Publications by authors named "Takayuki Kondo"

167 Publications

Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring Mutation in Early Clinical Experience.

J Cancer 2022 16;13(8):2656-2661. Epub 2022 May 16.

Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of locus. A total of eight patients (24.2%) exhibited at least one mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT was comparable to those patients with WT . These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by mutation.
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http://dx.doi.org/10.7150/jca.71494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174847PMC
May 2022

Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis.

Int J Clin Oncol 2022 Jun 15. Epub 2022 Jun 15.

Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles.

Methods: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation CDx was investigated.

Results: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion.

Conclusions: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.
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http://dx.doi.org/10.1007/s10147-022-02195-9DOI Listing
June 2022

T cells from MS Patients with High Disease Severity Are Insensitive to an Immune-Suppressive Effect of Sulfatide.

Mol Neurobiol 2022 Jun 11. Epub 2022 Jun 11.

Department of Neurology, Kansai Medical University Medical Center, Moriguchi, Japan.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Its early phase is characterized by a relapse-remitting disease course, followed by disability progression in the later stage. While chronic inflammation accompanied with degeneration is well-established as the key pathological feature, the pathogenesis of MS, particularly progressive MS, remains elusive. Sulfatide is a major glycolipid component of myelin, and previous studies in experimental autoimmune encephalomyelitis mouse models have demonstrated it to have immune-protective functions. Notably, sulfatide concentration is increased in the serum and cerebrospinal fluid of patients with MS, particularly those in a progressive disease course. Here, we show that the myelin-glycolipid sulfatide displays an ability to suppress the proliferation of polyclonally activated human T cells. Importantly, this suppressive effect was impaired in T cells obtained from MS patients having higher disability status. Therefore, it is plausible that progression of MS is associated with an escape from the immune-regulatory effect of sulfatide. Our study suggests that, although the precise mechanisms remain unrevealed, an escape of T cells from immunosuppression by sulfatide is associated with disease progression in the advanced stage. Further studies will provide novel insights into the pathogenesis of MS, particularly regarding disease progression, and help develop novel treatment strategies for this challenging disease.
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http://dx.doi.org/10.1007/s12035-022-02881-9DOI Listing
June 2022

CDiP technology for reverse engineering of sporadic Alzheimer's disease.

J Hum Genet 2022 Jun 10. Epub 2022 Jun 10.

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive impairment for which neither treatable nor preventable approaches have been confirmed. Although genetic factors are considered to contribute to sporadic AD, for the majority of AD patients, the exact causes of AD aren't fully understood. For AD genetics, we developed cellular dissection of polygenicity (CDiP) technology to identify the smallest unit of AD, i.e., genetic factors at a cellular level. By CDiP, we found potential therapeutic targets, a rare variant for disease stratification, and polygenes to predict real-world AD by using the real-world data of AD cohort studies (Alzheimer's Disease Neuroimaging Initiative: ADNI and Japanese Alzheimer's Disease Neuroimaging Initiative: J-ADNI). In this review, we describe the components and results of CDiP in AD, induced pluripotent stem cell (iPSC) cohort, a cell genome-wide association study (cell GWAS), and machine learning. And finally, we discuss the future perspectives of CDiP technology for reverse engineering of sporadic AD toward AD eradication.
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http://dx.doi.org/10.1038/s10038-022-01047-8DOI Listing
June 2022

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Lab Invest 2022 May 28. Epub 2022 May 28.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chiba, 260-8677, Japan.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-A mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-A mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.
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http://dx.doi.org/10.1038/s41374-022-00807-6DOI Listing
May 2022

Comprehensive risk score of the E-PASS as a prognostic indicator for patients after elective and emergency curative colorectal cancer surgery: A multicenter retrospective study.

Int J Surg 2022 May 18;101:106631. Epub 2022 Apr 18.

Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Objective: To evaluate the prognostic value of the comprehensive risk score (CRS) of the Estimation of Physiologic Ability and Surgical Stress for managing patients with colorectal cancer (CRC) who underwent elective and emergency colorectal cancer surgery with curative intent.

Summary Background Data: CRS, which is calculated based on both clinical and surgical factors, is a good predictor of postoperative complications and mortality. However, the impact of CRS in CRC prognosis remains unclear.

Methods: Patients with CRC who underwent curative resection between 2010 and 2019 were retrospectively enrolled in this study. The cohort was divided into the low and high CRS groups. The prognostic value of CRS was evaluated via Cox regression and Kaplan-Meier analyses. The CRS cutoff value was obtained using the Youden index applied to OS curves and have not been validated by any validation cohorts.

Results: In total, 2407 patients, including 1359 and 1048 patients with low and high CRS, respectively, were enrolled in this study. Multivariate analysis revealed that a CRS was an independent prognostic factor of overall and recurrence-free survival regardless of disease stage. Furthermore, adjuvant chemotherapy was beneficial for the survival of patients with stage III CRC in both high and low CRS groups; however, the survival benefit was limited in elderly high CRS patients.

Conclusions: CRS was a strong prognostic factor for CRC regardless of disease stage and might be considered as a biomarker for selecting elderly patients who are eligible for adjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.ijsu.2022.106631DOI Listing
May 2022

Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial.

BMJ Open 2022 04 8;12(4):e059779. Epub 2022 Apr 8.

National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Introduction: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.

Methods And Analysis: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B.

Ethics And Dissemination: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication.

Trial Registration Number: jRCT2031210046.
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http://dx.doi.org/10.1136/bmjopen-2021-059779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995959PMC
April 2022

One-step induction of photoreceptor-like cells from human iPSCs by delivering transcription factors.

iScience 2022 Apr 8;25(4):103987. Epub 2022 Mar 8.

iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan.

Retinal dystrophies (RDs) lead to irreversible vision impairment with no radical treatment. Although photoreceptor cells (PRCs) differentiated from human induced pluripotent stem cells (iPSCs) are essential for the study of RDs as a scalable source, current differentiation methods for PRCs require multiple steps. To address these issues, we developed a method to generate PRCs from human iPSCs by introducing the transcription factors, CRX and NEUROD1. This approach enabled us to generate induced photoreceptor-like cells (iPRCs) expressing PRC markers. Single-cell RNA sequencing revealed the transcriptome of iPRCs in which the genes associated with phototransduction were expressed. Generated iPRCs exhibited their functional properties in calcium imaging. Furthermore, light-induced damage on iPRCs was inhibited by an antioxidant compound. This simple approach would facilitate the availability of materials for PRC-related research and provide a useful application for disease modeling and drug discovery.
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http://dx.doi.org/10.1016/j.isci.2022.103987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938283PMC
April 2022

Metabolites of soil microorganisms modulate amyloid β production in Alzheimer's neurons.

Sci Rep 2022 03 2;12(1):2690. Epub 2022 Mar 2.

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.

Microbial flora is investigated to be related with neuropathological conditions in Alzheimer's disease (AD), and is attracting attention as a drug discovery resource. However, the relevance between the soil microbiota and the pathological condition has not been fully clarified due to the difficulty in isolation culture and the component complexity. In this study, we established a library of secondly metabolites produced in microorganism to investigate the potential effect of microorganisms on the production of amyloid β (Aβ), one of the most representative pathogens of AD. We conducted a library screening to quantify Aβ and neuronal toxicity by using cortical neurons from human induced pluripotent stem cells (iPSCs) of AD patients after adding secondary metabolites. Screening results and following assessment of dose-dependency identified Verrucarin A, produced in Myrothecium spp., showed 80% decrease in Aβ production. Furthermore, addition of Mer-A2026A, produced in Streptomyces pactum, showed increase in Aβ42/40 ratio at the low concentration, and decrease in Aβ production at the higher concentration. As a result, established library and iPSC-based phenotyping assay clarified a direct link between Aβ production and soil microorganisms. These results suggest that Aβ-microorganism interaction may provide insight into the AD pathophysiology with potential therapeutics.
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http://dx.doi.org/10.1038/s41598-022-06513-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891331PMC
March 2022

Corticosteroid use in indeterminate acute liver failure.

Liver Int 2022 05 3;42(5):1209. Epub 2022 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/liv.15220DOI Listing
May 2022

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2022 Jan 6;11(1):48-60. Epub 2021 Dec 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet.

Approach And Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, = 267; period 2: 2013-2016, = 352; period 3: 2017-2019, = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC.

Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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http://dx.doi.org/10.1159/000519868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820147PMC
January 2022

Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma.

PLoS One 2022 27;17(1):e0261619. Epub 2022 Jan 27.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background/aims: Organ failure in patients with acute decompensation (AD) is a defining characteristic of acute-on-chronic liver failure (ACLF). However, the clinical features of AD during the long-term clinical course of hepatocellular carcinoma (HCC) are still poorly understood. This study aimed to clarify features and impact of AD/ACLF on the prognosis of patients after treatment for HCC.

Methods: This retrospective study enrolled 556 consecutive patients who were initially diagnosed with HCC, and analyses were conducted taking into account HCC treatment type, HCC stage, and presence or absence of cirrhosis.

Results: During follow-up, 299 patients with AD were hospitalized. AD occurrence is closely related to prognosis, regardless of the presence or absence of cirrhosis and HCC stage, and early-onset AD (within 90 days after HCC treatment) has negative impact on prognosis. In the intermediate-advanced-stage group, surgical resection had a positive impact on AD incidence post-treatment. After systemic therapy for HCC, renal impairment was the predictive factors for AD development. The 28/90-day mortality rate was higher among 41 cases (13.7%) with AD who exhibited ACLF as compared with cases without ACLF. AD without cirrhosis had similar ACLF incidence and short-term mortality, compared to AD with cirrhosis. The prognostic model using a decision-tree-based approach, which includes ACLF, bilirubin level, HCC progression, and MELD score is useful for predicting 90- or 28-day mortality after AD diagnosis.

Conclusions: Careful management of patients with HCC who are hospitalized with AD is necessary, considering ACLF, HCC progression, and liver function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794202PMC
February 2022

The role of RIPK1 mediated cell death in acute on chronic liver failure.

Cell Death Dis 2021 12 17;13(1). Epub 2021 Dec 17.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.

Acute-on-chronic liver failure (ACLF) is characterized predominantly by non-apoptotic forms of hepatocyte cell death. Necroptosis is a form of programmed lytic cell death in which receptor interacting protein kinase (RIPK) 1, RIPK3 and phosphorylated mixed lineage kinase domain-like (pMLKL) are key components. This study was performed to determine the role of RIPK1 mediated cell death in ACLF. RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL were measured in healthy volunteers, stable patients with cirrhosis, and in hospitalized cirrhotic patients with acutely decompensated cirrhosis, with and without ACLF (AD). The role of necroptosis in ACLF was studied in two animal models of ACLF using inhibitors of RIPK1, necrostatin-1 (NEC-1) and SML2100 (RIPA56). Plasma RIPK3 levels predicted the risk of 28- and 90-day mortality (AUROC, 0.653 (95%CI 0.530-0.776), 0.696 (95%CI 0.593-0.799)] and also the progression of patients from no ACLF to ACLF [0.744 (95%CI 0.593-0.895)] and the results were validated in a 2 patient cohort. This pattern was replicated in a rodent model of ACLF that was induced by administration of lipopolysaccharide (LPS) to bile-duct ligated rats and carbon tetrachloride-induced fibrosis mice administered galactosamine (CCL/GalN). Suppression of caspase-8 activity in ACLF rodent model was observed suggesting a switch from caspase-dependent cell death to necroptosis. NEC-1 treatment prior to administration of LPS significantly reduced the severity of ACLF manifested by reduced liver, kidney, and brain injury mirrored by reduced hepatic and renal cell death. Similar hepato-protective effects were observed with RIPA56 in a murine model of ACLF induced by CCL/GalN. These data demonstrate for the first time the importance of RIPK1 mediated cell death in human and rodent ACLF. Inhibition of RIPK1 is a potential novel therapeutic approach to prevent progression of susceptible patients from no ACLF to ACLF.
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http://dx.doi.org/10.1038/s41419-021-04442-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683430PMC
December 2021

Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment.

JGH Open 2021 Nov 1;5(11):1266-1274. Epub 2021 Oct 1.

Department of Diagnostic Pathology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability-high (MSI-H) by using tumor samples from advanced HCC patients eligible for systemic therapy.

Methods: MSI-H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD-L1, CD8, VEGF, and HLA-class1 was evaluated by immunohistochemistry. Whole-exome sequencing was performed for MSI-H tumor samples.

Results: Of 50 patients, one (2.0%) was confirmed with MSI-H. In the MSI-H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8 lymphocytes, and low expression of VEGF were identified. Although PD-L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR-21 and miR-155 overexpression and hypermethylation of the gene.

Conclusion: We identified a very small number of MSI-H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI-H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI-H in HCC and to analyze tumor microenvironments.
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http://dx.doi.org/10.1002/jgh3.12660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593775PMC
November 2021

Changes in therapeutic options for hepatocellular carcinoma in Asia.

Liver Int 2021 Nov 15. Epub 2021 Nov 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic-related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral-hepatitis-related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first-line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral-related HCC by metabolic-related HCC and the emergence of combination immune therapy.
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http://dx.doi.org/10.1111/liv.15101DOI Listing
November 2021

Posttreatment after Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2021 Sep 20;10(5):473-484. Epub 2021 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.

Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.

Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.

Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
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http://dx.doi.org/10.1159/000515552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527907PMC
September 2021

Radiological and Laboratory Features of Multiple Sclerosis Patients With Immunosuppressive Therapy: A Multicenter Retrospective Study in Japan.

Front Neurol 2021 13;12:749406. Epub 2021 Oct 13.

Department of Neurology, Kansai Medical University Medical Center, Osaka, Japan.

Multiple sclerosis (MS) is a relapsing, inflammatory, and demyelinating disease of central nervous system showing marked clinical heterogeneity. Many factors might influence the choice of relapse prevention drug, and treatment response varies among patients. Despite the enlargement of disease-modifying drugs for MS (MS-DMDs), some patients have been treated with corticosteroid and/or immunosuppressant (CS/IS). To clarify the radiological and laboratory features of MS treated with CS/IS for relapse prevention. Clinical records including radiological and laboratory findings, and drugs used for relapse prevention were reviewed retrospectively. Out of 92 consecutive MS patients, 25 (27%) were treated with CS/IS. The followings were observed less frequently in patients treated with CS/IS than in those with MS-DMDs: three or more periventricular lesions, ovoid lesions, subcortical lesions, typical contrast-enhancing lesions, negative for serum autoantibodies, and positive for oligoclonal bands in the cerebrospinal fluid. Multiple logistic regression analysis revealed that the absence of typical contrast-enhancing lesions and positivity for serum autoantibodies were independent factors associated with CS/IS prescription (odds ratio 25.027 and 14.537, respectively). In this cohort of Japanese patients clinically diagnosed with MS, radiological and serological findings atypical of MS were observed more frequently in patients treated with CS/IS than in those with MS-DMDs as a part of MS therapy. The absence of contrast-enhancing lesions typical of MS and positivity for serum autoantibodies were independent factors strongly associated with CS/IS use.
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http://dx.doi.org/10.3389/fneur.2021.749406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548818PMC
October 2021

Induction of inverted morphology in brain organoids by vertical-mixing bioreactors.

Commun Biol 2021 10 22;4(1):1213. Epub 2021 Oct 22.

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

Organoid technology provides an opportunity to generate brain-like structures by recapitulating developmental steps in the manner of self-organization. Here we examined the vertical-mixing effect on brain organoid structures using bioreactors and established inverted brain organoids. The organoids generated by vertical mixing showed neurons that migrated from the outer periphery to the inner core of organoids, in contrast to orbital mixing. Computational analysis of flow dynamics clarified that, by comparison with orbital mixing, vertical mixing maintained the high turbulent energy around organoids, and continuously kept inter-organoid distances by dispersing and adding uniform rheological force on organoids. To uncover the mechanisms of the inverted structure, we investigated the direction of primary cilia, a cellular mechanosensor. Primary cilia of neural progenitors by vertical mixing were aligned in a multidirectional manner, and those by orbital mixing in a bidirectional manner. Single-cell RNA sequencing revealed that neurons of inverted brain organoids presented a GABAergic character of the ventral forebrain. These results suggest that controlling fluid dynamics by biomechanical engineering can direct stem cell differentiation of brain organoids, and that inverted brain organoids will be applicable for studying human brain development and disorders in the future.
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http://dx.doi.org/10.1038/s42003-021-02719-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536773PMC
October 2021

Simple derivation of skeletal muscle from human pluripotent stem cells using temperature-sensitive Sendai virus vector.

J Cell Mol Med 2021 10 12;25(20):9586-9596. Epub 2021 Sep 12.

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

Human pluripotent stem cells have the potential to differentiate into various cell types including skeletal muscles (SkM), and they are applied to regenerative medicine or in vitro modelling for intractable diseases. A simple differentiation method is required for SkM cells to accelerate neuromuscular disease studies. Here, we established a simple method to convert human pluripotent stem cells into SkM cells by using temperature-sensitive Sendai virus (SeV) vector encoding myoblast determination protein 1 (SeV-Myod1), a myogenic master transcription factor. SeV-Myod1 treatment converted human embryonic stem cells (ESCs) into SkM cells, which expressed SkM markers including myosin heavy chain (MHC). We then removed the SeV vector by temporal treatment at a high temperature of 38℃, which also accelerated mesodermal differentiation, and found that SkM cells exhibited fibre-like morphology. Finally, after removal of the residual human ESCs by pluripotent stem cell-targeting delivery of cytotoxic compound, we generated SkM cells with 80% MHC positivity and responsiveness to electrical stimulation. This simple method for myogenic differentiation was applicable to human-induced pluripotent stem cells and will be beneficial for investigations of disease mechanisms and drug discovery in the future.
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http://dx.doi.org/10.1111/jcmm.16899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505837PMC
October 2021

Th1 - CD11c B Cell Axis Associated with Response to Plasmapheresis in Multiple Sclerosis.

Ann Neurol 2021 10;90(4):595-611

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: Although plasmapheresis is a treatment option for patients with autoimmune neurological diseases, treatment response varies greatly among patients. The main objective of this study was to find out if biological/immune traits correlate with a beneficial response.

Methods: We thoroughly analyzed immune phenotypes in paired blood samples from a cohort of 31 patients with multiple sclerosis before and after plasmapheresis, in parallel with clinical evaluation of treatment response.

Results: The frequency of IFN-γ Th1 cells was persistently higher in those who obtained benefit from plasmapheresis (responders) than nonresponders. The Th1 cell frequency before plasmapheresis provided a high predictive value for beneficial response, achieving area under the curve (AUC) of 0.902. Plasmapheresis treatment decreased inflammation-related gene expressions in Th1 cells. Meanwhile, IFNG expression in Th1 cells positively correlated with the frequency of CD11c B cells, of which a pathogenic role has been suggested in several autoimmune diseases. In line with this, in vitro experiments showed that CD11c B cells would increase in response to exogenous IFN-γ compared to IL-4, and secrete high amounts of IgG. B cell receptor analysis indicated that clonal expansion of CD11c B cells takes place in patients with multiple sclerosis. Interestingly, CD11c B cells, which showed unique gene expression profile, decreased after plasmapheresis treatment along with all the immunoglobulin subsets in the circulation.

Interpretation: Taken together, we postulate that Th1 cell - CD11c B cell axis is involved in treatment response to plasmapheresis, giving us clues to better understanding of complicated pathogenesis of autoimmune diseases, and getting closer to a personalized therapy. ANN NEUROL 2021;90:595-611.
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http://dx.doi.org/10.1002/ana.26202DOI Listing
October 2021

Establishment of induced pluripotent stem cells from schizophrenia discordant fraternal twins.

Stem Cell Res 2021 08 14;55:102504. Epub 2021 Aug 14.

iPSC-based Drug-Discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan. Electronic address:

Schizophrenia (SCZ) is one of the major psychiatric disorders. The genetic factor is certainly influential in the onset of the disease but is not decisive. There is no identified molecular/cellular marker of the disease, and the pathomechanism is still unknown. In this study, we generated human induced pluripotent stem cells (iPSCs) derived from SCZ-discordant fraternal twins, and they could contribute to elucidation of the pathomechanism of SCZ.
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http://dx.doi.org/10.1016/j.scr.2021.102504DOI Listing
August 2021

Surgical glove perforation during laparoscopic colorectal procedures.

Surg Endosc 2022 05 11;36(5):3489-3494. Epub 2021 Aug 11.

Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: It has been reported that in conventional open surgery, approximately 10% of surgical gloves are perforated during surgery without being noticed. To protect both the patient and medical staff from harm, double gloving or changing gloves routinely at certain intervals during surgery is recommended. However, whether these protective measures are also necessary for laparoscopic colorectal surgery is unknown because the actual perforation rate during laparoscopic procedures is unclear.

Methods: Seventy-seven laparoscopic colorectal surgeries were evaluated, and a total of 616 surgical gloves used in the surgeries were collected for analysis. The presence of glove perforation was tested by the standard water-leak test method (EN455-1).

Results: Seven perforations were detected (1.1%). The duration of the laparoscopic procedure was not a statistically significant risk factor for glove perforation (p = 0.41). Postoperative surgical site infections (SSIs) were observed in 12 cases (15.6%), but there was no significant correlation between the presence of glove perforation and SSI (p = 0.92). According to the bacterial cultivation results, the majority of causative agents of SSI were enterobacteria, which belong to the major gut flora.

Conclusion: Although the perforation rate was considerably lower than that in open surgery, surgical glove perforation occurred during laparoscopic procedures. Double gloving in laparoscopic colorectal surgery is recommended not to prevent SSI but to protect medical workers from harmful infections after direct contact with the patient.
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http://dx.doi.org/10.1007/s00464-021-08670-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356683PMC
May 2022

Repurposing bromocriptine for Aβ metabolism in Alzheimer's disease (REBRAnD) study: randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer's disease with presenilin 1 (PSEN1) mutations.

BMJ Open 2021 06 30;11(6):e051343. Epub 2021 Jun 30.

Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Introduction: Alzheimer's disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD.

Methods And Analysis: This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted.

Ethics And Dissemination: The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process.

Trial Registration Number: jRCT2041200008, NCT04413344.
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http://dx.doi.org/10.1136/bmjopen-2021-051343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246358PMC
June 2021

Skeletal Muscle Volume Is an Independent Predictor of Survival after Sorafenib Treatment Failure for Hepatocellular Carcinoma.

Cancers (Basel) 2021 May 7;13(9). Epub 2021 May 7.

Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.

Few studies exist on the relationship between post-progression survival (PPS) and skeletal muscle volume in hepatocellular carcinoma (HCC) patients receiving sorafenib. This study aimed to analyze the effects of muscle volume on clinical outcomes. We retrospectively enrolled 356 HCC patients. Various clinical parameters, including skeletal muscle index, were analyzed as predictors of overall survival (OS), progression-free survival (PFS), and PPS. Patients with high muscle volume showed longer survival or PPS than those with low muscle volume (median survival time: 12.8 vs. 9.5 months, = 0.005; median PPS: 8.2 vs. 6.3 months, = 0.015); however, no differences in PFS were found. Multivariate analysis indicated that muscle volume was an independent predictor of PPS and OS. Skeletal muscle volume was a PPS predictor in HCC patients receiving sorafenib. Therefore, survival can be prolonged by the upregulation of skeletal muscle volume, especially in HCC patients with skeletal muscle depletion.
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http://dx.doi.org/10.3390/cancers13092247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124673PMC
May 2021

[Secondary Progressive Multiple Sclerosis].

Brain Nerve 2021 May;73(5):450-457

Department of Neurology, Kansai Medical University Medical Center.

Secondary progressive multiple sclerosis (SPMS) is defined by the slowly progressive deterioration of clinical symptoms independent of relapse, following the early relapsing-remitting disease course. Diagnosis of SPMS is challenging and usually retrospective because of the lack of reliable diagnostic tests. There is also a lack of reliable clinical symptoms other than gait disturbance, which are well evaluated in the clinical setting. The pathogenic mechanisms driving SPMS are poorly understood, and therapy for SPMS remains limited. It is assumed that the characteristic features of neurodegeneration observed in SPMS are caused by chronic inflammation with compartmentalized T and B cells from the periphery, glial and mitochondrial dysfunction, and other factors. Neuroprotective agents, promotion of remyelination, and immunological modifications may be key targets for novel treatment strategies.
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http://dx.doi.org/10.11477/mf.1416201785DOI Listing
May 2021

[Late line systemic therapy for advanced hepatocellular carcinoma].

Nihon Shokakibyo Gakkai Zasshi 2021 ;118(5):418-427

Department of Gastroenterology, Graduate School of Medicine, Chiba University.

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http://dx.doi.org/10.11405/nisshoshi.118.418DOI Listing
May 2021

Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma.

J Cancer 2021 5;12(9):2694-2701. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is typically accompanied by abundant arterial blood flow. Although angiogenic growth factors such as Angiopoietin 2 (Ang2) play a central role in tumor angiogenesis in HCC, the role of serum Ang2 as a biomarker in HCC remains unclear. In this study, we aimed to investigate the potential of Ang2 as a diagnostic and prognostic biomarker in HCC using a sandwich enzyme-linked immunosorbent assay (ELISA). The median Ang2 levels in controls (n=20), chronic liver disease patients (n=98), and HCC patients (n=275) were 1.58, 2.33, and 3.53 ng/mL, respectively. The optimal cut-off value of Ang2 was determined as 3.5 ng/mL by receiver operating curve analysis. The sensitivity, specificity, and accuracy of Ang2 for HCC detection were 50.9, 83.7, and 59.5%, respectively. Spearman's rank correlation coefficient analysis demonstrated only a weak correlation between Ang2 serum levels and alpha-fetoprotein (AFP) or des-gamma-carboxy prothrombin (DCP) serum levels. The diagnostic value of Ang2 was comparable to those of other existing markers. In addition, 24 out of 73 patients with normal AFP and DCP levels (32.9%) demonstrated abnormally high Ang2 levels (≥3.5 ng/mL). Although no significant difference in overall survival was found between Ang2 and Ang2 patients with curative ablation therapy, recurrence-free survival (RFS) in Ang2 patients was observed to be significantly shorter than those in Ang2 patients. Multivariate analysis demonstrated that high serum Ang2 levels (≥3.5 ng/mL) and the presence of multiple tumors were poor prognostic factors. In conclusion, our findings indicate that serum Ang2 is a potential novel biomarker for both diagnosis and prognosis in HCC.
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http://dx.doi.org/10.7150/jca.56436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040723PMC
March 2021

Human induced pluripotent stem cells generated from a patient with idiopathic basal ganglia calcification.

Stem Cell Res 2021 05 3;53:102274. Epub 2021 Mar 3.

iPSC-based Drug-Discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan. Electronic address:

Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disease, characterized by abnormal calcium deposits in basal ganglia of the brain. The affected individuals exhibit movement disorders, and progressive deterioration of cognitive and psychiatric ability. The genetic cause of the disease is mutation in one of several different genes, SLC20A2, PDGFB, PDGFRB, XPR1 or MYORG, which inheritably or sporadically occurs. Here we generated an induced pluripotent stem cell (iPSC) line from an IBGC patient, which is likely be a powerful tool for revealing the pathomechanisms and exploring potential therapeutic candidates of IBGC.
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http://dx.doi.org/10.1016/j.scr.2021.102274DOI Listing
May 2021

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2021 04 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021
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