Publications by authors named "Akira Tanaka"

425 Publications

Comparison of the Japan Society of Clinical Chemistry reference method and CDC method for HDL and LDL cholesterol measurements using fresh sera.

Pract Lab Med 2021 May 23;25:e00228. Epub 2021 Apr 23.

Department of Food and Nutritional Sciences, Practice Center for Registered Dietitian, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan.

Objectives: In 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method.

Design: and methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 ​mmol/L (1000 ​mg/dL).

Results: For LDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.991x + 0.009 ​mmol/L; r ​= ​0.999; and Sy/x ​= ​0.025 ​mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.988x + 0.041 ​mmol/L, r ​= ​0.999, and Sy/x ​= ​0.019 ​mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method.

Conclusions: The JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia.
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http://dx.doi.org/10.1016/j.plabm.2021.e00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145738PMC
May 2021

Awareness of Complications of Dental Treatment in Patients Treated with Drugs Affecting the Immune System : A Nationwide Questionnaire Survey of Dental Practitioners in Japan.

Acta Med Okayama 2021 Apr;75(2):115-123

The survey and research-planning committee, Japanese Society for Dentistry of Medically Compromised Patient.

The aim of this study was to investigate the awareness and experience, among dental practitioners, of adverse events resulting from dental treatment of patients undergoing therapy with drugs that affect the immune system [angiogenesis inhibitors, biological agents, immunosuppressants, and disease-modifying anti-rheumatic drugs (DMARDs)]. For this purpose, a nationwide questionnaire survey was conducted. Questionnaires were sent to 2,050 dentists, of which 206 (10.1%) were completed and returned. The results showed that most dentists were aware of complications associated with dental treatment of patients treated with drugs that affect the immune system, and about half had actually experienced such complications. Delayed wound healing, osteonecrosis of the jaw (ONJ), and postoperative infections were reported. Whereas approximately 50% of dentists did not discontinue the drugs during dental treatment, about 18% did. During temporary drug discontinuation, some patients experienced aggravation of the primary disease, such as worsening of rheumatism, growth of tumors, and rejection reactions of transplanted organs. As for medical cooperation, only less than half of the dentists were asked for oral hygiene management by a physician prior to starting the drug treatment. Prospective studies are needed because evidence for dental treatments in patients treated with these drugs remains limited.
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http://dx.doi.org/10.18926/AMO/61877DOI Listing
April 2021

Effects of the prevention of medication-related osteonecrosis of the jaw by local administration of a dental pulp stem cell-conditioned medium to the rat tooth extraction socket.

Odontology 2021 Apr 27. Epub 2021 Apr 27.

Course of Clinical Science, Field of Oral and Maxillofacial Surgery and Systemic Medicine, Oral and Maxillofacial Surgery, Graduate School of Life Dentistry At Niigata, The Nippon Dental University, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan.

The onset of osteonecrosis of the jaw, which is a side effect of bisphosphonates, often develops after tooth extraction; measures for its prevention have not yet been established. While treatment with systemic administration of bone marrow stem cell-derived conditioned medium for medication-related osteonecrosis of the jaw (MRONJ) has been reported, its preventive effects have not been clarified yet, and the high degree of invasiveness of bone marrow fluid collection remains an issue. Therefore, we created a rat model of MRONJ using BP zoledronic acid, used a dental pulp stem cell-conditioned medium (DPSC-CM), which can be collected relatively easily, and locally applied it to the tooth extraction socket with atelocollagen and gelatin sponges. The preventive effect on the onset of MRONJ was subsequently examined. The results demonstrated that the bone exposure width of the extraction socket was reduced, and the mucosal covering was promoted in the atelocollagen + DPSC-CM group as compared with the other groups. Furthermore, histological results indicated a decrease in the number of empty bone lacunae, whereas immunohistochemical staining revealed the presence of many vascular endothelial growth factor (VEGF)-positive cells. Moreover, the results of the investigation of the sustained release of atelocollagen using VEGF indicated the release of VEGF over time. Our results suggest that local administration of DPSC-CM using atelocollagen may be a useful method for the prevention of MRONJ triggered by tooth extraction.
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http://dx.doi.org/10.1007/s10266-021-00607-2DOI Listing
April 2021

[A case of gastric hamartomatous inverted polyp (GHIP), preoperatively diagnosed based on EUS findings].

Nihon Shokakibyo Gakkai Zasshi 2021 ;118(4):327-339

Department of Gastroenterology, Saitama Medical Center, Jichi Medical University.

We report the case of a patient with a gastric hamartomatous inverted polyp (GHIP) and discuss the relevant literature. A 65-year-old woman was referred to our hospital because of a slow-growing pedunculated polyp measuring 30mm in diameter, present in the greater curvature of the fundic region of the stomach. It was covered with normal gastric mucosa, and the top was reddish. A biopsy specimen taken from the reddish area;it showed inflamed gastric mucosa with hyperplastic and mildly distorted foveolar glands. Abdominal contrast computed tomography showed a protruding tumor that was unevenly enhanced and contained multiple cystic lesions inside. Endoscopic ultrasonography (EUS, Olympus GIF-UCT260) showed a heterogeneous tumor with multiple anechoic or low-echoic cystic lesions, originating from the second or third layer of the stomach wall. The patient had no clinical symptoms, no family history, and no laboratory data abnormalities. Based on these findings, we diagnosed her with GHIP. As the polyp had shown an increase in size (5mm/5 years) and about 20% of GHIPs were reported to coexist with precancerous or cancerous lesions, we performed endoscopic polypectomy. The tumor was histologically characterized by submucosal growth of hypertrophic glands with cystic dilatation, accompanied by smooth muscle proliferation, branching from the bundles. Thus, the final diagnosis was GHIP. Though GHIP is a rare and basically benign polyp, the rate with gastric cancer was reported to be relatively high. EUS findings are important for the diagnosis and when GHIP is suspected, the lesion requires to be monitored closely. If there are some signs that suggest a malignancy (growth, changes in surface mucosa, etc.), endoscopic en bloc resection or surgical resection should be considered.
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http://dx.doi.org/10.11405/nisshoshi.118.327DOI Listing
April 2021

Successful living donor liver transplantation for liver failure due to maternal T cell engraftment following cord blood transplantation in X-linked severe combined immunodeficiency disease: Case report.

Am J Transplant 2021 Apr 1. Epub 2021 Apr 1.

Department of Gastroenterological, General and Transplant Surgery, Jichi Medical University, Tochigi-ken, Japan.

Maternal T cells from perinatal transplacental passage have been identified in up to 40% of patients with severe combined immunodeficiency (SCID). Although engrafted maternal T cells sometimes injure newborn tissue, liver failure due to maternal T cells has not been reported. We rescued a boy with X-linked SCID who developed liver failure due to engrafted maternal T cell invasion following living donor liver transplantation (LDLT) following unrelated umbilical cord blood transplantation (UCBT). After developing respiratory failure 3 weeks postpartum, he was diagnosed with X-linked SCID. Pathological findings showed maternal T cells engrafted in his liver and hepatic fibrosis gradually progressed. He underwent UCBT at 6 months, but hepatic function did not recover and liver failure progressed. Therefore, he underwent LDLT using an S2 monosegment graft at age 1.3 years. The patient had a leak at the Roux-en-Y anastomosis, which was repaired. Despite occasional episodes of pneumonia and otitis media, he is generally doing well 6 years after LDLT with continued immunosuppression agents. In conclusion, the combination of hematopoietic stem cell transplantation (HSCT) and liver transplantation may be efficacious, and HSCT should precede liver transplantation for children with X-linked SCID and liver failure.
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http://dx.doi.org/10.1111/ajt.16588DOI Listing
April 2021

Optimal Contact Concentration of Paclitaxel in the Collagen Gel Droplet-Embedded Culture Drug Sensitivity Test for Human Oral Squamous Cell Carcinoma and Evaluation of Combination with Cetuximab.

Chemotherapy 2021 Feb 9;65(5-6):147-157. Epub 2021 Feb 9.

Department of Oral and Maxillofacial Surgery, The Nippon Dental University School of Life Dentistry at Niigata, Niigata, Japan.

Objective: A combination of the taxane anticancer drug paclitaxel (PTX) and molecular target drug cetuximab (cMab) is effective for the treatment of head and neck squamous cell carcinoma (HNSCC). However, its use is associated with serious side effects, such as neuropathy and myelosuppression. In addition, it is administered regardless of patient sensitivity because biomarkers indicating its efficacy are unavailable. Therefore, we investigated the usefulness of setting the indicated contact concentration of PTX and predicted the antitumor effect of combined contact with cMab using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST).

Method: Twelve human oral squamous cell carcinoma (OSCC) cell lines (i.e., SAS, HSC-2, HSC-3, HSC-4, OSC-19, OSC-20, KON, HO-1-N-1, HO-1-u-1, SAT, SCC-4, and Nialym) were used. Using the CD-DST, we calculated the optimal contact concentration of the cells with PTX based on the clinical response rate of HNSCC and evaluated the combined contact with cMab. Furthermore, nude mice were treated with standalone PTX and PTX + cMab, and the results were compared with those of the CD-DST.

Results: Based on the CD-DST, 0.1 μg/mL was the optimal contact concentration of PTX, to which the cells showed dose-dependent sensitivity. Moreover, the CD-DST method was used to evaluate the antitumor effects on OSCC even when PTX was used in combination with cMab. The antitumor effects in the CD-DST and nude mice were correlated (p < 0.05).

Conclusion: The CD-DST results suggested that it was possible to predict the clinical effects of single-contact PTX and the enhancing effect of cMab + PTX.
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http://dx.doi.org/10.1159/000512542DOI Listing
February 2021

Intestinal perforation secondary to intestinal Burkitt lymphoma.

Int J Surg Case Rep 2021 Feb 25;79:417-420. Epub 2021 Jan 25.

Department of Surgery, Jichi Medical University Saitama Medical Center, 1-chome-847 Amanuma-cho, Omiya-ku, Saitama City, Saitama, 330-8503, Japan. Electronic address:

Introduction And Importance: Small intestinal perforation in patients with Burkitt lymphoma is extremely rare. We present the first report of such a case.

Case Presentation: A 53-year-old woman was admitted with abdominal pain and vomiting. Abdominal examination revealed rigidity and tenderness in the upper abdomen. Computed tomography scan showed thickening of the wall of the jejunum, intra-abdominal free gas, and ascites; the patient was diagnosed with small intestinal perforation, and underwent emergency surgery on the same day. Laparoscopic findings were a 50 mm jejunal perforation and perforation in the transverse mesocolon. A partial jejunal resection of the perforated area, partial transverse colectomy, temporary colostomy, and intra-abdominal drainage were performed. Histological examination showed diffuse infiltration of medium-sized atypical lymphocytes in the perforated area, exhibiting a "starry sky" appearance. Immunostaining results showed that the atypical lymphocytes were CD20 and virtually 100% Ki-67 positive, and CD56, CD30, and EBER negative. The lesion was identified as Burkitt lymphoma (BL). The postoperative course was favorable. On postoperative day 18 the patient began chemotherapy through the hematology department. Currently, the patient is in remission.

Clinical Discussion: The majority of the malignant lymphomas occurring in the digestive tract are identified in the stomach; over 90% are B-cell lymphomas and mucosa-associated lymphoid tissue lymphoma Nakamura et al. BL originating from the small intestine accounts for only about 9%.

Conclusion: The incidence of BL in the small intestine is low. Pretreatment BL can lead to bowel perforation. Prompt involvement of the hemato-oncologist after definitive diagnosis, and commencing chemotherapy as early as possible after surgery, are thought to improve prognosis.
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http://dx.doi.org/10.1016/j.ijscr.2021.01.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851420PMC
February 2021

Questionnaire survey of angiogenesis inhibitor-related oral complications based on a nation-wide study in Japan.

J Dent Sci 2021 Jan 15;16(1):375-379. Epub 2020 Mar 15.

Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Mibu, Japan.

Background/purpose: The prevalence of oral adverse events and dental treatments related complications during the molecular targeted drugs therapy remains unclear. The purpose of this study was to investigate the contents of dental treatment-related complications in Japanese patients during molecular targeted therapy.

Materials And Methods: The nation-wide survey of dental treatment related complications was performed by the Japanese Society of Dentistry for Medically Compromised Patient as retrospective cohort study.

Results: Among 212 dentists, 87.3% recognized the possibility of dental treatments related complications in patients with angiogenesis inhibitors. The oral adverse events including dental treatment-related complications associated with angiogenesis inhibitors were 79 cases. In patients with angiogenesis inhibitors, 73.4% of patients were administrated with bevacizumab. The average administration period of angiogenesis inhibitors was 14.0 ± 10.0 months. As the dental treatment related complications, delayed wound healing was most commonly seen in 45 patients (57.0%), followed by osteonecrosis of the jaw in 25 (31.6%). The triggered factor of complications was tooth extraction in 51 cases (96.2%).

Conclusion: The extraction of the tooth with pre-existing inflammation may be suggested as one of risk factors for angiogenesis inhibitor-related dental treatment complications.
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http://dx.doi.org/10.1016/j.jds.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770245PMC
January 2021

Presence of anti-transcriptional intermediary factor-1 gamma antibodies in a dermatomyositis patient with retroperitoneal cancer of unknown primary site.

Mod Rheumatol Case Rep 2021 01 9;5(1):62-68. Epub 2020 Jul 9.

Division of Rheumatology, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

A 71-year-old woman with dermatomyositis (DM) received glucocorticoid steroid (GCS) and tacrolimus treatment. Relapse of skin symptoms was observed after tapering the GCS dose, and the patient tested positive for anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibody. Examinations for malignancy were repeatedly performed. However, no obvious findings indicative of a tumour were observed. Two years after, a retroperitoneal tumour was detected and pathologically diagnosed as poorly differentiated adenocarcinoma. The patient developed intestinal and biliary obstruction and eventually died of sepsis. Herein, we report the presence of anti-TIF1-γ antibodies in a DM patient with cancer of unknown primary site.
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http://dx.doi.org/10.1080/24725625.2020.1789302DOI Listing
January 2021

The diagnosis and treatment of hereditary angioedema patients in Japan: A patient reported outcome survey.

Allergol Int 2021 Apr 6;70(2):235-243. Epub 2020 Nov 6.

Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; HAEJ Registered NPO, Japan. Electronic address:

Background: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs.

Methods: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis.

Results: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect.

Conclusions: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.
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http://dx.doi.org/10.1016/j.alit.2020.09.008DOI Listing
April 2021

Expression of clock gene in omental and mesenteric adipose tissue in patients with type 2 diabetes.

BMJ Open Diabetes Res Care 2020 08;8(1)

Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Introduction: We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor ( and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity.

Research Design And Methods: The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2).

Results: Acetylation of histone H3K9 at the promoter region of and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue.

Conclusions: The changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.
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http://dx.doi.org/10.1136/bmjdrc-2020-001465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437886PMC
August 2020

Cutaneous carcinomatous lymphangiosis mimicking angiosarcoma of the face possibly caused by salivary duct carcinoma.

J Dermatol 2020 Nov 4;47(11):e414-e415. Epub 2020 Aug 4.

Department of Dermatology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

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http://dx.doi.org/10.1111/1346-8138.15531DOI Listing
November 2020

Myofibroblast phagocytic cutaneous mucinosis: phagocytosis of mucinous substances by myofibroblasts in a distinctive cutaneous mucinosis: A case report.

Medicine (Baltimore) 2020 Jul;99(29):e20867

Department of Pathology.

Rationale: Phagocytosis is an important physiological process for eliminating unnecessary substances or dead cells after tissue damage, such as inflammation or infarction. Phagocytosis was previously considered to be mainly performed by professional phagocytotic cells, such as macrophages. In contrast, we previously demonstrated that the phagocytosis of dead cells and unnecessary substances by myofibroblasts is as important as that by professional phagocytotic cells in myocardial infarction. Based on our discovery, we speculated that phagocytosis by myofibroblasts may be a more common pathological phenomenon also in other diseases than previously believed.

Patient Concerns: A 44-year-old male patient with atopic dermatitis developed a cutaneous reddish nodule with an underlying induration on his thigh.

Interventions: The cutaneous lesion was surgically removed.

Diagnoses: Histopathological examination demonstrated that the cutaneous lesion had solid infiltration by inflammatory cells, namely, plasma cells, histiocytes, and lymphocytes, in the dermis. The cutaneous lesion included mucinosis in the dermis. Inside the mucinosis, we detected cells with clear areas of mucinous substances. Some of the cells were α-smooth muscle actin-positive myofibroblasts. Electron microscopic images demonstrated that there were collagen bands in the cells with mucinous engulfment. Based on these pieces of evidence, we conclude that these mucinous phagocytotic cells were myofibroblasts, not professional phagocytotic cells, such as macrophages.

Outcomes: There was no recurrence of the lesion.

Lessons: The clinical appearance of this case resembled that of previously reported solitary cutaneous focal mucinoses. However, our case had distinctive characteristics, such as the phagocytosis of mucinous substances by myofibroblasts, multiple mucinous lesions in a single eruption, and the presence of inflammatory cells, which have not been previously reported. For this distinct cutaneous lesion, a clear dermatological and pathological name has yet to be determined. We propose "myofibroblast phagocytic cutaneous mucinosis" as a candidate name. In addition, our discoveries suggest that phagocytosis by myofibroblasts is not rare but rather is a common pathological phenomenon that has been undetected or unrecognized.
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http://dx.doi.org/10.1097/MD.0000000000020867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373612PMC
July 2020

Investigating the effect of antiseptic solution on the release of interleukin-6 and transforming growth factor beta 1 from human gingival fibroblasts using wound healing assays.

J Oral Sci 2020 ;62(3):293-297

Advanced Research Center, The Nippon Dental University School of Life Dentistry at Niigata.

This in vitro study evaluated the effect of different antiseptics and different concentrations thereof in a model of wound healing using human gingival fibroblasts. The fibroblasts were rinsed with four different antiseptic solutions: sodium hypochlorite (HYP), hydrogen peroxide (HO), chlorhexidine digluconate (CHX), and benzalkonium chloride (BC). The effect on the release of interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-β1) was investigated using enzyme-linked immunosorbent assays (ELISAs). In addition, the effects of the antiseptics on wound healing at 1, 12, 24, and 48 h were assessed through a wound healing assay. The viability of the fibroblasts rinsed with antiseptics was investigated with respect to the concentrations inhibiting cell growth by 50% (IC), 25% (IC), and ≤2% (IC). A statistically significant increased release of IL-6 was obtained with BC IC and IC after 12, 24, and 48 h (P < 0.01). For TGF-β1, no significant release was found for CHX IC after 24 and 48 h or for IC and IC after 12 h. There was no significant effect on wound healing capacity for CHX or for BC IC and IC. This study demonstrated that antiseptic rinses of human gingival fibroblasts alter the release of IL-6 and TGF-β1 and impact wound healing capacity, with both BC and CHX conferring neutral effects.
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http://dx.doi.org/10.2334/josnusd.19-0151DOI Listing
June 2020

Verrucous lupus erythematosus localized to the oral mucosa and fingers rapidly progressed to systemic lupus erythematosus followed by fatal invasive aspergillosis.

Int J Dermatol 2020 Dec 23;59(12):e445-e447. Epub 2020 Jun 23.

Division of General Medicine, Department of Comprehensive Medicine 1, Jichi Medical University Saitama Medical Center, Saitama City, Japan.

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http://dx.doi.org/10.1111/ijd.15016DOI Listing
December 2020

Leukotriene B receptor 1 exacerbates inflammation following myocardial infarction.

FASEB J 2020 06 8;34(6):8749-8763. Epub 2020 May 8.

Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Leukotriene B receptor 1 (BLT1), a high-affinity G-protein-coupled receptor for leukotriene B4 (LTB ), is expressed on various inflammatory cells and plays critical roles in several inflammatory diseases. In myocardial infarction (MI), various inflammatory cells are known to be recruited to the infarcted area, but the function of BLT1 in MI is poorly understood. Here, we investigated the role of BLT1 in MI and the therapeutic effect of a BLT1 antagonist, ONO-4057, on MI. Mice with infarcted hearts showed increased BLT1 expression and LTB levels. BLT1-knockout mice with infarcted hearts exhibited attenuated leukocyte infiltration, proinflammatory cytokine production, and cell death, which led to reduced mortality and improved cardiac function after MI. Bone-marrow transplantation studies showed that BLT1 expressed on bone marrow-derived cells was responsible for the exacerbation of inflammation in infarcted hearts. Furthermore, ONO-4057 administration attenuated the inflammatory responses in hearts surgically treated for MI, which resulted in reduced mortality and improved cardiac function after MI. Our study demonstrated that BLT1 contributes to excessive inflammation after MI and could represent a new therapeutic target for MI.
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http://dx.doi.org/10.1096/fj.202000041RDOI Listing
June 2020

Biosynthetic gene cluster identification and biological activity of lucilactaene from sp. RK97-94.

Biosci Biotechnol Biochem 2020 Jun 11;84(6):1303-1307. Epub 2020 Feb 11.

Chemical Biology Research Group, RIKEN CSRS, Wako, Saitama, Japan.

We identified the biosynthetic gene cluster for lucilactaene, a cell cycle inhibitor from a filamentous fungus sp. RK 97-94. The knockout strain accumulated demethylated analogs, indicating the involvement of Luc1 methyltransferase in lucilactaene biosynthesis. Lucilactaene showed potent antimalarial activity. Our data suggested that methylation and ether ring formation are essential for its potent antimalarial activity.
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http://dx.doi.org/10.1080/09168451.2020.1725419DOI Listing
June 2020

Ileectomy performed on a case of adult intussusception due to inversion of Meckel's diverticulum.

J Surg Case Rep 2020 Jan 13;2020(1):rjz367. Epub 2020 Jan 13.

Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

We report a rare case of adult intussusception caused by an inverted Meckel's diverticulum with ectopic pancreatic tissue. A 43-year-old woman was referred to our hospital with complaints of abdominal distention, intermittent abdominal pain and nausea that she experienced 3 months ago. Abdominal computed tomography scans demonstrated ileo-ileal intussusception that contained a tumor with fat density as the lead point. Laparoscopic-assisted partial resection of the small intestine was performed. The surgical specimen showed an elongated polypoid lesion invaginated into the intestinal tract indicating an inverted Meckel's diverticulum. Pathological findings showed a true diverticulum that ran antimesentrically, with tall columnar epithelium, a mucous gland and an islet of Langerhans. The postoperative period was uneventful, and she was discharged on the ninth postoperative day.
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http://dx.doi.org/10.1093/jscr/rjz367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963164PMC
January 2020

Exercise-induced allergic reactions on desensitization to wheat after rush oral immunotherapy.

Allergy 2020 06 6;75(6):1414-1422. Epub 2020 Feb 6.

Department of Allergy, Aichi Children's Health and Medical Center, Obu, Japan.

Background: The effect of oral immunotherapy (OIT) on wheat allergy is promising in terms of the potential to obtain desensitization; however, the frequency of exercise-induced allergic reactions on desensitization (EIARDs) and the associated risk factors remain to be determined.

Methods: Twenty-five patients underwent rush OIT for wheat allergy, and 21 achieved the full-dose intake of wheat products (5 g of wheat protein). Exercise-provocation tests were repeatedly performed after the ingestion of a full-dose wheat product. The time-course of the levels of the specific IgEs (sIgE) to wheat extract, total gliadin, deamidated gliadin, recombinant gliadin components (α/β-, γ- and ω-5-), and glutenin (high and low molecular weight) components was analyzed using ImmunoCAP , ELISA, or IgE immunoblotting.

Results: Fourteen patients (66.7%) were diagnosed as EIARD+, which remained 5 years after rush OIT in 11 patients (52.4%). There were no differences in the clinical backgrounds of the EIARD+ and EIARD- patients. However, EIARD+ patients showed significantly higher sIgE levels to all gliadin and glutenin components than EIARD- patients before OIT. The sIgE levels to each component decreased equally after 1 and 2 years of OIT. On IgE immunoblotting, sera from all patients reacted to the multiple gluten bands, and some reacted to the water-soluble bands. The intensity of all IgE-reactive bands also became equally lighter after OIT.

Conclusions: EIARDs were frequently observed and remained for a long period after successful OIT for wheat allergy. None of the specific wheat components were found to contribute to EIARDs.
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http://dx.doi.org/10.1111/all.14182DOI Listing
June 2020

Identification of the optimal cetuximab concentration that is effective against oral squamous cell carcinoma in collagen gel droplet embedded culture drug sensitivity testing.

Mol Clin Oncol 2020 Jan 20;12(1):51-56. Epub 2019 Nov 20.

Department of Oral and Maxillofacial Surgery, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan.

Anticancer drug sensitivity testing using the collagen gel droplet embedded culture drug sensitivity test (CD-DST) on oral squamous cell carcinoma (OSCC) samples beginning from 2010 has been conducted. The present study investigated the effect of adding cetuximab (Erbitux), a molecularly targeted drug, on anticancer drug activity against clinical OSCC specimens. A total of 25 specimens were obtained from 25 patients with OSCC between October 2013 and December 2017. The present study conducted anticancer drug sensitivity testing for cisplatin (CDDP), 5-fluorouracil (5-FU), cetuximab, three-drug combination, single agent and multi drug combinations, and cetuximab addition to the aforementioned regimens using CD-DST. In addition, the optimum concentration of each drug was evaluated. The overall evaluation success rate of the CD-DST method for OSCC specimens was 84.0% (21 of 25 cases); sensitivity to anticancer drugs and cetuximab could be evaluated. The efficacy rate of a cetuximab single agent and CDDP + 5-FU (PF) at a cut-off value of 50% was similar to the known clinical response rate. However, at a cut-off value of 50%, the efficacy of PF + cetuximab was calculated to be 40%, which was higher than the clinical response rate. The CD-DST method could be used to evaluate cetuximab, a molecularly targeted drug. Furthermore, its additive effect on conventional chemotherapy could be evaluated. The CD-DST method is suitable for evaluating and selecting chemotherapy regimens, including molecularly targeted drugs. Future studies are required to generate and evaluate relevant clinical data.
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http://dx.doi.org/10.3892/mco.2019.1953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904869PMC
January 2020

Reduced Toxicity of Trichothecenes, Isotrichodermol, and Deoxynivalenol, by Transgenic Expression of the 3--Acetyltransferase Gene in Cultured Mammalian FM3A Cells.

Toxins (Basel) 2019 11 10;11(11). Epub 2019 Nov 10.

Graduate School of Science and Engineering, Toyo University, 2100 Kujirai, Kawagoe, Saitama 350-8585, Japan.

In trichothecene-producing fusaria, isotrichodermol (ITDol) is the first intermediate with a trichothecene skeleton. In the biosynthetic pathway of trichothecene, a 3--acetyltransferase, encoded by , acetylates ITDol to a less-toxic intermediate, isotrichodermin (ITD). Although trichothecene resistance has been conferred to microbes and plants transformed with , there are no reports of resistance in cultured mammalian cells. In this study, we found that a 3--acetyl group of trichothecenes is liable to hydrolysis by esterases in fetal bovine serum and FM3A cells. We transfected the cells with under the control of the MMTV-LTR promoter and obtained a cell line G3 with the highest level of C-3 acetylase activity. While the wild-type FM3A cells hardly grew in the medium containing 0.40 μM ITDol, many G3 cells survived at this concentration. The IC values of ITDol and ITD in G3 cells were 1.0 and 9.6 μM, respectively, which were higher than the values of 0.23 and 3.0 μM in the wild-type FM3A cells. A similar, but more modest, tendency was observed in deoxynivalenol and 3-acetyldeoxynivalenol. Our findings indicate that the expression of conferred trichothecene resistance in cultured mammalian cells.
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http://dx.doi.org/10.3390/toxins11110654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891669PMC
November 2019

A prospective clinical study assessing the presence of exfoliated cancer cells and rectal washout including tumors in patients who receive neoadjuvant chemoradiotherapy for rectal cancer.

Surg Today 2020 Apr 21;50(4):352-359. Epub 2019 Oct 21.

Department of Surgery, School of Medicine, Tokai University, 143 Shimokasuya Isehara, Tokyo, Kanagawa, 259-1193, Japan.

Purpose: Rectal washout is performed in rectal cancer surgery to eliminate exfoliated cancer cells. Before rectal washout, a cross-clamp should generally be placed distal to the tumor. In some patients with lower rectal cancer, however, the tumor cannot be adequately isolated. We, therefore, hypothesized that neoadjuvant chemoradiotherapy (nCRT) can decrease the number of exfoliated cancer cells even after the rectal washout including tumors.

Methods: We prospectively studied 86 patients with rectal cancer who underwent proctectomy after nCRT. A cross-clamp was applied proximal to the tumor, and the rectum was washed with 2000 mL of physiological saline solution. The initial 100 mL used to wash the rectum was collected as a pre-washout sample. After the rectum was washed with the remaining 1900 mL, the solution remaining in the rectum was collected as a post-washout sample. Cells classified as class IV or higher according to the papanicolaou classification were considered to indicate a positive diagnosis.

Results: The cytological diagnosis was positive in pre-washout samples in 21 patients (24%) and post-washout samples in two patients (2%).

Conclusion: In patients with rectal cancer, nCRT may decrease the number of exfoliated cancer cells in the rectum, and rectal washout including the tumor may be oncologically acceptable.
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http://dx.doi.org/10.1007/s00595-019-01883-wDOI Listing
April 2020

Oncogenic Ras mutant causes the hyperactivation of NF-κB via acceleration of its transcriptional activation.

Mol Oncol 2019 11 18;13(11):2493-2510. Epub 2019 Oct 18.

Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University, Shimotsuke, Japan.

It is well established that nuclear factor κB (NF-κB) acts as one of the most important transcription factors for tumor initiation and progression, as it both protects cells from apoptotic/necrotic signals and accelerates angiogenesis and tumor metastasis, which is mediated via the expression of target genes. However, it has not yet been clarified how oncogenic signals accelerate the activation of NF-κB. In the current study, we utilized untransformed NIH-3T3 cells stably harboring a κB-driven luciferase gene to show that an oncogenic mutant of Ras GTPase augmented TNFα-induced NF-κB activation. Notably, enforced expression of cyclin-dependent kinase inhibitors, such as p27 and p21 , effectively canceled the accelerated activation of NF-κB, suggesting that oncogenic Ras-induced cell cycle progression is essential for the hyperactivation of NF-κB. Furthermore, we found that Ras (G12V) augmented the transcriptional activation of NF-κB, and this activation required the p38 MAP kinase. We observed that a downstream kinase of p38 MAP kinase, MSK1, was activated by Ras (G12V) and catalyzed the phosphorylation of p65/RelA at Ser-276, which is critical for its transcriptional activation. Significantly, phosphorylation of the p65/RelA subunit at Ser-276 was elevated in patient samples of colorectal cancer harboring oncogenic mutations of the K-Ras gene, and the expression levels of NF-κB target genes were drastically enhanced in several cancer tissues. These observations strongly suggest that oncogenic signal-induced acceleration of NF-κB activation is caused by activation of the p38 MAP kinase-MSK1 signaling axis and by cell cycle progression in cancer cells.
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http://dx.doi.org/10.1002/1878-0261.12580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822247PMC
November 2019

Difficult Diagnosis of Peritoneal Serous Papillary Carcinoma in a 63-year-old Woman: A Case Report.

Tokai J Exp Clin Med 2019 Sep 20;44(3):49-53. Epub 2019 Sep 20.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Background: Peritoneal serous papillary carcinoma (PSPC) is a rare disease. It is clinically and histologically similar to progressive ovarian serous adenocarcinoma and involves normal-sized ovaries, making it challenging to diagnose. In this report, we describe a case of peritoneal serous papillary carcinoma that was difficult to identify and how we made a correct diagnosis in order to begin a timely course of treatment.

Case Presentation: A 63-year-old woman with chief complaints of dizziness and abdominal pain was examined, but showed no particular abnormality. Class III cytology of the endometrium was detected through magnetic resonance imaging and a laparotomy was performed on suspicion of endometrial cancer. The patient was finally diagnosed with peritoneal serous papillary carcinoma and was treated with surgical resection and the standard indicated course of chemotherapy.

Conclusions: The diagnosis and treatment of peritoneal serous papillary carcinoma may be delayed or may not be performed unless Class III findings are detected through uterine mucosal cytology before surgery. Surgeons should not hesitate to perform laparotomy when necessary to identify and appropriately treat patients, even if abnormalities are not detected in the preoperative examination.
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September 2019

Preventive effects of a synthetic absorbable antiadhesive film (seprafilm) on small bowel obstruction in patients who underwent elective surgery for colon cancer: A randomized controlled trial.

J Surg Oncol 2019 Nov 7;120(6):1038-1043. Epub 2019 Aug 7.

Department of Surgery, Tokai University Hospital, Kanagawa, Japan.

Background: Seprafilm did not decrease small bowel obstruction (SBO), but significantly decreased reoperation in patients with inflammatory bowel disease. However, the preventive effect in colon cancer remains unclear.

Methods: We conducted a randomized controlled trial in patients with colon cancer. The study group comprised 345 patients with colon cancer. In the seprafilm group (n = 166), two sheets of seprafilm were inserted under a midline incision. Patients who were admitted and required decompression were considered to have SBO.

Results: The median follow-up was 61.9 months. Patient characteristics were well balanced. There was no significant difference in the incidence of SBO between the seprafilm group (7.8%) and the control group (10.6%) (P = .46). In patients who underwent reoperation, SBO occurred in a midline incision in one patient and at other sites in four patients in the seprafilm group as compared with two patients and five patients, respectively, in the control group. Multivariate analysis showed that only a history of laparotomy was an independent risk factor for SBO.

Conclusions: Seprafilm did not decrease SBO or reoperation in colon cancer. The incidence of SBO caused by adhesion to the midline incision was relatively low as compared with that caused by adhesion to other sites.
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http://dx.doi.org/10.1002/jso.25664DOI Listing
November 2019

Unclassified Vasculitis with Episcleritis, Thrombophlebitis, Deep Vein Thrombosis, Pulmonary Vasculitis, and Intracranial Vasculitis: An Autopsy Case Report.

Am J Case Rep 2019 Jun 23;20:886-895. Epub 2019 Jun 23.

Department of Rheumatology, Saitama Medical Center, Jichi Medical University, Saitama City, Saitama, Japan.

BACKGROUND Systemic vasculitides constitute heterogenous conditions affecting many organs and systems through blood vessel inflammation. Although there are some classifications for vasculitis, several vasculitides are "unclassified" because they cannot be clearly assigned to one of the known entities. CASE REPORT We report an autopsy case of a 67-year-old Japanese man who presented with fever, ocular pain, erythema, chest pain, and headache. The disease caused episcleritis, thrombophlebitis, extensive deep vein thrombosis, multiple pulmonary nodules and masses, hypertrophic pachymeningitis, and hyper-intensity areas in brain parenchyma on magnetic resonance images. Histopathology of the pulmonary nodule confirmed vasculitis affecting medium-to-small veins and arteries without necrotizing vasculitis or granulomatous inflammation. We diagnosed the patient with unclassified vasculitis based on the clinicopathological characteristics. Steroids in combination with immunosuppressants were used, but the disease was refractory and relapsing. The disease activity was eventually controlled with rituximab, but the patient died of bronchopneumonia. On autopsy, lung and brain findings indicated healed vascular inflammation. CONCLUSIONS This is the first case report of unclassified vasculitis, which is characterized as medium-to-small-sized arteritis and phlebitis, causing episcleritis, thrombophlebitis, deep vein thrombosis, pulmonary vasculitis, and intracranial vasculitis. The clinical conditions share some similarities with granulomatosis with polyangiitis and Behçet's disease; however, they meet no classification criteria of any specific vasculitis. More cases need to be analyzed to confirm our findings.
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http://dx.doi.org/10.12659/AJCR.915527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604764PMC
June 2019

Pancreatic carcinoma metastasis to a lung carcinoma lesion and pulmonary fibrotic regions, overtaking the stromal microenvironment: A case report.

Medicine (Baltimore) 2019 Jun;98(24):e15888

Department of Pathology.

Rationale: Suppression and of cancer metastasis is one of the most important issues in cancer care. Considering the typical clinical course of metastases, cancer cells might prefer certain environments or conditions. However, favorable environments for cancer metastasis have not been clearly identified. We had previously described a case of dual, yet separate, pancreatic and colon cancer, in which the metastatic pancreatic cancer was localized at the invasive portion of the colon cancer. We hypothesized that metastatic pancreatic cancer took over the colon cancer microenvironment.

Patient Concerns: We experienced an another case of double cancer in a 65-year-old man who had lung squamous cell carcinoma and an independent pancreatic adenocarcinoma that metastasized to the liver as well as to the lung cancer lesion and pulmonary fibrotic regions associated with pneumothorax and bronchiolization.

Interventions: The pneumothorax could not be controlled by conservative treatment. Thus, an emergency surgery with partial resection of the lower lobe of right lung was performed.

Diagnoses: We found multiple pancreatic cancer metastases in the lung cancer and fibrotic lesions in the surgical specimen. However, we detected no metastasis in normal lung tissues except inside small arteries, although the lung cancer and fibrotic tissue areas were smaller than the normal lung tissue areas in the surgical specimen.

Outcomes: The patient died 50 days after the surgery.

Lessons: This case may thus provide evidence to strengthen our hypothesis that pancreatic cancer prefers to metastasize to other independent cancer lesions, overtaking the cancer microenvironment constructed by other independent cancers. The lung cancer microenvironment, rich in myofibroblasts and/or cancer-associated fibroblasts, might be suitable for pancreatic carcinoma metastasis. In addition, we propose the hypothesis that compared with normal tissues, noncancerous fibrotic lesions are preferable destinations for cancer metastasis. Furthermore, metastasis of pancreatic carcinoma to lung cancer and fibrotic tissues might be more common, although such cases have not been previously reported.
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http://dx.doi.org/10.1097/MD.0000000000015888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587633PMC
June 2019

Selectively high efficacy of eribulin against high-grade invasive recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Oncol Lett 2019 Jun 19;17(6):5064-5072. Epub 2019 Mar 19.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis. Over the past decade, a major development in the first-line treatment of R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy. Currently, a promising novel treatment option in R/M SCCHN has emerged, termed immune checkpoint inhibitors. However, only a few patients presenting with R/M SCCHN have exhibited meaningful tumor regression with these agents. Therefore, novel agents are required to order improve the overall survival of patients with R/M SCCHN. Recently, we demonstrated that R/M SCCHN cells are highly sensitive to eribulin. In the present study, the effects of eribulin, paclitaxel and vinblastine were investigated in R/M SCCHN (OLC-01 and OSC-19) and locally advanced SCCHN (OSC-20) cells. Tumour-inhibitory activities of eribulin against R/M SCCHN were evaluated in orthotopic xenograft models. The data revealed that eribulin has sub-nM growth inhibitory activities against OLC-01 cells, and that it is more potent than paclitaxel and vinblastine. The reduced expression of Tubulin Beta 3 Class III (TUBB3) following treatment was correlated with a high sensitivity to eribulin. Histological analysis of OLC-01 cells in NOD-SCID mice demonstrated that they had a higher invasiveness in the tissue around the alveolar cancer when compared with the histology of OSC-19 cells, which has been reported in our previous study. Treatment with eribulin revealed marked inhibitory activities at 0.125 mg/kg against OLC-01 cells orthotopic xenografts. In conclusion, the results highlight the existence of invasive-type heterogeneity in R/M SCCHN with respect to eribulin sensitivity. Eribulin is already an approved clinical agent; therefore, the continued investigation of its preclinical antitumor attributes may contribute significantly to the future process of identifying novel uses of eribulin against R/M SCCHN.
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http://dx.doi.org/10.3892/ol.2019.10165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507455PMC
June 2019