EGFR-TKI resistance, was identified as a novel gene that plays a critical role in the drug-tolerant state. and experiments demonstrated that CD74 upregulation confers resistance to the EGFR-TKI osimertinib and blocks apoptosis, enabling tumor regrowth. Overall, this study provides new insight into the mechanisms underlying resistance to EGFR-TKIs. SIGNIFICANCE: Single-cell analyses identify diverse mechanisms of resistance as well as the state of tolerant cells that give rise to resistance to EGFR tyrosine kinase inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448980PMC
September 2021

Predictive markers based on transcriptome modules for vinorelbine-based adjuvant chemotherapy for lung adenocarcinoma patients.

Lung Cancer 2021 08 10;158:115-125. Epub 2021 Jun 10.

Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. Electronic address:

Objectives: Microtubule inhibitors (MTIs) are widely used as anti-cancer drugs for various types of tumors. Vinorelbine, an MTI, is utilized in postoperative adjuvant chemotherapy, especially for lung adenocarcinoma. However, no molecular markers are able to identify patients for whom MTIs would be effective. In this study, we attempted to identify practical markers to predict the efficacy of MTI-based adjuvant chemotherapy.

Materials And Methods: We explored a novel combination of molecular marker candidates, based on gene expression network analysis constructed using an omics panel of 26 lung adenocarcinoma cell lines. We then applied the obtained classification method to predict the efficacy of MTI treatment in patients who received adjuvant chemotherapy. RNA sequencing (RNA-seq) analysis was conducted using surgical specimens from 24 Japanese lung adenocarcinoma patients treated postoperatively with vinorelbine.

Results: We identified four modules within the network with module activities that were significantly associated with sensitivity to MTIs. Two modules were associated with high sensitivity to MTIs: genes with low differentiation or transdifferentiation of lung adenocarcinomas. On the other hand, MTI-low sensitivity modules were enriched in common epithelial genes and markers of well-differentiated lung adenocarcinomas. We also classified lung adenocarcinoma cases using the module activities associated with MTI efficacy and stratify the cases with MTI resistance.

Conclusion: We demonstrate that the constructed classification method is useful for identifying patients with MTI resistance which results in a high risk of cancer relapse.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.011DOI Listing
August 2021

"Why did our baby die soon after birth?"-Lessons on neonatal death in rural Cambodia from the perspective of caregivers.

PLoS One 2021 7;16(6):e0252663. Epub 2021 Jun 7.

Project for Improving Continuum of Care with focus on Intrapartum and Neonatal Care in Cambodia, Japan International Cooperation Agency, Phnom Penh, Cambodia.

Introduction: Neonatal deaths represent around half the deaths of children less than five-years old in Cambodia. The process from live birth to neonatal death has not been well described. This study aimed to identify problems in health care service which hamper the reduction of preventable neonatal deaths in rural Cambodia.

Methods: This study adopted a method of qualitative case study design using narrative data from the verbal autopsy standard. Eighty and forty villages were randomly selected from Kampong Cham and Svay Rieng provinces, respectively. All households in the target villages were visited between January and February 2017. Family caregivers were asked to describe their experiences on births and neonatal deaths between 2015 and 2016. Information on the process from birth to death was extracted with open coding, categorized, and summarized into several groups which represent potential problems in health services.

Results: Among a total of 4,142 children born in 2015 and 2016, 35 neonatal deaths were identified. Of these deaths, 74% occurred within one week of birth, and 57% were due to low-birth weight. Narrative data showed that three factors should be improved, 1) the unavailability of a health-care professional, 2) barriers in the referral system, and 3) lack of knowledge and skill to manage major causes of neonatal deaths.

Conclusion: The current health system has limitations to achieve further reduction of neonatal deaths in rural Cambodia. The mere deployment of midwives at fixed service points such as health centers could not solve the problems occurring in rural communities. Community engagement revisiting the principle of primary health care, as well as health system transformation, is the key to the solution and potential breakthrough for the future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252663PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183999PMC
June 2021

Long-read whole-genome methylation patterning using enzymatic base conversion and nanopore sequencing.

Nucleic Acids Res 2021 Aug;49(14):e81

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.

Long-read whole-genome sequencing analysis of DNA methylation would provide useful information on the chromosomal context of gene expression regulation. Here we describe the development of a method that improves the read length generated by using the bisulfite-sequencing-based approach. In this method, we combined recently developed enzymatic base conversion, where an unmethylated cytosine (C) should be converted to thymine (T), with nanopore sequencing. After methylation-sensitive base conversion, the sequencing library was constructed using long-range polymerase chain reaction. This type of analysis is possible using a minimum of 1 ng genomic DNA, and an N50 read length of 3.4-7.6 kb is achieved. To analyze the produced data, which contained a substantial number of base mismatches due to sequence conversion and an inaccurate base read of the nanopore sequencing, a new analytical pipeline was constructed. To demonstrate the performance of long-read methylation sequencing, breast cancer cell lines and clinical specimens were subjected to analysis, which revealed the chromosomal methylation context of key cancer-related genes, allele-specific methylated genes, and repetitive or deletion regions. This method should convert the intractable specimens for which the amount of available genomic DNA is limited to the tractable targets.
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http://dx.doi.org/10.1093/nar/gkab397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373077PMC
August 2021

Cells/colony motion of oral keratinocytes determined by non-invasive and quantitative measurement using optical flow predicts epithelial regenerative capacity.

Sci Rep 2021 05 17;11(1):10403. Epub 2021 May 17.

Division of Biomimetics, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

Cells/colony motion determined by non-invasive, quantitative measurements using the optical flow (OF) algorithm can indicate the oral keratinocyte proliferative capacity in early-phase primary cultures. This study aimed to determine a threshold for the cells/colony motion index to detect substandard cell populations in a subsequent subculture before manufacturing a tissue-engineered oral mucosa graft and to investigate the correlation with the epithelial regenerative capacity. The distinctive proliferating pattern of first-passage [passage 1 (p1)] cells reveals the motion of p1 cells/colonies, which can be measured in a non-invasive, quantitative manner using OF with fewer full-screen imaging analyses and cell segmentations. Our results demonstrate that the motion index lower than 40 μm/h reflects cellular damages by experimental metabolic challenges although this value shall only apply in case of our culture system. Nonetheless, the motion index can be used as the threshold to determine the quality of cultured cells while it may be affected by any different culture conditions. Because the p1 cells/colony motion index is correlated with epithelial regenerative capacity, it is a reliable index for quality control of oral keratinocytes.
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http://dx.doi.org/10.1038/s41598-021-89073-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128884PMC
May 2021

Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD.

Hepatol Commun 2021 04 18;5(4):598-607. Epub 2021 Jan 18.

Division of Gastroenterology Department of Medicine Duke University Durham NC USA.

The development of fibrosis in nonalcoholic fatty liver disease (NAFLD) is influenced by genetics, sex, and menopausal status, but whether genetic susceptibility to fibrosis is influenced by sex and reproductive status is unclear. Our aim was to identify metabolism-related single nucleotide polymorphisms (SNPs), whose effect on NAFLD fibrosis is significantly modified by sex and menopausal status. We performed a cross-sectional, proof-of-concept study of 616 patients in the Duke NAFLD Clinical Database and Biorepository. The primary outcome was nonalcoholic steatohepatitis-Clinical Research Network (NASH-CRN) fibrosis stage. Menopause status was self-reported; age 51 years was used as a surrogate for menopause in patients with missing menopause data. The Metabochip was used to obtain 98,359 SNP genotypes in known metabolic pathway genes for each patient. We used additive genetic models to characterize sex and menopause-specific effects of SNP genotypes on NAFLD fibrosis stage. In the main effects analysis, none of the SNPs were associated with fibrosis at  < 0.05 after correcting for multiple comparisons. Twenty-five SNPs significantly interacted with sex/menopause to affect fibrosis stage (interaction  < 0.0001). After removal of loci in linkage disequilibrium, 10 independent loci were identified. Six were in the following genes: (potassium voltage-gated channel interacting protein 4), (psoriasis susceptibility 1 candidate 1), (Kelch-like family member 8), (glycine receptor alpha 1), (notch receptor 2), and (protein kinase C eta), and four SNPs were intergenic. In stratified models, four SNPs were significant in premenopausal and postmenopausal women, three only in postmenopausal women, two in men and postmenopausal women, and one only in premenopausal women. We identified 10 loci with a significant sex/menopause interaction with respect to fibrosis. None of these SNPs were significant in all sex/menopause groups, suggesting modulation of genetic susceptibility to fibrosis by sex and menopause status. Future studies of genetic predictors of NAFLD progression should account for sex and menopause.
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http://dx.doi.org/10.1002/hep4.1668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034580PMC
April 2021

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI.

J Hepatol 2021 Aug 18;75(2):333-341. Epub 2021 May 18.

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA. Electronic address:

Background & Aims: Although most drug-induced liver injury (DILI) cases resolve after the offending medication is discontinued, time to recovery varies among patients, with 6 -12% developing a chronic disease. Herein, we investigated clinical factors and drug properties as potential risk determinants that influence the time course for DILI recovery and developed a model to predict its trajectory.

Methods: We applied an accelerated failure time model to 294 cases collected by the International Drug-Induced Liver Network Consortium (iDILIC). Factors included in the multivariate recovery score model were selected through univariate analysis. The model was externally validated using 257 cases from the Spanish DILI Registry and 191 cases from the LiverTox database.

Results: Higher serum bilirubin and alkaline phosphatase (ALP) at DILI onset, a longer time to onset, and non-significant drug metabolism were associated with a longer recovery and were included in the recovery score model. We defined high- and low-risk groups based on the scores assigned by the model. The estimated probability of recovery by 6 months was 0.46 (95% CI 0.26-0.61) for the high-risk group and 0.93 (95% CI 0.58-0.99) for the low-risk group in the iDILIC. Model performance was validated in both validation sets. The high- and low-risk cases identified by the model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner.

Conclusion: The trajectory of biochemical recovery from DILI is predicted by the extent of drug metabolism, serum bilirubin and ALP at DILI onset. The model can be used to compute an estimated DILI recovery and, when a significant delay is predicted, clinicians may consider additional investigations such as histologic evaluation or extended follow-up.

Lay Summary: In this study, we investigated whether drug properties and clinical factors are associated with the time it takes to recover from drug-induced liver injury (DILI). We found that total bilirubin, alkaline phosphatase level at DILI onset, time to onset, and extent of drug metabolism were consistently associated with recovery time. Using these factors, we built a model to predict the trajectory of recovery from DILI and validated this model in 2 independent cohorts. Our findings offer important insights into the factors influencing the trajectory of recovery from DILI. Additional investigations and longer follow-ups can be planned in those for whom a delayed recovery is predicted.
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http://dx.doi.org/10.1016/j.jhep.2021.03.021DOI Listing
August 2021

Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy.

Gastric Cancer 2021 07 9;24(4):810-822. Epub 2021 Apr 9.

Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Background: Cancer progression following chemotherapy is a significant barrier to effective cancer treatment. We aimed to evaluate the role of drug-exposed cancer-associated fibroblasts (CAFs) in the growth and progression of drug-exposed gastric cancer (GC) cells and to explore the underlying molecular mechanism.

Methods: The human GC cell line 44As3 and CAFs were treated with 5-fluorouracil and oxaliplatin (5FU + OX). 5FU + OX-pretreated 44As3 cells were then cultured in a conditioned medium (CM) from 5FU + OX-pretreated CAFs, and the growth and migration/invasion ability of the cells were evaluated. We also compared the clinicopathological characteristics of the GC patients treated with S1 + OX in accordance with the properties of their resected specimens, focusing on the number of CAFs. Changes in gene expression in CAFs and 44As3 cells were comprehensively analyzed using RNA-seq analysis.

Results: The CM from 5FU + OX-pretreated CAFs promoted the migration and invasion of 5FU + OX-pretreated 44As3 cells. Although the number of cases was relatively small (n = 21), the frequency of positive cases of lymphovascular invasion and the recurrence rate were significantly higher in those with more residual CAF. RNA-seq analysis revealed 5FU + OX-pretreated CAF-derived glycoprotein 130 (gp130) as a candidate factor contributing to the increased migration of 5FU + OX-pretreated 44As3 cells. Administration of the gp130 inhibitor SC144 prevented the increased migration ability of 5FU + OX-pretreated 44As3 cells owing to drug-treated CAFs.

Conclusions: Our findings provide evidence regarding the interactions between GC cells and CAFs in the tumor microenvironment following chemotherapy, suggesting that ligands for gp130 may be novel therapeutic targets for suppressing or preventing metastasis in GC.
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http://dx.doi.org/10.1007/s10120-021-01174-9DOI Listing
July 2021

Transcript Identification Through Long-Read Sequencing.

Methods Mol Biol 2021 ;2284:531-541

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-shi, Chiba, Japan.

RNA-seq using long-read sequencing, such as nanopore and SMRT (Single Molecule, Real-Time) sequencing, enabled the identification of the full-length structure of RNA molecules. Several tools for long-read RNA-seq were developed recently. In this section, we introduce an analytical pipeline of long-read RNA-seq for isoform identification and the estimation of expression levels using minimap2, TranscriptClean, and TALON. We applied this pipeline to the public direct RNA-seq data of the HAP1 and HEK293 cell lines to identify transcript isoforms which can be detected only using long-read RNA-seq data.
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http://dx.doi.org/10.1007/978-1-0716-1307-8_29DOI Listing
June 2021

Significance of mesothelin and CA125 expression in endometrial carcinoma: a retrospective analysis.

Diagn Pathol 2021 Apr 8;16(1):28. Epub 2021 Apr 8.

Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan.

Background: This study aimed to investigate the association between clinicopathologic factors, mesothelin, and cancer antigen (CA) 125 in endometrial carcinoma.

Methods: Between 1989 and 2017, patients with endometrial carcinoma who underwent total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either or both immunochemical expression of mesothelin and CA125 and clinicopathological features were retrospectively examined.

Results: Among 485 patients, 171 were positive for mesothelin, 368 were positive for CA125, and 167 were positive for mesothelin and CA125. The expression of mesothelin and CA125 was positively correlated (p < 0.01). More patients with mesothelin expression showed myometrial invasion of more than 50% (p = 0.028) and positive lymphovascular invasion (p = 0.027). Similarly, more patients with co-expression of mesothelin and CA125 had myometrial invasion of more than 50% (p = 0.016) and positive lymphovascular invasion (p = 0.02). Patients with mesothelin expression and co-expression of mesothelin and CA125 demonstrated worse progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, mesothelin expression and co-expression were poor prognostic factors for PFS (mesothelin expression: hazard ratio [HR] = 2.14, p < 0.01; co-expression: HR = 2.19, p < 0.01) and OS (mesothelin expression: HR = 2.18, p < 0.01; co-expression: HR = 2.22, p < 0.01).

Conclusions: Mesothelin expression and co-expression might be associated with tumor aggressiveness and poor prognosis in patients with endometrial carcinoma. Persons with mesothelin-expressing endometrial cancers present a particularly high medical unmet need.
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http://dx.doi.org/10.1186/s13000-021-01093-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034188PMC
April 2021

Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast.

Commun Biol 2021 04 1;4(1):438. Epub 2021 Apr 1.

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-shi, Chiba, Japan.

In a substantial number of patients, ductal carcinoma in situ (DCIS) of the breast will never progress to invasive ductal carcinoma, and these patients are often overtreated under the current clinical criteria. Although various candidate markers are available, relevant markers for delineating risk categories have not yet been established. In this study, we analyzed the clinical characteristics of 431 patients with DCIS and performed whole-exome sequencing analysis in a 21-patient discovery cohort and targeted deep sequencing analysis in a 72-patient validation cohort. We determined that age <45 years, HER2 amplification, and GATA3 mutation are possible indicators of relapse. PIK3CA mutation negativity and PgR negativity were also suggested to be risk factors. Spatial transcriptome analysis further revealed that GATA3 dysfunction upregulates epithelial-to-mesenchymal transition and angiogenesis, followed by PgR downregulation. These results reveal the existence of heterogeneous cell populations in DCIS and provide predictive markers for classifying DCIS and optimizing treatment.
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http://dx.doi.org/10.1038/s42003-021-01959-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016951PMC
April 2021

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer.

Stem Cell Reports 2021 Apr 11;16(4):954-967. Epub 2021 Mar 11.

Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. Electronic address:

Metastasis is the major cause of cancer-related death, but whether metastatic lesions exhibit the same cellular composition as primary tumors has yet to be elucidated. To investigate the cellular heterogeneity of metastatic colorectal cancer (CRC), we established 72 patient-derived organoids (PDOs) from 21 patients. Combined bulk transcriptomic and single-cell RNA-sequencing analysis revealed decreased gene expression of markers for differentiated cells in PDOs derived from metastatic lesions. Paradoxically, expression of potential intestinal stem cell markers was also decreased. We identified OLFM4 as the gene most strongly correlating with a stem-like cell cluster, and found OLFM4 cells to be capable of initiating organoid culture growth and differentiation capacity in primary PDOs. These cells were required for the efficient growth of primary PDOs but dispensable for metastatic PDOs. These observations demonstrate that metastatic lesions have a cellular composition distinct from that of primary tumors; patient-matched PDOs are a useful resource for analyzing metastatic CRC.
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http://dx.doi.org/10.1016/j.stemcr.2021.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072036PMC
April 2021

Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach.

Arch Toxicol 2021 05 5;95(5):1793-1803. Epub 2021 Mar 5.

UGC Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga - IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.

Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69-84%). A simplified logistic regression model developed for practical use, consisting of patient's age, drug's lipoaffinity, and hybridization ratio, achieved a fair prediction (68-74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient's age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.
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http://dx.doi.org/10.1007/s00204-021-03013-3DOI Listing
May 2021

Liquid Biopsy Cell-free DNA Biomarkers in Patients With Oligometastatic Colorectal Cancer Treated by Ablative Radiotherapy.

Anticancer Res 2021 Feb;41(2):829-834

Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Chiba, Japan.

Background/aim: To investigate the usefulness of cell-free DNA (cfDNA) in patients with oligometastasis.

Patients And Methods: This study included oligometastatic colorectal cancer (CRC) patients who underwent ablative irradiation using stereotactic body radiotherapy or proton beam therapy for metastatic lesions at a single institution. cfDNA was purified from the plasma of pretreated patients and gene mutations were analyzed by next-generation sequencing. Progression-free survival (PFS) was statistically compared according to gene mutation, clonality or allele frequency.

Results: A total of 20 patients were analyzed. Mutations were detected in the following genes; TP53 (45%), APC (40%), KRAS (15%), PIK3CA (15%), NF1 (5%), BRCA1 (5%), ERBB2 (5%), FBXW7 (5%), KIT (10%), and HRAS (10%). Patients with multi-clonality of gene mutation showed tendency for poor PFS (p=0.07). Among 7 patients whose metastatic site was the lung, those with no cfDNA detected had significantly better PFS than those with cfDNA (p=0.02).

Conclusion: cfDNA profiles could be predictive tools for early recurrence of oligometastatic CRC patients after ablative radiotherapy.
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http://dx.doi.org/10.21873/anticanres.14835DOI Listing
February 2021

Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study.

BMC Cancer 2021 Jan 25;21(1):97. Epub 2021 Jan 25.

HealthCore, Inc., 123 Justison Street, Suite 200, Wilmington, DE, 19801, USA.

Background: There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer.

Methods: We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted.

Results: There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1-8.4).

Conclusions: This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).
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http://dx.doi.org/10.1186/s12885-021-07790-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831235PMC
January 2021

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens.

Sci Rep 2021 01 11;11(1):341. Epub 2021 Jan 11.

Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan.

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.
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http://dx.doi.org/10.1038/s41598-020-79385-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801605PMC
January 2021

Investigation of the Distribution and Content of Acetylcholine, a Novel Functional Compound in Eggplant.

Foods 2021 Jan 4;10(1). Epub 2021 Jan 4.

Department of Science and Technology, Graduate School of Medicine, Science and Technology, Shinshu University, 8304, Minamiminowa, Nagano 399-4598, Japan.

Eggplants are rich in acetylcholine (ACh), which can improve high blood pressure and negative psychological states. However, information on ACh content in individual parts of eggplant and the changes in ACh content during eggplant development is limited. Therefore, we investigated the ACh content in various parts of eggplant, namely, the leaf, root, bud, calyx, ovary, fruit, exocarp, mesocarp, partition, placenta, core, fruit base, fruit center, and fruit top in 26 eggplant varieties. Furthermore, the effect of heat treatment on ACh content was investigated. The ACh content significantly differed among the eggplant varieties. The difference between the varieties with the highest and lowest ACh content was 100-fold (Tosataka: 11 ± 0.61 mg/100 g fresh weight (FW) and Ryoma: 0.11 ± 0.046 mg/100 g FW, respectively). Eggplant fruit presented the highest ACh content (4.8 mg/100 g FW); it was three times higher than that in other parts combined (1.6 mg/100 g FW). The root contained the lowest ACh content among all parts. The ACh content increased with growth after flowering. The ACh content in the fruit 1.5 months after flowering was 400 times that in the ovary. ACh was uniformly distributed in eggplant flesh. Heat treatment did not cause ACh loss in eggplant. Thus, eggplant is an excellent raw material for functional foods.
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http://dx.doi.org/10.3390/foods10010081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823263PMC
January 2021

Aberrant splicing isoforms detected by full-length transcriptome sequencing as transcripts of potential neoantigens in non-small cell lung cancer.

Genome Biol 2021 01 4;22(1). Epub 2021 Jan 4.

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.

Background: Long-read sequencing of full-length cDNAs enables the detection of structures of aberrant splicing isoforms in cancer cells. These isoforms are occasionally translated, presented by HLA molecules, and recognized as neoantigens. This study used a long-read sequencer (MinION) to construct a comprehensive catalog of aberrant splicing isoforms in non-small-cell lung cancers, by which novel isoforms and potential neoantigens are identified.

Results: Full-length cDNA sequencing is performed using 22 cell lines, and a total of 2021 novel splicing isoforms are identified. The protein expression of some of these isoforms is then validated by proteome analysis. Ablations of a nonsense-mediated mRNA decay (NMD) factor, UPF1, and a splicing factor, SF3B1, are found to increase the proportion of aberrant transcripts. NetMHC evaluation of the binding affinities to each type of HLA molecule reveals that some of the isoforms potentially generate neoantigen candidates. We also identify aberrant splicing isoforms in seven non-small-cell lung cancer specimens. An enzyme-linked immune absorbent spot assay indicates that approximately half the peptide candidates have the potential to activate T cell responses through their interaction with HLA molecules. Finally, we estimate the number of isoforms in The Cancer Genome Atlas (TCGA) datasets by referring to the constructed catalog and found that disruption of NMD factors is significantly correlated with the number of splicing isoforms found in the TCGA-Lung Adenocarcinoma data collection.

Conclusions: Our results indicate that long-read sequencing of full-length cDNAs is essential for the precise identification of aberrant transcript structures in cancer cells.
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http://dx.doi.org/10.1186/s13059-020-02240-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780684PMC
January 2021

Comparative study on pharmacokinetics and toxicity of intravitreal and sub-Tenon injection of triamcinolone acetonide in ocular tissues.

Int J Ophthalmol 2020 18;13(12):1864-1871. Epub 2020 Dec 18.

Sagami Research Laboratories, Wakamoto Pharmaceutical Corporation Ltd., Kanagawa 2580018, Japan.

Aim: To compare the differences in kinetics, distribution, and toxicity of triamcinolone acetonide (TA) between the injection methods, sub-Tenon and intravitreal injections in rabbit ocular tissues.

Methods: TA was injected into the vitreous or the sub-Tenon in rabbits. For pharmacokinetic study, rabbits were sacrificed periodically and then TA in blood and ocular tissues (retina/choroids, vitreous, and aqueous humor) were measured over 91d. For toxicological study, clinical signs, slit-lamp microscopic examination, ophthalmological test were performed. The eyeballs and surrounding tissues were collected and fixed with glutaraldehyde-formalin solution, and then paraffin embedded for histological investigation.

Results: Higher levels of TA were distributed in the intraocular tissues when injected into the vitreous compared to the sub-Tenon. Conversely, TA level was remarkably lower in the rabbits which received intravitreal TA injections than those treated with sub-Tenon injection throughout the study period in plasma. Optical discharge probably caused by systemic circulation of TA was observed by receiving sub-Tenon TA injection. Meanwhile, technic-associated toxicological ocular symptoms and findings were more frequently observed in intravitreal injection than in sub-Tenon injection.

Conclusion: There are significant differences in kinetics and distribution of TA in vitreous body, aqueous humor and plasma, between the two injection methods. Although further study is needed to explain the species difference between human and rabbit, it is assumed that the difference in the frequency of intraocular pressure elevation and cataract formation by TA between the two injection methods are directly related to the TA concentrations in aqueous humor and vitreous body in each injection methods. Systemic toxicity and technic-associated toxicity are also closely related to kinetics of TA in plasma and each injection method itself, respectively.
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http://dx.doi.org/10.18240/ijo.2020.12.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708352PMC
December 2020

Manufacturing micropatterned collagen scaffolds with chemical-crosslinking for development of biomimetic tissue-engineered oral mucosa.

Sci Rep 2020 12 17;10(1):22192. Epub 2020 Dec 17.

Division of Biomimetics, Faculty of Dentistry and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

The junction between the epithelium and the underlying connective tissue undulates, constituting of rete ridges, which lack currently available soft tissue constructs. In this study, using a micro electro mechanical systems process and soft lithography, fifteen negative molds, with different dimensions and aspect ratios in grid- and pillar-type configurations, were designed and fabricated to create three-dimensional micropatterns and replicated onto fish-scale type I collagen scaffolds treated with chemical crosslinking. Image analyses showed the micropatterns were well-transferred onto the scaffold surfaces, showing the versatility of our manufacturing system. With the help of rheological test, the collagen scaffold manufactured in this study was confirmed to be an ideal gel and have visco-elastic features. As compared with our previous study, its mechanical and handling properties were improved by chemical cross-linking, which is beneficial for grafting and suturing into the complex structures of oral cavity. Histologic evaluation of a tissue-engineered oral mucosa showed the topographical microstructures of grid-type were well-preserved, rather than pillar-type, a well-stratified epithelial layer was regenerated on all scaffolds and the epithelial rete ridge-like structure was developed. As this three-dimensional microstructure is valuable for maintaining epithelial integrity, our micropatterned collagen scaffolds can be used not only intraorally but extraorally as a graft material for human use.
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http://dx.doi.org/10.1038/s41598-020-79114-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747639PMC
December 2020

Relationship between cervical elastography and spontaneous onset of labor.

Sci Rep 2020 11 12;10(1):19685. Epub 2020 Nov 12.

Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan.

Cervical elastography might be an objective method for evaluating cervical ripening during pregnancy, but its usefulness has not been fully investigated. We examined the significance of cervical elastography in the last trimester of pregnancy. Cervical elastography was performed at weekly checkups after 36 weeks of gestation in 238 cases delivered at our hospital from 2017 to 2018. The correlation with the onset time of natural labor, which is an index for judging maternal delivery preparation status, was examined. A total of 765 examinations were conducted, and cervical stiffness determined by cervical elastography was positively correlated with the Bishop score (r = 0.46, p < 0.0001). When examined separately for each week, only the examinations performed at 39 weeks were associated with the onset of spontaneous labor up to 7 days later (p = 0.0004). Furthermore, when stratified and analyzed by the Bishop score at 39 weeks of gestation, cervical elastography was associated with the occurrence of spontaneous labor pain for up to seven days in the groups with Bishop scores of 3-5 and 6-8 (p = 0.0007 and p = 0.03, respectively). In conclusion, cervical elastography at 39 weeks of pregnancy is useful for judging the delivery time.
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http://dx.doi.org/10.1038/s41598-020-76753-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661529PMC
November 2020

Comparison of trough concentration and area under the curve of vancomycin associated with the incidence of nephrotoxicity and predictors of a high trough level.

J Infect Chemother 2021 Mar 2;27(3):455-460. Epub 2020 Nov 2.

Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Tokyo, Japan. Electronic address:

Purpose: A high vancomycin trough concentration during therapy is associated with increased nephrotoxicity, and the recent guidelines for therapeutic monitoring of vancomycin recommend target of the ratio of area under the curve (AUC) to minimum inhibitory concentration. We aimed to determine vancomycin trough concentration and AUC that induce nephrotoxicity and evaluate predictive factors associated with a high serum vancomycin trough level according to the initial dosing strategy.

Methods: We conducted a retrospective cohort study in patients administered intravenous vancomycin from June 2013 to February 2017. Totally, 346 patients were included.

Results: 38 experienced nephrotoxicity during therapy. The both trough level and AUC were significant risk factors for the occurrence of vancomycin induced-nephrotoxicity (p < 0.001, p = 0.001). The exposure-response analysis revealed that the trough level of 15 μg/mL was associated with 12.0% nephrotoxicity incidence and AUC of 600 was associated with 12.9% nephrotoxicity incidence. During the treatment, 90 patients had an initial trough concentration of ≥15 μg/mL, and 124 patients had AUC of ≥600 μg h/mL. The multiple logistic regression analysis revealed body weight (p = 0.001), serum creatinine level (p = 0.028), daily vancomycin dose (p = 0.001), and ICU (p = 0.015) were independent predictive factors for a high trough concentration. And same factors were selected for the high AUC.

Conclusion: The risk factors for vancomycin induced nephrotoxicity were comparable in both trough concentration and AUC. The incidence of nephrotoxicity can be reduced by controlling vancomycin trough concentration similarly AUC and promoting antimicrobial stewardship.
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http://dx.doi.org/10.1016/j.jiac.2020.10.014DOI Listing
March 2021
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