Publications by authors named "Shinya Sato"

309 Publications

The response-guided ATG treatment provides a survival benefit and KPS recovery for patients with steroid refractory acute GVHD: The Nagasaki Transplant Group Experience.

Transpl Immunol 2021 Aug 28;67:101417. Epub 2021 May 28.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan; Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is a serious complication that negatively affects the prognosis and quality of life of patients who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Antithymocyte globulin (ATG) is one of the second-line treatments for SR-aGVHD. We retrospectively evaluated Karnofsky Performance Status (KPS) recovery and clinical response in 11 patients who received the response-guided low-dose ATG treatment for SR-aGVHD after allo-HSCT using alternative donors. The median dose of ATG per cycle was 1.0 mg/kg (range, 1.0-1.25 mg/kg) and the median number of cycles of ATG was 2 (range, 1-4). The overall response rate was 63.6%, and the estimated overall survival rate at 1 year was 63.6%. Two out of seven patients who survived 1 year after the response-guided ATG treatment had KPS of 80 or higher. The remaining 5 patients had KPS of lower than 80 due to moderate chronic GVHD (cGVHD) and/or ≥grade 3 infectious complications. Based on the poor prognosis of patients with SR-aGVHD, the response-guided ATG treatment represents one therapeutic option. The present results also suggest that chronic GVHD and infectious complications after the response-guided ATG treatment were associated with decreased KPS recovery and impaired social function.
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http://dx.doi.org/10.1016/j.trim.2021.101417DOI Listing
August 2021

A Patient with a Type I Split Cord Malformation and an Open Myelomeningocele without Advanced Lower Limb Paresis: A Case Report and a Review of the Literature.

NMC Case Rep J 2021 Apr 2;8(1):75-78. Epub 2021 Apr 2.

Department of Neurosurgery, Yamagata University, Faculty of Medicine, Yamagata, Yamagata, Japan.

We report a rare case of a split cord malformation (SCM) combined with an open myelomeningocele (MMC) on the right hemicord. The patient was a male neonate, who exhibited an MMC in the lumbosacral region at birth. Both of his lower limbs moved with slight spasticity, but no atrophic changes or clubfoot deformities were seen. Three-dimensional computed tomography (CT) demonstrated a bony septum, and the patient was diagnosed with a type I SCM. Magnetic resonance imaging (MRI) showed an MMC on the right hemicord (a hemimyelomeningocele). The repair of the open MMC and the removal of the septum were performed immediately to prevent infection and neurological deterioration. Intraoperatively, the right hemicord was thinner than the left hemicord. No additional neurological deficits or complications appeared during treatment. Our findings suggest that when a minor hemicord is affected by both an SCM and an open MMC, good functional outcomes of the lower limbs can be achieved.
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http://dx.doi.org/10.2176/nmccrj.cr.2020-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116924PMC
April 2021

Evaluating the efficacy and safety of ureteral stent placement as a preoperative procedure for gynecological cancer surgeries: A retrospective cohort study.

J Obstet Gynaecol Res 2021 May 11. Epub 2021 May 11.

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori Prefecture, Japan.

Aim: To evaluate the efficacy and safety of ureteral stent placement (USP) as a preoperative procedure for gynecological cancer surgeries.

Methods: This was a single-institution retrospective cohort study of 259 patients with gynecological cancer who underwent laparotomy. In 126 patients (USP+ group), a ureteral stent was inserted into the bilateral ureters after the induction of general anesthesia. The remaining 133 patients (USP- group) did not undergo USP. We compared operation time, blood loss, and frequency of laparotomy-related perioperative urinary complications between the groups. The stent was removed 5-7 days postoperatively. Patients were evaluated for signs of hydronephrosis at discharge. The Fisher's exact test was used to investigate the significance of differences in patient characteristics, and multivariate analysis was performed using a Cox proportional hazards model. A p-value of <0.05 was considered statistically significant.

Results: There were no significant differences in age and body mass index between the groups. Two patients in the USP- group experienced intraoperative ureteral injury. Total operation time and blood loss were significantly increased in the USP+ group. The risk of bladder tamponade and postoperative hydronephrosis was influenced by USP. USP was unaffected by a history of abdominal surgery, stage of tumor progression, lymphadenectomy type, or hysterectomy type.

Conclusions: The incidence of bladder tamponade and hydronephrosis postoperatively was significantly higher in patients with USP than in those without USP.
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http://dx.doi.org/10.1111/jog.14829DOI Listing
May 2021

Machine learning-based image analysis for accelerating the diagnosis of complicated preneoplastic and neoplastic ductal lesions in breast biopsy tissues.

Breast Cancer Res Treat 2021 May 1. Epub 2021 May 1.

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.

Purpose: Diagnosis of breast preneoplastic and neoplastic lesions is difficult due to their similar morphology in breast biopsy specimens. To diagnose these lesions, pathologists perform immunohistochemical analysis and consult with expert breast pathologists. These additional examinations are time-consuming and expensive. Artificial intelligence (AI)-based image analysis has recently improved, and may help in ordinal pathological diagnosis. Here, we showed the significance of machine learning-based image analysis of breast preneoplastic and neoplastic lesions for facilitating high-throughput diagnosis.

Methods: Images were obtained from normal mammary glands, hyperplastic lesions, preneoplastic lesions and neoplastic lesions, such as usual ductal hyperplasia (UDH), columnar cell lesion (CCL), ductal carcinoma in situ (DCIS), and DCIS with comedo necrosis (comedo DCIS) in breast biopsy specimens. The original enhanced convoluted neural network (CNN) system was used for analyzing the pathological images.

Results: The AI-based image analysis provided the following area under the curve values (AUC): normal lesion versus DCIS, 0.9902; DCIS versus comedo DCIS, 0.9942; normal lesion versus CCL, 0.9786; and UDH versus DCIS, 1.000. Multiple comparison analysis showed precision and recall scores similar to those of single comparison analysis. Based on the gradient-weighted class activation mapping (Grad-CAM) used to visualize the important regions reflecting the result of CNN analysis, the ratio of stromal tissue in the whole weighted area was significantly higher in UDH and CCL than that in DCIS.

Conclusions: These analyses may provide a more accurate and rapid pathological diagnosis of patients. Moreover, Grad-CAM identifies uncharted important histological characteristics for newer pathological findings and targets of research for understanding diseases.
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http://dx.doi.org/10.1007/s10549-021-06243-2DOI Listing
May 2021

Relationship between resting medial gastrocnemius stiffness and drop jump performance.

J Electromyogr Kinesiol 2021 Jun 20;58:102549. Epub 2021 Apr 20.

Graduate School of Engineering and Science, Shibaura Institute of Technology, Saitama, Japan; College of System Engineering and Science, Shibaura Institute of Technology, Saitama, Japan.

Although the influence of the series elastic element of the muscle-tendon unit on jump performance has been investigated, the corresponding effect of the parallel elastic element remains unclear. This study examined the relationship between the resting calf muscle stiffness and drop jump performance. Twenty-four healthy men participated in this study. The shear moduli of the medial gastrocnemius and the soleus were measured at rest as an index of muscle stiffness using ultrasound shear wave elastography. The participants performed drop jumps from a 15 cm high box. The Spearman rank correlation coefficient was used to examine the relationships between shear moduli of the muscles and drop jump performance. The medial gastrocnemius shear modulus showed a significant correlation with the drop jump index (jump height/contact time) (r = 0.414, P = 0.044) and jump height (r = 0.411, P = 0.046), but not with contact time (P > 0.05). The soleus shear modulus did not correlate with these jump parameters (P > 0.05). These results suggest that the resting medial gastrocnemius stiffness can be considered as one of the factors that influence drop jump performance. Therefore, increase in resting muscle stiffness should enhance explosive athletic performance in training regimens.
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http://dx.doi.org/10.1016/j.jelekin.2021.102549DOI Listing
June 2021

Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component.

Transl Lung Cancer Res 2021 Mar;10(3):1292-1304

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.

Background: Fetal adenocarcinoma of the lung is a rare variant of lung adenocarcinoma and is subcategorized into low-grade and high-grade (H-FLAC) fetal adenocarcinoma. We previously reported poor prognosis in pulmonary adenocarcinomas with an H-FLAC component; however, the genetic abnormalities involved in H-FLAC remain unclear. Therefore, this study aimed to elucidate molecular abnormalities as potential therapeutic targets for H-FLACs.

Methods: We performed immunohistochemical analysis and comprehensive genetic analyses using whole-exome sequencing in 16 lung cancer samples with an H-FLAC component. DNA was extracted from formalin-fixed paraffin-embedded tissues after macrodissection of the H-FLAC component.

Results: Cancer-related mutations were identified in (7/16 cases), (6/16 cases), (4/16 cases), (3/16 cases), (3/16 cases), (2/16 cases), and (1/16 cases). A high tumor mutation burden of ≥10 mutations per megabase was observed in 3/16 cases. A high microsatellite instability was not detected in any case. Based on the cosine similarity with the Catalogue of Somatic Mutations in Cancer mutational signatures, H-FLACs were hierarchically clustered into three types: common adenocarcinoma-like (five cases), surfactant-deficient (ten cases), and signatures 2 and 13-related (one case). All common adenocarcinoma-like cases presented thyroid transcription factor-1 (TTF-1) expression, whereas surfactant-deficient cases often presented loss of TTF-1 and surfactant protein expression and included cases with mutations in the surfactant system genes and . H-FLACs displayed low programmed death ligand-1 (PD-L1) expression (1-49% of tumor cells) in 5/16 cases, and no case displayed high PD-L1 expression (≥50% of tumor cells).

Conclusions: This study indicates that lung cancers with an H-FLAC component rarely harbor currently targetable driver gene mutations for lung cancer but display a high frequency of mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.
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http://dx.doi.org/10.21037/tlcr-20-1158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044470PMC
March 2021

Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892;

Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. (), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.
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http://dx.doi.org/10.1073/pnas.2019633118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092404PMC
April 2021

Docetaxel and carboplatin chemotherapy for treating patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix: a phase II study.

Int J Clin Oncol 2021 Apr 7. Epub 2021 Apr 7.

Matsue City Hospital, 32-1, Noshira-cho, Matsue, Shimane, 690-8509, Japan.

Background: This phase II study evaluated the efficacy and safety of docetaxel/carboplatin chemotherapy for treating patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix.

Methods: A total of 50 patients with International Federation of Gynecology and Obstetrics stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix were enrolled and administered docetaxel at a dose of 60 mg/m, followed by carboplatin at a dose based on the area under the receiver operating characteristic curve of 6. The treatments were repeated every 21 days until disease progression or unacceptable adverse events. Except for two patients, 48 were eligible for evaluation. Another patient withdrew consent before treatment; adverse events were evaluated in 47.

Results: The response rate was 47.9% with 5 patients achieving complete response, 18 partial response, 14 stable disease, and 6 progressive disease. The disease control rate was 77.1%. With a median follow-up duration of 368 days, the median progression-free survival and overall survival were 6.1 months (95% CI 5.5-8.6) and 15.8 months (95% CI 18.2-28.3), respectively. The most frequent grade 3 and grade 4 hematological toxicity was neutropenia, with 38 patients (81%) having grade 4 and 4 (9%) having grade 3 neutropenia. The non-hematological toxicities were mainly grade 1 or 2 in severity.

Conclusion: Docetaxel/carboplatin chemotherapy was effective, with a higher disease control rate and well-tolerated chemotherapeutic regimen for patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix.
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http://dx.doi.org/10.1007/s10147-021-01903-1DOI Listing
April 2021

Tissue factor pathway inhibitor‑2 is specifically expressed in ovarian clear cell carcinoma tissues in the nucleus, cytoplasm and extracellular matrix.

Oncol Rep 2021 03 20;45(3):1023-1032. Epub 2021 Jan 20.

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241‑8515, Japan.

Tissue factor pathway inhibitor‑2 (TFPI‑2) is a promising candidate as a serum biomarker of ovarian clear cell carcinoma (OCCC), a lethal histological subtype of epithelial ovarian cancer (EOC). TFPI‑2 is a secreted serine protease inhibitor that suppresses cancer progression through the inhibition of matrix protease activities. Previous studies have also identified TFPI‑2 in the nucleus, and a possible function of nuclear TFPI‑2 as a transcriptional repressor of matrix metalloproteinase‑2 (MMP‑2) was recently demonstrated. We are currently establishing TFPI‑2 as a serum biomarker for OCCC patients; however, TFPI‑2 expression in OCCC tissues has not been previously investigated. In the present study, we examined TFPI‑2 expression and its localization in 11 OCCC cell lines by western blotting and enzyme‑linked immune assay. Four cell lines expressed TFPI‑2 in the nucleus, cytoplasm and culture plate-attached extracellular fraction, while four other cell lines expressed TFPI‑2 only in the extracellular fraction. In the remaining three cell lines, TFPI‑2 was not identified in any fraction. The amount of secreted soluble TFPI‑2 showed similar trends to that of the plate‑attached fraction. We next investigated the expression levels and distribution of TFPI‑2 in surgically resected EOC tissues by immunohistochemistry. In 52 of the 77 (67.5%) OCCC tumors, TFPI‑2 expression was detected in at least one of the nuclear, cytoplasmic and extracellular matrix fractions. In contrast, we did not identify TFPI‑2 in the other EOC subtypes (n=65). TFPI‑2‑positive expression distinguished CCC from the other EOC tissues with a sensitivity of 67.5% and specificity of 100%. Although the inherent tumor suppressor function, statistical analyses failed to demonstrate correlations between TFPI‑2 expression and clinical parameters, including 5‑year overall survival, except for the patient age. In conclusion, we identified TFPI‑2 expression in the nucleus, cytoplasm and extracellular matrix in OCCC tissues. The high specificity of TFPI‑2 may support its use for diagnosis of OCCC in combination with existing markers.
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http://dx.doi.org/10.3892/or.2021.7944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859994PMC
March 2021

Efficacy and Cardiovascular Adverse Events of Long-term Treatment with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Report from the Nagasaki CML Study Group.

Intern Med 2021 Feb 22. Epub 2021 Feb 22.

Department of Hematology, Sasebo City General Hospital, Japan.

Objective The standard treatment for chronic myeloid leukemia (CML) is the continuous use of tyrosine kinase inhibitors (TKIs), which results in a favorable prognosis for the majority of patients. Recent studies have identified cardiovascular diseases (CVDs) as late adverse events (AEs) related to TKIs. In this study, we evaluated the long-term efficacy and AEs of TKIs, focusing on CVDs. Methods We performed a retrospective survey of CML patients (diagnosed from 2001 to 2016) treated with TKIs in Nagasaki Prefecture. Clinical data were obtained from their medical records. We analyzed the survival, estimated cumulative incidence of CVDs, and risk factors for CVD among CML patients treated with TKIs. Results The overall survival rate of 264 CML patients treated with TKIs (median age 58 years old) was 89.6% [95% confidence interval (CI), 84.9-92.9%], and 80.5% (95% CI, 73.4-85.9%) at 5 and 10 years after the CML diagnosis, respectively. CVD events occurred in 26 patients (9.8%, median age 67.5 years old) with a median 65.5 months of TKI treatment. The cumulative incidences at 2 and 5 years was 2.4% (95% CI, 1.0-4.8%) and 5.2% (95% CI, 2.8-8.6%), respectively. Hypertension and a high SCORE chart risk at the diagnosis of CML were associated with CVD events during TKI treatment. Conclusion TKI treatment contributed to the long-term survival of CML patients in Nagasaki Prefecture in a "real-world" setting, but the incidence of CVDs seemed to be increased in these patients. A proper approach to managing risk factors for CVD is warranted to reduce CVD events during TKI treatment.
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http://dx.doi.org/10.2169/internalmedicine.6620-20DOI Listing
February 2021

Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy.

J Clin Med 2021 Feb 7;10(4). Epub 2021 Feb 7.

Department of Gastroenterology and Hepatology, Nara Medical University, Nara 634-8521, Japan.

Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP ( = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.
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http://dx.doi.org/10.3390/jcm10040629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914951PMC
February 2021

Clonal hematopoiesis in adult pure red cell aplasia.

Sci Rep 2021 Jan 26;11(1):2253. Epub 2021 Jan 26.

Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.
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http://dx.doi.org/10.1038/s41598-021-81890-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838416PMC
January 2021

Association between peripheral eosinophils and clinical outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

Pol Arch Intern Med 2021 02 25;131(2):152-160. Epub 2021 Jan 25.

Division of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Introduction: Programmed cell death ligand 1 is considered a predictor of the therapeutic effect of immune checkpoint inhibitors (ICPIs), but a more simple and useful predictor is needed.

Objectives: The aim of this study was to identify the relationship between eosinophil counts and percentages and response to ICPI therapy.

Patients And Methods: In 190 patients with non-small cell lung cancer (NSCLC) treated with ICPI therapy, peripheral eosinophil counts and percentages at the time of ICPI therapy initiation, the maximum counts and percentages of eosinophils during ICPI therapy, response to therapy, and time to treatment failure (TTF) were investigated.

Results: Both an increase in the peripheral eosinophil count and an elevation of eosinophil percentage following the initiation of ICPI therapy were observed, regardless of whether the patients had controlled or progressive disease. The median time to the maximum eosinophil percentage was 5 weeks in patients with controlled disease and 2 weeks in those with progressive disease. The cutoff value for the maximum eosinophil counts and percentage during ICPI therapy was set at 300/μl and 5%, respectively, to identify the presence or absence of a therapeutic effect. Time to treatment failure was longer in patients with maximum eosinophil counts exceeding 300/μl and a maximum eosinophil percentage above 5%. In a multivariable analysis, a maximum eosinophil percentage of 5% during ICPI therapy was a significant predictive factor for therapeutic efficacy.

Conclusions: The measurement of peripheral eosinophils up to around 5 weeks following the initiation of treatment, especially the maximum eosinophils count and percentage, might provide useful information about the efficacy of ICPIs.
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http://dx.doi.org/10.20452/pamw.15776DOI Listing
February 2021

Differentially methylated CpG sites related to fertility in Japanese Black bull spermatozoa: epigenetic biomarker candidates to predict sire conception rate.

J Reprod Dev 2021 Apr 14;67(2):99-107. Epub 2021 Jan 14.

Institute of Livestock and Grassland Science, NARO, Ibaraki 305-0901, Japan.

For semen suppliers, predicting the low fertility of service bull candidates before artificial insemination would help prevent economic loss; however, predicting bull fertility through in vitro assessment of semen is yet to be established. In the present study, we focused on the methylated CpG sites of sperm nuclear DNA and examined methylation levels to screen new biomarkers for predicting bull fertility. In frozen-thawed semen samples collected from Japanese Black bulls, for which the sire conception rate (SCR) was recorded, the methylation level of each CpG site was analyzed using human methylation microarray. According to regression analysis, 143 CpG sites related to SCR were significantly differentially methylated. Whole genome bisulfite sequence data were obtained from three semen samples and the differentially methylated regions (DMRs) that included the target CpG sites selected by human methylation microarray were confirmed. Using combined bisulfite restriction analysis, fertility-related methylation changes were detected in 10 DMRs. With the exception of one DMR, the methylation levels of these DMRs were significantly different between groups with high fertility (> 50%) and low fertility (< 40%). From multiple regression analysis of methylation levels and SCR, three DMRs were selected that could effectively predict bull fertility. We suggest that these fertility-related differences in spermatozoal methylation levels could be new epigenetic biomarkers for predicting bull fertility.
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http://dx.doi.org/10.1262/jrd.2020-137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075730PMC
April 2021

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

Sci Rep 2021 Jan 12;11(1):607. Epub 2021 Jan 12.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.
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http://dx.doi.org/10.1038/s41598-020-79833-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804194PMC
January 2021

Pro-inflammatory cytokines suppress HYBID (hyaluronan (HA) -binding protein involved in HA depolymerization/KIAA1199/CEMIP) -mediated HA metabolism in human skin fibroblasts.

Biochem Biophys Res Commun 2021 02 8;539:77-82. Epub 2021 Jan 8.

Department of Cosmetic Health Science, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan. Electronic address:

In the skin, the metabolism of hyaluronan (HA) is highly regulated. Aging leads to chronic low-grade inflammation, which is characterized by elevated levels of pro-inflammatory cytokines; however, the relationship between inflammation and HA metabolism is not clear. Herein, we investigated the effects of a mixture of pro-inflammatory cytokines containing TNF-α, IL-1β, and IL-6 on HA metabolism in human skin fibroblasts. Treatment with the cytokine mixture for 24 h suppressed HA depolymerization via downregulation of HYBID (HA-binding protein involved in HA depolymerization/KIAA1199/CEMIP) and promoted HA synthesis via upregulation of HAS2 in human skin fibroblasts. Moreover, HAS2-dependent HA synthesis was driven mainly by IL-1β with partial contribution from TNF-α. Transmembrane protein 2 (TMEM2/CEMIP2), which was previously reported as a candidate hyaluronidase, was upregulated by the cytokine mixture, suggesting that TMEM2 might not function as a hyaluronidase in human skin fibroblasts. Furthermore, the effects of the cytokine mixture on HA metabolism were observed in fibroblasts after 8 days of treatment with cytokines during three passages. Thus, we have shown that HYBID-mediated HA metabolism is negatively regulated by the pro-inflammatory cytokine mixture, providing novel insights into the relationship between inflammation and HA metabolism in the skin.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.082DOI Listing
February 2021

Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway.

J Nutr Biochem 2021 03 31;89:108573. Epub 2020 Dec 31.

Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan.

Alcoholic liver disease (ALD)-related fibrosis results from a variety of mechanisms including the accumulation of acetaldehyde, reactive oxygen species, and hepatic overload of endogenous lipopolysaccharide (LPS). Alcohol cessation is the therapeutic mainstay for patients with all stages of ALD, whereas pharmacological strategies for liver fibrosis have not been established. Sulforaphane, a phytochemical found in cruciferous vegetables, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts anticancer, antidiabetic, and antimicrobial effects; however, few studies investigated its efficacy in the development of ALD-related fibrosis. Herein, we investigated the effect of sulforaphane on acetaldehyde metabolism and liver fibrosis in HepaRG and LX-2 cells, human hepatoma and hepatic stellate cell lines, respectively, as well as in a mouse model of alcoholic liver fibrosis induced by ethanol plus carbon tetrachloride (EtOH/CCl). Sulforaphane treatment induced the activity of acetaldehyde-metabolizing mitochondrial aldehyde dehydrogenase in HepaRG cells and suppressed the acetaldehyde-induced proliferation and profibrogenic activity in LX-2 cells with upregulation of Nrf2-regulated antioxidant genes, including HMOX1, NQO1, and GSTM3. Moreover, sulforaphane attenuated the LPS/toll-like receptor 4-mediated sensitization to transforming growth factor-β with downregulation of NADPH oxidase 1 (NOX1) and NOX4. In EtOH/CCl-treated mice, oral sulforaphane administration augmented hepatic acetaldehyde metabolism. Additionally, sulforaphane significantly inhibited Kupffer cell infiltration and fibrosis, decreased fat accumulation and lipid peroxidation, and induced Nrf2-regulated antioxidant response genes in EtOH/CCl-treated mice. Furthermore, sulforaphane treatment blunted hepatic exposure of gut-derived LPS and suppressed hepatic toll-like receptor 4 signaling pathway. Taken together, these results suggest sulforaphane as a novel therapeutic strategy in ALD-related liver fibrosis.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108573DOI Listing
March 2021

[Multiloculated Hydrocephalus Complicated by Meningitis and Ventriculitis Treated with Staged Fenestration:A Case Report].

No Shinkei Geka 2020 Dec;48(12):1121-1128

Department of Neurosurgery, Faculty of Medicine, Yamagata University.

Multiloculated hydrocephalus following severe meningitis with ventriculitis is often therapeutically challenging. Neonatal meningitis is commonly associated with ventricular inflammation, and approximately 30% of patients show septum formation. Although placement of a single ventriculoperitoneal shunt system could serve as optimal treatment for a multiloculated cerebrospinal cavity that is converted into a single chamber, multiple devices are often required for disease stability. We report a case of multiloculated hydrocephalus that occurred after meningitis in a patient who was successfully treated with a single shunt system using staged multimodality treatments.
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http://dx.doi.org/10.11477/mf.1436204335DOI Listing
December 2020

Ascites symptom inventory-7 is a valuable tool for evaluating the effectiveness of tolvaptan in patients with cirrhotic ascites.

Exp Ther Med 2021 Jan 10;21(1):30. Epub 2020 Nov 10.

Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan.

Patients with liver cirrhosis frequently experience non-specific symptoms and report severe reductions in their quality of life (QOL). The underlying mechanisms of the disease are multifactorial that may be specific to the disease or directly related to the liver. The major concern of liver cirrhosis with ascites, however, is the decreased QOL. Therefore, in the present study, the Ascites Symptom Inventory-7 (ASI-7) questionnaire was applied to subjectively evaluate the symptoms in patients with cirrhotic ascites following tolvaptan administration. In total, 69 patients with liver cirrhosis with ascites hospitalized to Nara Medical University were evaluated after being treated with tolvaptan (3.75-7.5 mg/day) and conventional diuretics between December 2013 and April 2018. A follow-up assessment was conducted 7 days after tolvaptan treatment, whilst ASI-7 was used on days 1 and 8 of the study. After an uneventful 7-day tolvaptan treatment regimens, 49 patients (71.0%) lost >1.5 kg of their body weight, who were referred to as responders, with the change in the ASI-7 score being found to correlate with the body weight change. By contrast, changes in urine volume did not correlate with those in the ASI-7 score. The responders experienced a greater reduction in the ASI-7 score after 7 days compared with those in the non-responders (P<0.01). ASI-7 scores were also found to correlate with body weight after tolvaptan administration. In conclusion, ASI-7 accurately reflected changes in body weight but not urine volume and results of the study highlighted the value of ASI-7 in the evaluation of ascitic volume and effectiveness of tolvaptan in cirrhotic ascites. The present clinical trial was registered onto the UMIN-Clinical Trial Registry on 1st March 2014 (registration no. UMIN000013095).
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http://dx.doi.org/10.3892/etm.2020.9462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690238PMC
January 2021

Effect of L-carnitine on health-related quality of life in patients with liver cirrhosis.

Biomed Rep 2020 Dec 20;13(6):65. Epub 2020 Oct 20.

Department of Gastroenterology and Metabolism, Nara Medical University, Kashihara, Nara 634-8522, Japan.

L-carnitine (4--trimethylammonium-3-hydroxybutyric acid) is the physiologically active form of carnitine and is a natural compound that has been shown to exhibit antioxidant activity. L-carnitine is used as a supplementary treatment in patients with cirrhosis with hepatic encephalopathy, hyperammonemia or muscle cramps. In the present study, the effect of L-carnitine supplementation on health-related quality of life in 30 patients with cirrhosis was prospectively examined. L-carnitine (1,800 mg/day) was administered orally for 6 months. To assess the effects of L-carnitine on chronic fatigue, patients filled out a self-report questionnaire regarding their physical and mental health. The levels of total and free carnitine, and acylcarnitine were found to be significantly higher 1, 3 and 6 months after therapy initiation compared with before treatment. Serum albumin levels were significantly increased 3 and 6 months after initiation of therapy. L-carnitine supplementation significantly increased the BAP/d-ROM ratio, a marker of antioxidant status in patients with cirrhosis. Changes in serum carnitine concentrations were positively correlated with changes in serum albumin levels (R=0.369; P=0.012), but not with changes in serum ammonia levels (R= 0.005; P=0.78). Total and mental health scores improved significantly, and physical scores improved marginally 3 and 6 months after initiation of L-carnitine. These findings may be attributed to the enhanced serum albumin levels and oxidative stress rather than the reduced serum ammonia levels. Based on these results, it is suggested that L-carnitine can potentially alleviate chronic fatigue, along with the increased BAP/d-ROM ratio, which were involved in increased oxidative stress in patients with cirrhosis. The specific mechanisms by which L-carnitine ameliorates chronic fatigue is not fully understood and requires further investigation.
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http://dx.doi.org/10.3892/br.2020.1372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605124PMC
December 2020

Accuracy of Fibrosis-4 Index in Identification of Patients with Cirrhosis Who Could Potentially Avoid Variceal Screening Endoscopy.

J Clin Med 2020 Oct 29;9(11). Epub 2020 Oct 29.

Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.

A potential restriction of the Baveno VI consensus, which helps to avoid unnecessary endoscopies, is the limited availability of FibroScan. We aimed to identify serum fibrosis indices that might aid in ruling out the presence of high-risk varices in cirrhotic patients. This retrospective study included 541 consecutive patients with cirrhosis who underwent endoscopy and had data available for nine serum fibrosis indices, including platelet count, hyaluronic acid, 7S fragment of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, fibrosis index based on four factors (FIB-4), aspartate transaminase/platelet ratio index and enhanced liver fibrosis score. Optimal index cutoffs for predicting high-risk varices were calculated in an estimation cohort ( = 127) and evaluated in a validation cohort ( = 351). The diagnostic performance of the indices was assessed by receiver operating characteristic curve analysis. In the estimation cohort, a FIB-4 cutoff of 2.78 provided the greatest diagnostic accuracy in predicting both all-grade and high-risk varices. FIB-4 had a negative predictive value of 1.00 for high-risk varices in both cohorts, and 21.3% (27/127) and 14.8% (52/351) of the estimation and validation cohorts, respectively, avoided esophagogastroduodenoscopy; no high-risk varices were missed in either cohort. FIB-4 correctly identifies the absence of high-risk varices in patients with cirrhosis. Therefore, those with a FIB-4 of ≥2.78 should undergo esophagogastroduodenoscopy, and FIB-4 determination should be recommended every 6-12 months concurrently with the other blood tests until the index value reaches 2.78 in those with a FIB-4 of <2.78.
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http://dx.doi.org/10.3390/jcm9113510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692323PMC
October 2020

Correction to: Programmed death 1 ligand (PD-L1) in solid cancers after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Nagasaki Transplant Group.

Int J Hematol 2020 Dec;112(6):906

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

In the original publication of the article, the authors would like to alter the color of characters in the Supplemental Table 1 and 2.
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http://dx.doi.org/10.1007/s12185-020-03019-0DOI Listing
December 2020

Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells.

Int J Mol Sci 2020 Oct 14;21(20). Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.

Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker and downregulating the anti-apoptotic markers and . Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes , , , and in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA.
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http://dx.doi.org/10.3390/ijms21207588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589854PMC
October 2020

Ripe for reassessment: A synthesis of available molecular data for the speciose diatom family Bacillariaceae.

Mol Phylogenet Evol 2021 05 13;158:106985. Epub 2020 Oct 13.

Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA.

The Bacillariaceae is a very species-rich family of raphid diatoms and includes the large and taxonomically difficult genus Nitzschia, whose species are often small-celled and finely structured and have few discrete morphological characters visible in the light microscope. The classification of Nitzschia is still mostly based on one developed in the second half of the 19th century by Grunow, who separated the genus into a series of sections largely on cell shape and symmetry, the position of the raphe, transverse extension of the fibulae, and folding of the valve. We assembled and analysed single-gene and concatenated alignments of nSSU, nLSU, rbcL, psbC and cox1 to test Grunow's and subsequent classifications and to examine selected morphological characters for their potential to help define monophyletic groups. The maximum likelihood trees were equivocal as to monophyly of the family itself but showed good support for each of eight main clades of Bacillariaceae, three of which corresponded more or less to existing genera (Hantzschia, Cylindrotheca and Bacillaria). The other five main clades and some subclades comprised groups of Nitzschia species or assemblies of Nitzschia species with other genera (Pseudo-nitzschia, Fragilariopsis, Neodenticula, Tryblionella, Psammodictyon). Relationships between most of the eight main clades were not resolved robustly but all analyses recovered Nitzschia as non-monophyletic. The Grunowian classification of Nitzschia into sections was not supported, though in some respects (e.g. treatment of sigmoid species) it is better than subsequent reclassifications. Several of the main clades and subclades are cryptic (lacking morphological synapomorphies) and homoplasy is common in both light microscopical and ultrastructural characters (to the extent that organisms initially assigned to the same species sometimes prove to belong to a different main clade). Nevertheless, some characters, including the structure of the raphe canal and girdle, seem to be sufficiently conservative evolutionarily to give a provisional estimate of relationships if molecular data are unavailable. No new formal classifications are proposed but various options are explored and research needs identified.
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http://dx.doi.org/10.1016/j.ympev.2020.106985DOI Listing
May 2021

Rhodopsin-mediated light-off-induced protein kinase A activation in mouse rod photoreceptor cells.

Proc Natl Acad Sci U S A 2020 10 12;117(43):26996-27003. Epub 2020 Oct 12.

Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, 606-8501 Kyoto, Japan.

Light-induced extrasynaptic dopamine release in the retina reduces adenosine 3',5'-cyclic monophosphate (cAMP) in rod photoreceptor cells, which is thought to mediate light-dependent desensitization. However, the fine time course of the cAMP dynamics in rods remains elusive due to technical difficulty. Here, we visualized the spatiotemporal regulation of cAMP-dependent protein kinase (PKA) in mouse rods by two-photon live imaging of retinal explants of PKAchu mice, which express a fluorescent biosensor for PKA. Unexpectedly, in addition to the light-on-induced suppression, we observed prominent light-off-induced PKA activation. This activation required photopic light intensity and was confined to the illuminated rods. The estimated maximum spectral sensitivity of 489 nm and loss of the light-off-induced PKA activation in rod-transducin-knockout retinas strongly suggest the involvement of rhodopsin. In support of this notion, rhodopsin-deficient retinal explants showed only the light-on-induced PKA suppression. Taken together, these results suggest that, upon photopic light stimulation, rhodopsin and dopamine signals are integrated to shape the light-off-induced cAMP production and following PKA activation. This may support the dark adaptation of rods.
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http://dx.doi.org/10.1073/pnas.2009164117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604457PMC
October 2020

Genetic factors for susceptibility to and manifestations of neuromyelitis optica.

Ann Clin Transl Neurol 2020 11 26;7(11):2082-2093. Epub 2020 Sep 26.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: To identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD).

Methods: Genome-wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti-aquaporin-4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA-DRB1 and HLA-DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD.

Results: A SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10 ). HLA-DRB1*08:02 (OR = 2.86, P = 3.03 × 10 ) and HLA-DRB1*16:02 (OR = 8.39, P = 1.92 × 10 ) were risk alleles for NMOSD susceptibility whereas HLA-DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10 ). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) gene was associated with disability score with genome-wide significance (rs1516512, P = 2.33 × 10 ) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD.

Interpretation: Specific HLA-DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD.
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http://dx.doi.org/10.1002/acn3.51147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664265PMC
November 2020

No clear survival benefit of azacitidine for lower-risk myelodysplastic syndromes: A retrospective study of Nagasaki.

Cancer Sci 2020 Dec 23;111(12):4490-4499. Epub 2020 Oct 23.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The efficacy of azacitidine (AZA) on survival of lower risk (LR) - myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long-term survival benefit of AZA for patients with LR-MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR-MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis-stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection-related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR-MDS patients.
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http://dx.doi.org/10.1111/cas.14653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734160PMC
December 2020

Eight-Week Low-Intensity Squat Training at Slow Speed Simultaneously Improves Knee and Hip Flexion and Extension Strength.

Front Physiol 2020 24;11:893. Epub 2020 Jul 24.

Graduate School of Engineering and Science, Shibaura Institute of Technology, Saitama, Japan.

Considering that the squat exercise requires flexion and extension of the knee and hip joints, a resistance training program based on squat exercises should efficiently increase the flexion and extension strength of both the knee and hip. To our knowledge, however, no study has simultaneously investigated the effects of squat training on both flexion and extension strength in both the knee and hip. Low-intensity squat exercises at slow speeds can be expected to effectively and safely improve knee and hip flexion and extension strength in a wide range of individuals. This study aimed to clarify whether knee and hip flexion and extension strength improved after an 8-week low-intensity squat training program at slow speed. Twenty-four untrained young men were randomly assigned to a training or control group. Participants in the training group performed 40% one-repetition maximum parallel squats at slow speed (4 s for concentric/eccentric actions), 3 days per week for 8 weeks. Before and after the intervention, isometric peak torque of the knee and hip flexors and extensors during maximal voluntary contraction (MVC) was determined. For the knee flexors and extensors, muscle volume was also measured. There were significant training-induced increases in peak torque ( < 0.05). The training effects on knee and hip extension torque (effect size = 0.36-0.38) were higher than those on knee and hip flexion torque (effect size = 0.09-0.13). The squat training used here increased both knee and hip flexion and extension strength, but the training effects on the flexion strength were less than those on the extension strength. Regarding the knee extensors, a significant training-related increase in muscle volume was found ( < 0.05) without neuromuscular adaptations. In addition, there were significant correlations between the training-induced increases in muscle volume and peak torque of KE. These results suggest that muscle hypertrophy may be responsible for increased muscle strength of the knee extensors after an 8-week low-intensity squat training program at slow speed.
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http://dx.doi.org/10.3389/fphys.2020.00893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396687PMC
July 2020

Effects of pretreatment radiological and pathological lymph node statuses on prognosis in patients with ovarian cancer who underwent interval debulking surgery with lymphadenectomy following neoadjuvant chemotherapy.

J Obstet Gynaecol Res 2021 Jan 23;47(1):152-158. Epub 2020 Aug 23.

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori, Japan.

Aim: To analyze whether radiological and pathological lymph node statuses affected prognosis in patients with epithelial ovarian cancer who underwent neoadjuvant chemotherapy followed by interval debulking surgery.

Methods: In total, 82 patients undergoing interval debulking surgery, including systematic retroperitoneal lymphadenectomy, were eligible for this study. We retrospectively analyzed the association among radiological diagnosed retroperitoneal lymphadenopathy by computed tomographic scan before (rLN) and after (yrLN) neoadjuvant chemotherapy, pathological lymph node metastasis (pLN) and prognosis. Patient survival distribution was calculated using the Kaplan-Meier method.

Results: There were 36 rLN+ cases (44%); there were no significant differences between rLN+ and rLN- with respect to progression-free survival and overall survival. Progression-free survival and overall survival did not differ between yrLN+ cases and yrLN- cases. Thirty-nine cases (47.5%) were pLN+, and both progression-free survival and overall survival were significantly shorter in pLN+ cases than in pLN- cases (P < 0.001 and P = 0.004, respectively). In univariate analysis, FIGO stage, pLN and surgical completion were prognostic factors for overall survival. Moreover, in multivariate analysis, pLN+ was the independent prognostic factor for progression-free survival (P = 0.001, 95% confidence interval: 1.911-15.69), and pLN and surgical completion were the only independent prognostic factors for overall survival (P = 0.046, P = 0.012).

Conclusion: Radiological lymph node status may not be a prognostic factor in patients with ovarian cancer who underwent neoadjuvant chemotherapy followed by interval debulking surgery. Pathological lymph node metastasis affects progression-free survival and overall survival.
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http://dx.doi.org/10.1111/jog.14446DOI Listing
January 2021

Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix.

Biochem Biophys Res Commun 2020 09 4;529(4):1195-1200. Epub 2020 Aug 4.

Organoid Biology Unit, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Electronic address:

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.
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http://dx.doi.org/10.1016/j.bbrc.2020.06.043DOI Listing
September 2020