Intratumoral reciprocal expression of monocarboxylate transporter 4 and glypican-3 in hepatocellular carcinomas

Abstract Objective We previously reported the identification of monocarboxylate transporter 4 (MCT4) and glypican-3 (GPC3) as prognostic factors for hepatocellular carcinoma (HCC), which are now considered significant poor prognostic factors for the disease. This study aimed to clarify the detailed interaction of these two factors in HCC to improve our understanding of aggressive HCC phenotypes. A total of 225 Japanese patients with HCC from our previous study were subjected to immunohistochemical analyses. Results The number of MCT4-positive (MCT4+) HCC cases was 47 (21%), and most MCT4+ HCC showed high GPC3 expression (94%, 44/47 cases). In 44 MCT4+/GPC3+ HCC cases, intratumoral heterogeneity of GPC3 or MCT4 expression was further evaluated. We observed reciprocal (inverse), synergistic, mixed reciprocal and synergistic, or irrelevant interaction of MCT4 and GPC3 expression in 29 (66%), 5 (11%), 1 (2%), and 9 cases (21%), respectively. The cases exhibiting reciprocal expression of both markers tended to have cirrhosis without a history of neoadjuvant therapy. In summary, although MCT4+ HCC cases are mostly GPC3+, intratumoral expression patterns of MCT4 and GPC3 are frequently reciprocal each other, suggesting that dual targeting of MCT4 and GPC3 may achieve a better antitumor effect for MCT4+ HCC cases.

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Intratumoral reciprocal expression of monocarboxylate transporter 4 and glypican-3 in hepatocellular carcinomas

10.21203/rs.2.15684/v1 ◽

2019 ◽

Author(s):

Kenji Yorita ◽

Akinobu Ohno ◽

Takahiro Nishida ◽

Kazuhiro Kondo ◽

Toshihiko Ohtomo ◽

...

Keyword(s):

Prognostic Factors ◽

Expression Patterns ◽

Japanese Patients ◽

Monocarboxylate Transporter ◽

Two Factors ◽

Gpc3 Expression ◽

History Of ◽

Reciprocal Expression ◽

Immunohistochemical Analyses ◽

Monocarboxylate Transporter 4

Abstract Objective: We previously reported the identification of monocarboxylate transporter 4 (MCT4) and glypican-3 (GPC3) as prognostic factors for hepatocellular carcinoma (HCC), which are now considered significant poor prognostic factors for the disease. This study aimed to clarify the detailed interaction of these two factors in HCC t o improve our understanding of aggressive HCC phenotype s. A total of 225 Japanese patients with HCC from our previous study were subjected to immunohistochemical analyses. Results: The number of MCT4-positive (MCT4+) HCC cases was 47 (21%), and most MCT4+ HCC showed high GPC3 expression (94%, 44/47 cases). In 44 MCT4+/GPC3+ HCC cases, intratumoral heterogeneity of GPC3 or MCT4 expression was further evaluated. We observed reciprocal (inverse), synergistic, mixed reciprocal and synergistic, or irrelevant interaction of MCT4 and GPC3 expression in 29 (66%), 5 (11%), 1 (2%), and 9 cases (21%), respectively. The cases exhibiting reciprocal expression of both markers tended to have cirrhosis without a history of neoadjuvant therapy. In summary, although MCT4+ HCC cases are mostly GPC3+, intratumoral expression patterns of MCT4 and GPC3 are frequently reciprocal each other, suggesting that dual targeting of MCT4 and GPC3 may achieve a better antitumor effect for MCT4+ HCC cases.

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Intratumoral reciprocal expression of monocarboxylate transporter 4 and glypican-3 in hepatocellular carcinomas

10.21203/rs.2.15684/v2 ◽

2019 ◽

Author(s):

Kenji Yorita ◽

Akinobu Ohno ◽

Takahiro Nishida ◽

Kazuhiro Kondo ◽

Toshihiko Ohtomo ◽

...

Keyword(s):

Prognostic Factors ◽

Expression Patterns ◽

Japanese Patients ◽

Monocarboxylate Transporter ◽

Two Factors ◽

Gpc3 Expression ◽

History Of ◽

Reciprocal Expression ◽

Immunohistochemical Analyses ◽

Monocarboxylate Transporter 4

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Kant and the Science of Logic

10.1093/oso/9780190907136.001.0001 ◽

2018 ◽

Cited By ~ 3

Author(s):

Huaping Lu-Adler

Keyword(s):

History Of Philosophy ◽

Logical Pluralism ◽

Philosophy Of Logic ◽

Science Of Logic ◽

Transcendental Logic ◽

If Logic ◽

General Logic ◽

Two Factors ◽

History Of ◽

Philosophical Debates

This book is both a history of philosophy of logic told from the Kantian viewpoint and a reconstruction of Kant’s theory of logic from a historical perspective. Kant’s theory represents a turning point in a history of philosophical debates over the following questions: (1) Is logic a science, instrument, standard of assessment, or mixture of these? (2) If logic is a science, what is the subject matter that differentiates it from other sciences, particularly metaphysics? (3) If logic is a necessary instrument to all philosophical inquiries, how is it so entitled? (4) If logic is both a science and an instrument, how are these two roles related? Kant’s answer to these questions centers on three distinctions: general versus particular logic, pure versus applied logic, pure general logic versus transcendental logic. The true meaning and significance of each distinction becomes clear, this book argues, only if we consider two factors. First, Kant was mindful of various historical views on how logic relates to other branches of philosophy (viz. metaphysics and physics) and to the workings of common human understanding. Second, he first coined “transcendental logic” while struggling to secure metaphysics as a proper “science,” and this conceptual innovation would in turn have profound implications for his mature theory of logic. Against this backdrop, the book reassesses the place of Kant’s theory in the history of philosophy of logic and highlights certain issues that are still debated today, such as normativity of logic and the challenges posed by logical pluralism.

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Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study

Diabetologia ◽

10.1007/s00125-020-05351-w ◽

2021 ◽

Vol 64 (4) ◽

pp. 778-794 ◽

Cited By ~ 2

Author(s):

Matthieu Wargny ◽

◽

Louis Potier ◽

Pierre Gourdy ◽

Matthieu Pichelin ◽

...

Keyword(s):

Prognostic Factors ◽

Hospital Discharge ◽

Microvascular Complications ◽

White Cell Count ◽

Symptom Duration ◽

Protein Levels ◽

Reactive Protein ◽

Patients With Diabetes ◽

History Of ◽

Routine Therapy

Abstract Aims/hypothesis This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). Methods The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. Results We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th–75th percentile) 28.4 (25.0–32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5–14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. Conclusions/interpretation In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. Trial registration Clinicaltrials.gov identifier: NCT04324736 Graphical abstract

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Incidence of elevated intraocular pressure after intravitreal injection in Japanese patients with age-related macular degeneration

Scientific Reports ◽

10.1038/s41598-021-91832-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maiko Maruyama-Inoue ◽

Tatsuya Inoue ◽

Shaheeda Mohamed ◽

Yoko Kitajima ◽

Shoko Ikeda ◽

...

Keyword(s):

Risk Factors ◽

Intraocular Pressure ◽

Macular Degeneration ◽

Intravitreal Injection ◽

Odds Ratio ◽

Japanese Patients ◽

Age Related Macular Degeneration ◽

Age Related ◽

Elevated Intraocular Pressure ◽

History Of

AbstractThe purpose of this study was to report the incidence of elevated intraocular pressure (IOP) after intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) in Japanese patients with age-related macular degeneration (AMD). A retrospective study of chart review of patients who underwent ≥ 10 intravitreal anti-VEGF injections between April 2009 and December 2019 was conducted. Elevated IOP was defined as IOP ≥ 25 mmHg at one visit. Cases with elevated IOP resulting from IVI were identified. Furthermore, the association between elevated IOP and some parameters, as the risk factors that influence elevated IOP, was investigated. A total of 402 eyes of 370 patients were included in this study. Twenty-eight eyes of 26 patients (7.0%) were identified as cases with elevated IOP after IVI. The mean time of elevation after baseline was 50.6 ± 26.5 months. History of glaucoma (p = 0.021; odds ratio, 5.85), treatment modality (p = 0.019; odds ratio, 6.32), and total number of injections (p = 0.003; odds ratio, 1.03) were significantly associated with elevated IOP. A late complication of elevated IOP is associated with IVI in patients with AMD. Particularly, history of glaucoma and treat and extend regimen with frequent injections were found to be risk factors of elevated IOP.

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Safety and effectiveness of eculizumab in Japanese patients with generalized myasthenia gravis: interim analysis of post-marketing surveillance

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211001995 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110019

Author(s):

Hiroyuki Murai ◽

Shigeaki Suzuki ◽

Miki Hasebe ◽

Yuji Fukamizu ◽

Ema Rodrigues ◽

...

Keyword(s):

Myasthenia Gravis ◽

Interim Analysis ◽

Japanese Patients ◽

Phase Iii ◽

High Dose ◽

Complement Protein ◽

Double Blind ◽

Post Marketing Surveillance ◽

Post Marketing ◽

History Of

Background: Eculizumab, a humanized monoclonal antibody targeted to terminal complement protein C5, is approved in Japan for treatment of patients with anti-acetylcholine receptor antibody-positive (AChR+) generalized myasthenia gravis (gMG) whose symptoms are difficult to control with high-dose intravenous immunoglobulin (IVIg) therapy or plasmapheresis. Methods: This interim analysis of mandatory post-marketing surveillance in Japan assessed the safety and effectiveness of eculizumab at 26 weeks after treatment initiation in patients with AChR+ gMG. Results: Data were available for 40 adult patients in Japan [62.5% (25/40) female; mean age at eculizumab initiation, 51.0 years]. Fifteen patients had a history of thymoma. Six patients were excluded from the effectiveness analysis set due to participation in the open-label extension part of the phase III, randomized, double-blind, placebo-controlled REGAIN study [ClinicalTrials.gov identifier: NCT02301624]. After 26 weeks’ follow up, 32 patients (80%) were continuing eculizumab treatment. Adverse drug reactions were reported by seven patients [most frequently headache ( n = 3)]. One death was reported during eculizumab treatment (relationship unclear as determined by the treating physician) and there was one death 45 days after the last dose (considered unrelated). No meningococcal infections were reported. Mean (standard deviation) changes from baseline in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores were −3.7 (2.61) ( n = 27) and −5.6 (3.50) ( n = 26), respectively, at 12 weeks, and −4.3 (2.72) ( n = 26) and −5.6 (4.02) ( n = 24), respectively, at 26 weeks. Improvements in MG-ADL and QMG scores were generally similar in patients with/without a history of thymoma. Frequency of IVIg use decreased following eculizumab initiation. Conclusion: In a real-world setting, eculizumab was effective and well tolerated for the treatment of AChR+ gMG in adult Japanese patients whose disease was refractory to IVIg or plasmapheresis. These findings are consistent with the efficacy and safety results from the global phase III REGAIN study of eculizumab.

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Prevalence of bone fracture and its association with severe hypoglycemia in Japanese patients with type 1 diabetes

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-002099 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002099

Author(s):

Yuji Komorita ◽

Masae Minami ◽

Yasutaka Maeda ◽

Rie Yoshioka ◽

Toshiaki Ohkuma ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Fracture Risk ◽

Bone Fracture ◽

Severe Hypoglycemia ◽

Japanese Patients ◽

Anatomic Site ◽

Cross Sectional ◽

History Of

IntroductionType 1 diabetes (T1D) is associated with higher fracture risk. However, few studies have investigated the relationship between severe hypoglycemia and fracture risk in patients with T1D, and the results are controversial. Besides, none has investigated the risk factors for fracture in Asian patients with T1D. The aim of the present study was to investigate the prevalence of bone fracture and its relationship between severe hypoglycemia and other risk factors in Japanese patients with T1D.Research design and methodsThe single-center cross-sectional study enrolled 388 Japanese patients with T1D (mean age, 45.2 years; women, 60.4%; mean duration of diabetes, 16.6 years) between October 2019 and April 2020. The occurrence and circumstances of any fracture after the diagnosis of T1D were identified using a self-administered questionnaire. The main outcomes were any anatomic site of fracture and fall-related fracture. Severe hypoglycemia was defined as an episode of hypoglycemia that required the assistance of others to achieve recovery.ResultsA total of 92 fractures occurred in 64 patients, and 59 fractures (64%) were fall-related. Only one participant experienced fracture within the 10 years following their diagnosis of diabetes. In logistic regression analysis, the multivariate-adjusted ORs (95% CIs) of a history of severe hypoglycemia were 2.11 (1.11 to 4.09) for any fracture and 1.91 (0.93 to 4.02) for fall-related fracture. Fourteen of 18 participants with multiple episodes of any type of fracture had a history of severe hypoglycemia (p<0.001 vs no fracture).ConclusionsWe have shown that a history of severe hypoglycemia is significantly associated with a higher risk of bone fracture in Japanese patients with T1D.

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Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.009093 ◽

2019 ◽

Vol 294 (52) ◽

pp. 20135-20147 ◽

Cited By ~ 13

Author(s):

Yasna Contreras-Baeza ◽

Pamela Y. Sandoval ◽

Romina Alarcón ◽

Alex Galaz ◽

Francisca Cortés-Molina ◽

...

Keyword(s):

Monocarboxylate Transporter ◽

High Affinity ◽

High Lactate ◽

Monocarboxylate Transporter 4

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The hard clam genome reveals massive expansion and diversification of inhibitors of apoptosis in Bivalvia

BMC Biology ◽

10.1186/s12915-020-00943-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hao Song ◽

Ximing Guo ◽

Lina Sun ◽

Qianghui Wang ◽

Fengming Han ◽

...

Keyword(s):

Gene Family ◽

Stress Responses ◽

Tandem Duplication ◽

Expression Patterns ◽

Hard Clam ◽

Gene Repertoire ◽

Single Chromosome ◽

Inhibitors Of Apoptosis ◽

History Of ◽

Evolutionary Success

Abstract Background Inhibitors of apoptosis (IAPs) are critical regulators of programmed cell death that are essential for development, oncogenesis, and immune and stress responses. However, available knowledge regarding IAP is largely biased toward humans and model species, while the distribution, function, and evolutionary novelties of this gene family remain poorly understood in many taxa, including Mollusca, the second most speciose phylum of Metazoa. Results Here, we present a chromosome-level genome assembly of an economically significant bivalve, the hard clam Mercenaria mercenaria, which reveals an unexpected and dramatic expansion of the IAP gene family to 159 members, the largest IAP gene repertoire observed in any metazoan. Comparative genome analysis reveals that this massive expansion is characteristic of bivalves more generally. Reconstruction of the evolutionary history of molluscan IAP genes indicates that most originated in early metazoans and greatly expanded in Bivalvia through both lineage-specific tandem duplication and retroposition, with 37.1% of hard clam IAPs located on a single chromosome. The expanded IAPs have been subjected to frequent domain shuffling, which has in turn shaped their architectural diversity. Further, we observed that extant IAPs exhibit dynamic and orchestrated expression patterns among tissues and in response to different environmental stressors. Conclusions Our results suggest that sophisticated regulation of apoptosis enabled by the massive expansion and diversification of IAPs has been crucial for the evolutionary success of hard clam and other molluscan lineages, allowing them to cope with local environmental stresses. This study broadens our understanding of IAP proteins and expression diversity and provides novel resources for studying molluscan biology and IAP function and evolution.

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