Publications by authors named "Kei Sakamoto"

276 Publications

Comparison of Clinicopathological Characteristics Between the Anterior and Posterior Type of Squamous Cell Carcinoma of the Floor of the Mouth: The Anterior Type Is a Risk Factor for Multiple Primary Cancer.

Front Oncol 2021 29;11:682428. Epub 2021 Jun 29.

Department of Oral and Maxillofacial Surgery, Division of Oral Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Floor of the mouth (FOM) squamous cell carcinoma (SCC) accounts for approximately 10% of all oral SCCs. FOM SCC can be classified into the anterior and posterior types according to their site of origin, but few studies have compared these types. This study sought to clarify differences in clinicopathological characteristics between these two types.

Methods: A total of 1,220 patients with oral SCC were treated at our department from January 2001 to December 2015. Among these patients, 62 had FOM SCC. The FOM SCCs were classified into two groups: the anterior type and the posterior type. The anterior and posterior types were defined by the boundary connecting the spaces between the canine and the first premolar bilaterally. We retrospectively compared the sex, age, smoking and drinking history, clinical stage, treatment, histopathological diagnosis, multiple primary cancers, and outcomes of the two groups.

Results: Among the 62 patients, 32 had the anterior type, while 30 had the posterior type. The anterior type was found more significantly in men ( = 0.01) and individuals with a smoking history than the posterior type ( = 0.04). pN2-3 cervical lymph node metastasis was significantly more common in the anterior type than in the posterior type ( = 0.01). The median depth of invasion in the anterior type was 4 mm. Multivariate analysis showed that the anterior type was an independent risk factor for multiple primary cancer development in FOM SCC ( = 0.02). The cumulative 10-year disease-specific survival rates of the anterior and posterior types were 92.8 and 95.0%, respectively, while the overall survival rates were 65.4 and 95.0%, respectively. In the anterior type FOM SCC, a lower overall survival rate was associated with multiple primary cancers and smoking-related diseases.

Conclusion: Smoking cessation and adequate systemic screening for multiple primary cancers are needed to improve the prognosis of FOM SCC, particularly the anterior type.
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http://dx.doi.org/10.3389/fonc.2021.682428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276066PMC
June 2021

Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965.

Biochem J 2021 Jul 14. Epub 2021 Jul 14.

University of Copenhagen, Copenhagen, Denmark.

SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMPK inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK-activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥ 25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965.
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http://dx.doi.org/10.1042/BCJ20210284DOI Listing
July 2021

Detection of SARS-CoV-2 using qRT-PCR in saliva obtained from asymptomatic or mild COVID-19 patients, comparative analysis with matched nasopharyngeal samples.

PLoS One 2021 10;16(6):e0252964. Epub 2021 Jun 10.

Nagasaki University, Nagasaki, Japan.

Objectives: The accurate detection of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is essential for the diagnosis of coronavirus disease 2019 (COVID-19). We compared the quantitative RT-PCR results between nasopharyngeal swabs and saliva specimens.

Methods: A COVID-19 outbreak occurred on a cruise ship at Nagasaki port, Japan. We obtained 123 nasopharyngeal swabs and saliva each from asymptomatic or mild patients in the late phase of infection.

Results: The intervals from the diagnosis to the sampling were 25.5 days for nasopharyngeal swabs and 28.9 days for saliva. The positive rate was 19.5% (24/123) for nasopharyngeal swabs and 38.2% (47/123) for saliva (P = 0.48). The quantified viral copies (mean ± SEM copies/5 μl) were 9.3±2.6 in nasopharyngeal swabs and 920±850 in saliva (P = 0.0006).

Conclusions: The advantages of saliva specimens include positive rate improvement and accurate viral load detection. Saliva may be used as a reliable sample for SARS-CoV-2 detection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252964PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191987PMC
June 2021

Additional Treatment Following Noncurative Endoscopic Resection for Esophageal Squamous Cell Carcinoma: A Comparison of Outcomes between Esophagectomy and Chemoradiotherapy.

Ann Surg Oncol 2021 Jun 3. Epub 2021 Jun 3.

Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Endoscopic resection (ER) has been widely implemented for cT1N0 esophageal squamous cell carcinoma (ESCC). Additional therapy, including esophagectomy and chemoradiotherapy (CRT), is sometimes required after noncurative ER.

Methods: We retrospectively reviewed 108 patients who received any additional treatment following noncurative ER (positive vertical margins, lymphovascular invasion, or invasion depth of submucosa or more), and compared the short- and long-term outcomes between the two treatment modalities.

Results: Of 108 patients, 56 underwent esophagectomy (E group), and 52 received CRT (CRT group). A positive vertical margin was observed in 17 (14.8%) patients and high risks of occult lymph node metastasis were observed in 91 (85.2%) patients, as well as lymphovascular invasion in 35 (32.4%) patients, invasion depth of the submucosa or more in 27 (25.0%) patients, and both in 29 (26.9%) patients. The E group patients were significantly younger (p = 0.046) and tended to present with larger tumors than those in the CRT group (p = 0.057). Lymphatic invasion was more frequent in the E group (p = 0.019), and, furthermore, one treatment-related death was observed in the E group. There were no significant differences between the groups in overall and disease-specific survival (p = 0.406 and 0.151, respectively), however, recurrence was only observed in the CRT group.

Conclusion: Both esophagectomy and CRT are safe and effective as additional treatments after noncurative ER in patients with ESCC. Esophagectomy is oncologically safe, whereas a risk of postoperative morbidity and mortality remains. Although the adverse events are acceptable, CRT has a certain degree of risk of disease recurrence.
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http://dx.doi.org/10.1245/s10434-021-10225-5DOI Listing
June 2021

ASO Visual Abstract: Influence of Damaged Stomach on Anastomotic Leakage After Cervical Esophagogastrostomy for Patients with Esophageal Cancer.

Ann Surg Oncol 2021 May 31. Epub 2021 May 31.

Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1245/s10434-021-10199-4DOI Listing
May 2021

Influence of Damaged Stomach on Anastomotic Leakage following Cervical Esophagogastrostomy in Patients with Esophageal Cancer.

Ann Surg Oncol 2021 May 17. Epub 2021 May 17.

Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Anastomotic leakage (AL) is one of the most common complications after esophagectomy. Although some patients have a history of peptic ulcers or other prior stomach diseases, the influence of a damaged stomach (DS) on AL incidence remains unclear. Therefore, we investigated the association between DS and incidence of AL in patients who underwent esophagectomy.

Patients And Methods: Between 2015 and 2019, a total of 447 consecutive patients who underwent cervical esophagogastrostomy using gastric tube following esophagectomy were enrolled. DS was defined on the basis of endoscopic findings of ulcers or scars due to medical history or prior treatment. We compared the incidence of AL between patients with DS and those with a healthy stomach (HS). Univariate and multivariate logistic regression analyses were used to identify factors that could predict AL incidence.

Results: Fifty-one patients (11.4%) had DS. Causes of DS included peptic ulcer (n = 36), endoscopic resection for early gastric cancer (n = 9), percutaneous endoscopic gastrostomies (n = 5), and post-chemotherapy scar for gastric malignant lymphoma (n = 1). Overall, AL occurred in 35 patients (7.8%). The incidence of AL in the DS group was significantly higher than in the HS group (15.7 vs. 6.8%, p = 0.03). DS was one of the independent predictive factors for AL (odds ratio, 2.75; 95% confidence interval, 1.10-6.92; p = 0.03) on multivariate analysis. Further, the diseases in the lower third of the conduit were associated with AL.

Conclusions: Presence of DS can predict AL in patients who underwent cervical esophagogastrostomy after esophagectomy.
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http://dx.doi.org/10.1245/s10434-021-10145-4DOI Listing
May 2021

Airflow Limitation Predicts Postoperative Pneumonia after Esophagectomy.

World J Surg 2021 Aug 3;45(8):2492-2500. Epub 2021 May 3.

Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, 135-8550, Japan.

Background: Chronic obstructive pulmonary disease (COPD) is known to be a risk factor of pneumonia after esophagectomy. In this study, we investigated the relationship of airflow limitation with the occurrence and the severity of pneumonia in esophageal cancer patients who underwent esophagectomy.

Methods: We enrolled 844 patients who underwent curative esophagectomy between 2009 and 2018. The airflow limitation was evaluated using the percent-predicted forced expiratory volume at 1 s (%FEV1) with spirometry.

Results: There were 597 (70.7%), 141 (16.7%), 68 (8.1%), and 38 patients (4.5%) with %FEV1 of ≥ 90%, 80-90%, 70-80%, and < 70% categories, respectively. One hundred and ninety-one patients (22.6%) occurred pneumonia, and the incidences of pneumonia in each category of patients were 18.8%, 28.4%, 29.4%, and 50.0%, respectively. In multivariate analysis, the categories of 80%-90%, 70-80%, and < 70% were significantly associated with a higher incidence of postoperative pneumonia (OR 1.57; 95% CI 1.02-2.43, OR 1.87; 95% CI 1.04-3.36, OR 3.34; 95% CI 1.66-6.71, respectively), with the %FEV1 category of ≥ 90% as reference. The incidence of severe pneumonia of Clavien-Dindo grade III or higher was also significantly associated with the %FEV1. In patients without COPD, the incidence of pneumonia was significantly higher in those with %FEV1 < 90% than in those with %FEV1 ≥ 90% (32.2% versus 17.5%, p < 0.001).

Conclusions: The airflow limitation can help predict the occurrence of pneumonia after esophagectomy in patients with and without COPD. Exclusive preventive measures should be considered in patients with reduced %FEV1 undergoing esophagectomy.
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http://dx.doi.org/10.1007/s00268-021-06148-7DOI Listing
August 2021

Clinical Significance of Serum Squamous Cell Carcinoma Antigen for Patients with Recurrent Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2021 Apr 10. Epub 2021 Apr 10.

Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.

Background: Squamous cell carcinoma antigen (SCC-Ag) is a widely used tumor marker of SCC. However, the clinical significance of serum SCC-Ag levels in recurrent esophageal SCC (ESCC) remains unclear. This study aimed to investigate the clinical relevance of serum SCC-Ag levels in patients with recurrent ESCC after surgery.

Methods: This study retrospectively analyzed 208 patients who experienced recurrence after curative resection for ESCC. Serum SCC-Ag levels at the time of recurrence were collected from the patients' records. The patients were classified into tertiles based on the serum SCC-Ag values (low, middle, and high), and the clinical characteristics and outcomes were compared among the groups.

Results: Significant differences in sex (p = 0.001), pathologic T (p = 0.034), and N stages of primary cancer (p = 0.015) were observed among the groups. Although the recurrence patterns did not differ significantly, a high SCC-Ag was significantly associated with multiple recurrences (p = 0.019). The high-SCC-Ag group patients demonstrated a shorter time to recurrence than the other groups (p = 0.044). The SCC-Ag levels were significantly associated with overall survival after recurrence (p = 0.036). Multivariate analysis showed that serum SCC-Ag value at recurrence was an independent poor prognosticator (p = 0.031).

Conclusion: Elevated serum SCC-Ag levels at recurrence were significantly associated with a reduced time to recurrence, multiple recurrences, and a poor prognosis after recurrence. An alternative to the current standard treatment is required to improve the outcome for patients with high serum SCC-Ag levels at recurrence.
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http://dx.doi.org/10.1245/s10434-021-09945-5DOI Listing
April 2021

Compound- and fiber type-selective requirement of AMPKγ3 for insulin-independent glucose uptake in skeletal muscle.

Mol Metab 2021 Mar 30:101228. Epub 2021 Mar 30.

Nestlé Research, Société des Produits Nestlé S.A., EPFL Innovation Park, Lausanne, 1015, Switzerland; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark. Electronic address:

Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and potentially in BAT. Herein, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed whether γ3 plays a role in adipose thermogenesis and browning.

Methods: Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue, and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild-type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo as well as blood glucose clearance in response to small molecule AMPK activators that target the nucleotide-binding domain of the γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics, and function.

Results: Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high-fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and components, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose-lowering in vivo and glucose uptake specifically in glycolytic muscle ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice.

Conclusions: These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for β3-adrenergic receptor agonist-induced thermogenesis and browning of iWAT.
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http://dx.doi.org/10.1016/j.molmet.2021.101228DOI Listing
March 2021

Had COVID-19 spread in the community before the first confirmed case in Nagasaki, Japan?

Microbes Infect 2021 May-Jun;23(4-5):104812. Epub 2021 Mar 27.

Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan; Department of Laboratory Medicine, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, Japan.

This retrospective study evaluated stored nasopharyngeal swab samples from Japanese patients with influenza-like illness during the 2019/2020 season. We aimed to determine whether COVID-19 had spread in the community before the first confirmed case. The period of influenza season during 2019/2020 in Nagasaki was shorter than in previous influenza seasons. When the first COVID-19 case was reported in Nagasaki prefecture, the number of influenza cases were very low. No positive results for SARS-CoV-2 were detected in 182 samples that were obtained from adult outpatients. Our results revealed no large-scale spread of COVID-19 in the community before the first confirmed case.
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http://dx.doi.org/10.1016/j.micinf.2021.104812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997852PMC
July 2021

EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression.

Oncogenesis 2021 Mar 12;10(3):26. Epub 2021 Mar 12.

Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.

ETS homologous factor (EHF) belongs to the epithelium-specific subfamily of the E26 transformation-specific (ETS) transcription factor family. Currently, little is known about EHF's function in cancer. We previously reported that ETS1 induces expression of the ZEB family proteins ZEB1/δEF1 and ZEB2/SIP1, which are key regulators of the epithelial-mesenchymal transition (EMT), by activating the ZEB1 promoters. We have found that EHF gene produces two transcript variants, namely a long form variant that includes exon 1 (EHF-LF) and a short form variant that excludes exon 1 (EHF-SF). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting the EMT phenotypes of cancer cells. Most importantly, we identified a novel point mutation within the conserved ETS domain of EHF, and found that EHF mutations abolish its original function while causing the EHF protein to act as a potential dominant negative, thereby enhancing metastasis in vivo. Therefore, we suggest that EHF acts as an anti-EMT factor by inhibiting the expression of ZEBs, and that EHF mutations exacerbate cancer progression.
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http://dx.doi.org/10.1038/s41389-021-00313-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955083PMC
March 2021

Evaluation of a novel rapid TRC assay for the detection of influenza using nasopharyngeal swabs and gargle samples.

Eur J Clin Microbiol Infect Dis 2021 Aug 16;40(8):1743-1748. Epub 2021 Feb 16.

Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

We evaluated a novel transcription-reverse transcription concerted reaction (TRC) assay that can detect influenza A and B within 15 min using nasopharyngeal swab and gargle samples obtained from patients with influenza-like illness, between January and March 2018 and between January and March 2019. Based on the combined RT-PCR and sequencing results, in the nasal swabs, the sensitivity and specificity of TRC for detecting influenza were calculated as 1.000 and 1.000, respectively. In the gargle samples, the sensitivity and specificity of TRC were 0.946 and 1.000, respectively. The TRC assay showed comparable performance to RT-PCR in the detection of influenza viruses.
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http://dx.doi.org/10.1007/s10096-021-04193-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885976PMC
August 2021

Nodular lymphocyte-predominant Hodgkin lymphoma involving the hard palate.

Pathol Int 2021 Mar 27;71(3):213-215. Epub 2021 Jan 27.

Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

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http://dx.doi.org/10.1111/pin.13061DOI Listing
March 2021

A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner.

Biochem J 2021 02;478(3):633-646

Department of Experimental Medical Science, Lund University, Sweden.

Activation of AMP-activated protein kinase (AMPK) is considered a valid strategy for the treatment of type 2 diabetes. However, despite the importance of adipose tissue for whole-body energy homeostasis, the effect of AMPK activation in adipocytes has only been studied to a limited extent and mainly with the AMP-mimetic 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), which has limited specificity. The aim of this study was to evaluate the effect of the allosteric AMPK activators A-769662 and 991 on glucose uptake in adipocytes. For this purpose, primary rat or human adipocytes, and cultured 3T3-L1 adipocytes, were treated with either of the allosteric activators, or AICAR, and basal and insulin-stimulated glucose uptake was assessed. Additionally, the effect of AMPK activators on insulin-stimulated phosphorylation of Akt and Akt substrate of 160 kDa was assessed. Furthermore, primary adipocytes from ADaM site binding drug-resistant AMPKβ1 S108A knock-in mice were employed to investigate the specificity of the drugs for the observed effects. Our results show that insulin-stimulated adipocyte glucose uptake was significantly reduced by A-769662 but not 991, yet neither activator had any clear effects on basal or insulin-stimulated Akt/AS160 signaling. The use of AMPKβ1 S108A mutant-expressing adipocytes revealed that the observed inhibition of glucose uptake by A-769662 is most likely AMPK-independent, a finding which is supported by the rapid inhibitory effect A-769662 exerts on glucose uptake in 3T3-L1 adipocytes. These data suggest that AMPK activation per se does not inhibit glucose uptake in adipocytes and that the effects of AICAR and A-769662 are AMPK-independent.
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http://dx.doi.org/10.1042/BCJ20200659DOI Listing
February 2021

A General and Selective Synthesis of Methylmonochlorosilanes from Di-, Tri-, and Tetrachlorosilanes.

Org Lett 2021 Jan 29;23(2):601-606. Epub 2020 Dec 29.

Interdisciplinary Research Center for Catalytic Chemistry (IRC3), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.

Direct catalytic transformation of chlorosilanes into organosilicon compounds remains challenging due to difficulty in cleaving the strong Si-Cl bond(s). We herein report the palladium-catalyzed cross-coupling reaction of chlorosilanes with organoaluminum reagents. A combination of [Pd(CH)Cl] and DavePhos ligand catalyzed the selective methylation of various dichlorosilanes , trichlorosilanes , and tetrachlorosilane to give the corresponding monochlorosilanes.
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http://dx.doi.org/10.1021/acs.orglett.0c04175DOI Listing
January 2021

Homeobox transcription factor engrailed homeobox 1 is a possible diagnostic marker for adenoid cystic carcinoma and polymorphous adenocarcinoma.

Pathol Int 2021 Feb 17;71(2):113-123. Epub 2020 Dec 17.

Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Diagnostic utility of a homeobox transcription factor, engrailed homeobox 1 (En1) in the histopathology of salivary gland neoplasms was studied. The expression of En1 was immunohistochemically examined in 51 cases of adenoid cystic carcinoma (AdCC) and 143 cases of other salivary gland neoplasms. In all 51 AdCCs, En1 was expressed in 30-100% of tumor cells. In eight of nine polymorphous adenocarcinomas (PACs), En1 was expressed in 40-100% of tumor cells. Less than 5% of tumor cells expressed En1 in three of 12 epithelial-myoepithelial carcinomas, one of 17 basal cell adenomas (BCAs), and one of 34 pleomorphic adenomas (PAs). Among 55 other carcinoma cases, 1-30% of tumor cells expressed En1 in three salivary duct carcinomas (SDCs) ex PA. None of the myoepitheliomas and Warthin tumors expressed En1. When the cut-off value of the percentage of En1-expressing cells was set to 25%, all 51 AdCCs, eight of nine PACs and one SDC ex PA were En1-positive and the others were En1-negative. En1 is expressed consistently in AdCCs, frequently in PACs, but rarely in other salivary gland neoplasms. En1 is a possible diagnostic marker for AdCC and PAC in the histopathology of salivary gland neoplasms.
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http://dx.doi.org/10.1111/pin.13050DOI Listing
February 2021

A Methodology for Assessing Tumor Clonality of Adult T Cell Leukemia/Lymphoma.

Mol Ther Methods Clin Dev 2020 Dec 22;19:467-473. Epub 2020 Oct 22.

Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.

While clonal heterogeneity has been demonstrated in most cancers, quantitative assessment of individual tumor clones has not been translated to inform clinical practice. A few methods have been developed to investigate the tumor clonality of adult T cell leukemia/lymphoma (ATLL), but currently there is no clinically translatable method available for quantifying individual tumor clones in ATLL patients. Here, we present a methodology to assess the tumor clonality of ATLL and quantify patient-specific tumor clones in a clinical setting. The methodology consists of three steps: (1) selective amplification of restriction fragments containing a human T cell leukemia virus type 1 (HTLV-1) integration site, (2) amplicon deep sequencing to estimate the clonal structure and identify HTLV-1 integration sites of dominant clones, and (3) digital PCR targeting the HTLV-1 integration sites of the dominant clones to quantify specific tumor clones. We successfully tracked individual tumor clones using this approach and demonstrated that each clone had a distinct response to therapies. The procedure is straightforward and clinically feasible, which should facilitate the proper assessment and management of ATLL.
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http://dx.doi.org/10.1016/j.omtm.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701009PMC
December 2020

Primordial odontogenic tumor occurred in the maxilla with unique calcifications and its crucial points for differential diagnosis.

Pathol Int 2021 Jan 20;71(1):80-87. Epub 2020 Oct 20.

Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Primordial odontogenic tumor (POT) is a newly classified, mixed epithelial and mesenchymal odontogenic tumor, with only 17 reported cases to date. Herein, we report a case of POT that occurred in the right maxilla of a 10-year-old boy and reveal unique features in comparison with those previously reported. Radiologically, the lesion presented as a well-defined, unilocular radiolucency with notable radiopaque foci on the periphery. Microscopically, the tumor was mainly composed of dental papilla-like myxoid fibrous connective tissue, largely surrounded by non-keratinized squamous epithelium with numerous calcified particles, and partly enclosed by inner enamel epithelium-like columnar cells and enamel organ-like structures accompanied with cuboidal and/or stellate reticulum-like cells. Immunohistochemically, the epithelium tested positive for cytokeratin 14 and 19. Moreover, amelogenin and ameloblastin, matrix proteins relating to enamel formation, were positive in the covering epithelium. The tumor was enucleated as a whole, and no recurrence was recorded thereafter. Although the presence of numerous calcified particles was unique, we diagnosed this lesion as POT based on the above-described features. Furthermore, we emphasize the importance of the differential diagnosis of POT and other odontogenic tumors that resemble corresponding tooth germ components.
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http://dx.doi.org/10.1111/pin.13036DOI Listing
January 2021

[Clinicopathological features of hemorrhagic gastrointestinal stromal tumor].

Nihon Shokakibyo Gakkai Zasshi 2020 ;117(10):888-895

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University.

In order to demonstrate the bleeding risk factors of GIST (gastrointestinal stromal tumor), we retrospectively investigated clinicopathological features between hemorrhagic (H group, 24 cases) and nonhemorrhagic GIST (NH group, 30 cases). In addition, we investigated features between the E group (6 cases) necessitating TAE (trans-catheter arterial embolization) and NE group (other 48 cases). Whereas H group partly includes high-risk grade GIST with chronic bleeding, meanwhile the E group (reflecting acute bleeding) is characterized by a highly enhanced mass with ulceration, comprising of smaller low-risk grade GIST. Amongst the 29 cases for forceps biopsy, which were 6 cases (21%) including one of E group, needed be hospitalized for postbiopsy bleeding. Acute bleeding in GIST may not be associated with malignant transformation. Postbiopsy bleeding or massive hemorrhage can also be encountered particularly in highly enhanced GIST with ulceration, even with a small and low-risk grade.
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http://dx.doi.org/10.11405/nisshoshi.117.888DOI Listing
October 2020

Real-World Evaluation of Factors for Interstitial Lung Disease Incidence and Radiologic Characteristics in Patients With EGFR T790M-positive NSCLC Treated With Osimertinib in Japan.

J Thorac Oncol 2020 12 11;15(12):1893-1906. Epub 2020 Sep 11.

Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Introduction: Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed.

Methods: Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included.

Results: Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment.

Conclusions: The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.
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http://dx.doi.org/10.1016/j.jtho.2020.08.025DOI Listing
December 2020

Transcription factor EB and TFE3: new metabolic coordinators mediating adaptive responses to exercise in skeletal muscle?

Am J Physiol Endocrinol Metab 2020 10 24;319(4):E763-E768. Epub 2020 Aug 24.

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

In response to the increased energy demands of contractions, skeletal muscle adapts remarkably well through acutely regulating metabolic pathways to maintain energy balance and in the longer term by regulating metabolic reprogramming, such as remodeling and expanding the mitochondrial network. This long-term adaptive response involves modulation of gene expression at least partly through the regulation of specific transcription factors and transcriptional coactivators. The AMPK-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) pathway has long been known to orchestrate contraction-mediated adaptive responses, although AMPK- and PGC1α-independent pathways have also been proposed. Transcription factor EB (TFEB) and TFE3, known as important regulators of lysosomal biogenesis and autophagic processes, have emerged as new metabolic coordinators. The activity of TFEB/TFE3 is regulated through posttranslational modifications (i.e., phosphorylation) and spatial organization. Under nutrient and energy stress, TFEB and TFE3 are dephosphorylated and translocate to the nucleus, where they activate transcription of their target genes. It has recently been reported that exercise promotes nuclear translocation and activation of TFEB/TFE3 in mouse skeletal muscle through the Ca-stimulated protein phosphatase calcineurin. Skeletal muscle-specific ablation of TFEB exhibits impaired glucose homeostasis and mitochondrial biogenesis with reduced metabolic flexibility during exercise, and global TFE3 depletion results in diminished endurance and abolished exercise-induced metabolic benefits. Transcriptomic analysis of the muscle-specific TFEB-null mice has demonstrated that TFEB regulates the expression of genes involved in glucose metabolism and mitochondrial homeostasis. This review aims to summarize and discuss emerging roles for TFEB/TFE3 in metabolic and adaptive responses to exercise and contractile activity in skeletal muscle.
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http://dx.doi.org/10.1152/ajpendo.00339.2020DOI Listing
October 2020

A novel macrolide, solithromycin suppresses mucin overexpression induced by Pseudomonas aeruginosa LPS in airway epithelial cells.

J Infect Chemother 2020 Sep 8;26(9):1008-1010. Epub 2020 Jul 8.

Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan.

Some macrolides such as 14- and 15-membered macrolides have immunomodulatory effects such as suppression of mucin overproduction. Because a novel macrolide, solithromycin, was developed, we examined whether it suppresses the overexpression of mucin in vitro. A human airway epithelial cell line NCI-H292 was stimulated by Pseudomonas aeruginosa lipopolysaccharides to induce the overproduction of a major mucin, MUC5AC. Treatment with 10 μg/mL of solithromycin significantly inhibited LPS-induced MUC5AC in both mRNA and protein levels as well as a 15-membered macrolide, azithromycin. These findings support that solithromycin has a potential immunomodulatory effect.
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http://dx.doi.org/10.1016/j.jiac.2020.06.014DOI Listing
September 2020

Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan.

Jpn J Clin Oncol 2020 Aug;50(8):909-919

Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan.

Objective: Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan.

Methods: Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018.

Results: The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% [5/3578]), 5.9% (212/3578; Grade ≥ 3, 1.0% [35/3578]) and 11.4% (409/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively.

Conclusions: These data support the currently established benefit-risk assessment of osimertinib in this patient population.
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http://dx.doi.org/10.1093/jjco/hyaa067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401719PMC
August 2020

Polypropylene-Based Nanocomposite with Enhanced Aging Stability by Surface Grafting of Silica Nanofillers with a Silane Coupling Agent Containing an Antioxidant.

ACS Omega 2020 Jun 18;5(21):12431-12439. Epub 2020 May 18.

Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba 305-8565, Japan.

Simultaneous improvement in the mechanical properties and lifetime of polymer nanocomposites is crucially significant to further extend the versatility of polymer materials and reduce environmental impact. In this study, we fabricated reinforced polypropylene (PP)-based nanocomposites with improved aging stability by the addition of surface-modified well-ordered silica nanospheres with a silane coupling agent (SCA) containing hindered phenol antioxidant as a filler. Uniform grafting of the SCA on the filler surface contributed to homogeneous dispersion of the filler into the matrix, leading to improved properties (e.g., stiffness and ductility) and uniform distribution of the antioxidant component into the entire nanocomposite by filler dispersion. The grafting of SCA also likely provides an inhibitory effect on antioxidant migration, which leads to loss of polymer stability during the aging process. This novel idea for the material design of PP-based nanocomposites, which simultaneously enhances their mechanical properties and lifetime, is promising for application in the fabrication of various types of polymer nanocomposites.
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http://dx.doi.org/10.1021/acsomega.0c01198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271349PMC
June 2020

Magnetostrictive Performance of Electrodeposited TbDyFe Thin Film with Microcantilever Structures.

Micromachines (Basel) 2020 May 21;11(5). Epub 2020 May 21.

Department of Mechanical Systems Engineering, Tohoku University, Sendai 980-8579, Japan.

The microfabrication with a magnetostrictive TbDyFe thin film for magnetic microactuators is developed, and the magnetic and magnetostrictive actuation performances of the deposited thin film are evaluated. The magnetostrictive thin film of TbDyFe is deposited on a metal seed layer by electrodeposition using a potentiostat in an aqueous solution. Bi-material cantilever structures with the TbDyFe thin-film are fabricated using microfabrication, and the magnetic actuation performances are evaluated under the application of a magnetic field. The actuators show large magnetostriction coefficients of approximately 1250 ppm at a magnetic field of 11000 Oe.
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http://dx.doi.org/10.3390/mi11050523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281386PMC
May 2020

Genetic and histopathological analysis of a case of primary intraosseous carcinoma, NOS with features of both ameloblastic carcinoma and squamous cell carcinoma.

World J Surg Oncol 2020 Feb 29;18(1):45. Epub 2020 Feb 29.

Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.

Background: Primary intraosseous carcinoma (PIOC), NOS is an odontogenic carcinoma with unknown etiology. Its diagnosis may be used when central jaw carcinoma cannot be categorized as any other type of carcinoma. Further information on this extremely rare tumor is needed to improve our understanding and evaluate the classification of odontogenic carcinomas.

Case Presentation: We herein presented two patients with PIOC, NOS with different clinical and histopathological features and analyzed gene mutations in these patients using next-generation sequencing (NGS). The typical PIOC, NOS case had many histopathological similarities to oral squamous cell carcinoma (OSCC), including the missense point mutations of TP53 Glu285Val, KDR Gln472His, and APC Pro1433Leu, which are similar to those in other cancers; however, no mutations were detected in the other patient with an atypical presentation of PIOC, NOS, which was derived from a precursor cystic lesion with similarities to both ameloblastic carcinoma and OSCC.

Conclusions: Genetic analysis suggested that these two PIOC, NOS cases have different features and can be subcategorized.
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http://dx.doi.org/10.1186/s12957-020-01827-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049395PMC
February 2020

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy.

Nat Commun 2020 02 25;11(1):1032. Epub 2020 Feb 25.

Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074, Aachen, Germany.

The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.
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http://dx.doi.org/10.1038/s41467-020-14812-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042329PMC
February 2020

Lipidome-based rapid diagnosis with machine learning for detection of TGF-β signalling activated area in head and neck cancer.

Br J Cancer 2020 03 5;122(7):995-1004. Epub 2020 Feb 5.

Department of Anatomy and Cell Biology, Faculty of Medicine, University of Yamanashi, Chuo-city, Japan.

Background: Several pro-oncogenic signals, including transforming growth factor beta (TGF-β) signalling from tumour microenvironment, generate intratumoural phenotypic heterogeneity and result in tumour progression and treatment failure. However, the precise diagnosis for tumour areas containing subclones with cytokine-induced malignant properties remains clinically challenging.

Methods: We established a rapid diagnostic system based on the combination of probe electrospray ionisation-mass spectrometry (PESI-MS) and machine learning without the aid of immunohistological and biochemical procedures to identify tumour areas with heterogeneous TGF-β signalling status in head and neck squamous cell carcinoma (HNSCC). A total of 240 and 90 mass spectra were obtained from TGF-β-unstimulated and -stimulated HNSCC cells, respectively, by PESI-MS and were used for the construction of a diagnostic system based on lipidome.

Results: This discriminant algorithm achieved 98.79% accuracy in discrimination of TGF-β1-stimulated cells from untreated cells. In clinical human HNSCC tissues, this approach achieved determination of tumour areas with activated TGF-β signalling as efficiently as a conventional histopathological assessment using phosphorylated-SMAD2 staining. Furthermore, several altered peaks on mass spectra were identified as phosphatidylcholine species in TGF-β-stimulated HNSCC cells.

Conclusions: This diagnostic system combined with PESI-MS and machine learning encourages us to clinically diagnose intratumoural phenotypic heterogeneity induced by TGF-β.
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http://dx.doi.org/10.1038/s41416-020-0732-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109155PMC
March 2020

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression.

PLoS One 2020 3;15(2):e0222689. Epub 2020 Feb 3.

Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Autoimmune regulator (AIRE) is a transcriptional regulator that is primarily expressed in medullary epithelial cells, where it induces tissue-specific antigen expression. Under pathological conditions, AIRE expression is induced in epidermal cells and promotes skin tumor development. This study aimed to clarify the role of AIRE in the pathogenesis of oral squamous cell carcinoma (OSCC). AIRE expression was evaluated in six OSCC cell lines and in OSCC tissue specimens. Expression of STAT1, ICAM1, CXCL10, CXCL11, and MMP9 was elevated in 293A cells stably expressing AIRE, and conversely, was decreased in AIRE-knockout HSC3 OSCC cells when compared to the respective controls. Upregulation of STAT1, and ICAM in OSCC cells was confirmed in tissue specimens by immunohistochemistry. We provide evidence that AIRE exerts transcriptional control in cooperation with ETS1. Expression of STAT1, ICAM1, CXCL10, CXCL11, and MMP9 was increased in 293A cells upon Ets1 transfection, and coexpression of AIRE further increased the expression of these proteins. AIRE coprecipitated with ETS1 in a modified immunoprecipitation assay using formaldehyde crosslinking. Chromatin immunoprecipitation and quantitative PCR analysis revealed that promoter fragments of STAT1, ICAM1, CXCL10, and MMP9 were enriched in the AIRE precipitates. These results indicate that AIRE is induced in OSCC and supports cancer-related gene expression in cooperation with ETS1. This is a novel function of AIRE in extrathymic tissues under the pathological condition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222689PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996854PMC
April 2020
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