Publications by authors named "Norihiro Sato"

187 Publications

The type rather than the daily dose or number of antipsychotics affects the incidence of hyperglycemic progression.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Oct 9:110453. Epub 2021 Oct 9.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060-8638, Japan. Electronic address:

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H, M, M, and 5-HT receptors, the incidence of hyperglycemic progression was higher in the medium- and high-daily dose groups than in the low-daily dose group in the antipsychotic group with strong blockade of these receptors. Our study indicated that the type of antipsychotic had a greater affect on the incidence of hyperglycemic progression than the daily dose of antipsychotics or their number. Among these, zotepine was most likely to increase the incidence of hyperglycemic progression, suggesting the need for caution when these antipsychotics are prescribed.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110453DOI Listing
October 2021

Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer.

Sci Rep 2021 Sep 14;11(1):18193. Epub 2021 Sep 14.

Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by dense desmoplasia and hypoxic microenvironment. Our previous reports demonstrated that hyaluronan (HA), especially low-molecular-weight HA, provides a favourable microenvironment for PDAC progression. However, the effect of hypoxia on HA metabolism remains unknown. Using quantitative real-time RT-PCR and western blot analysis, we analysed the changes in the expression of HA-synthesizing enzymes (HAS2 and HAS3) and HA-degrading enzymes (HYAL1, KIAA1199/CEMIP) in PDAC cell lines under hypoxic conditions. Hypoxia increased the mRNA and protein expression of KIAA1199, whereas it decreased HYAL1 expression. The expression of HAS3 was increased and HAS2 remained unchanged in response to hypoxia. The effect of KIAA1199 on hypoxia-induced cell migration was determined using a transwell migration assay and small-interfering RNA (siRNA). Hypoxia enhanced the migratory ability of PDAC cells, which was inhibited by KIAA1199 knockdown. We also used immunohistochemistry to analyse the protein expression of hypoxia inducible factor (HIF) 1α and KIAA1199 in PDAC tissues. There was a significant immunohistochemically positive correlation between KIAA1199 and HIF1α. These findings suggest that hypoxia-induced KIAA1199 expression may contribute to enhanced motility in PDAC.
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http://dx.doi.org/10.1038/s41598-021-97752-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440617PMC
September 2021

Exploratory clinical trial on the safety and capability of dMD-001 in lumbar disc herniation: Study protocol for a first-in-human pilot study.

Contemp Clin Trials Commun 2021 Sep 29;23:100805. Epub 2021 Jun 29.

Department of Orthopaedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Japan.

Herniated nucleus pulposus (NP), one of the most common diseases of the spine, is surgically treated by removing the sequestered NP. However, intervertebral disc (IVD) defects may remain after discectomy, leading to inadequate tissue healing and predisposing patients to IVD degeneration. An acellular, bioresorbable, ultra-purified alginate (UPAL) gel (dMD-001) implantation system can be used to fill any IVD defects in order to prevent IVD degeneration after discectomy. This first-in-human pilot study aims to determine the feasibility, safety, and perceived patient response to a combined treatment involving discectomy and UPAL gel implantation for herniated NP. We designed a one-arm, double-centre, open-label, pilot trial. The study started in November 2018 and will run until a sample of 40 suitable participants is established. Patients aged 20-49 years, diagnosed with isolated lumbar IVD herniation and scheduled for discectomy represent suitable candidates. All eligible participants who provide informed consent undergo standard discectomy followed by UPAL gel implantation. The primary outcomes of the trial will be the feasibility and safety of the procedure. Secondary outcomes will include self-assessed clinical scores and magnetic resonance imaging-based measures of morphological and compositional quality of the IVD tissue. Initial outcomes will be published at 24 weeks. Analysis of feasibility and safety will be performed using descriptive statistics. Both intention-to-treat and per-protocol analyses of treatment trends of effectiveness will be conducted.
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http://dx.doi.org/10.1016/j.conctc.2021.100805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261539PMC
September 2021

Selective alkylation of parallel G-quadruplex structure.

Org Biomol Chem 2021 04 11;19(13):2891-2894. Epub 2021 Feb 11.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan.

The selective alkylation of nucleic acids is important for a medicinal approach and biological study. We now report a novel selective alkylation of the parallel G-quadruplex structure using the conjugate of the macrocyclic hexaoxazole L2G2-6OTD-1M1PA and vinyl-quinazolinone-S(O)Me (6OTD-VQ-S(O)Me).
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http://dx.doi.org/10.1039/d0ob02365eDOI Listing
April 2021

Multiple system atrophy in Hokkaido, Japan: a prospective registry study of natural history and symptom assessment scales followed for 5 years.

BMJ Open 2021 02 8;11(2):e045100. Epub 2021 Feb 8.

Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

Objectives: Multiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional registry was launched to complement clinical information on MSA.

Setting: Patient recruitment started in November 2014 and is ongoing at the time of submission. The number of participating facilities was 66. Postal surveys were sent to medical facilities and patients with MSA in Hokkaido, Japan.

Participants: After obtaining written consent from 196 participants, 184 overview surveys and 115 detailed surveys were conducted.

Primary And Secondary Outcome Measures: An overview survey evaluated conformity to diagnostic criteria and a detailed survey implemented an annual assessment based on the Unified Multiple System Atrophy Rating Scale (UMSARS).

Results: At the time of registration, 58.2% of patients were diagnosed with cerebellar symptoms predominant type MSA (MSA-C) and 29.9% were diagnosed with parkinsonism predominant type MSA (MSA-P). UMSARS Part Ⅳ score of 4 or 5 accounted for 53.8% of participants. The higher the UMSARS Part Ⅳ score, the higher the proportion of MSA-P. At baseline, levodopa was used by 69 patients (37.5%) and the average levodopa dose was 406.7 mg/day. The frequency of levodopa use increased over time. Eleven cases changed from MSA-C to MSA-P during the study, but the opposite was not observed. Information about survival and causes of death was collected on 54 cases. Half of deaths were respiratory-related. Sudden death was recorded even in the group with UMSARS Part Ⅳ score of 1.

Conclusions: This study is the first large-scale prospective MSA cohort study in Asia. MSA-C was dominant, but the use of antiparkinsonian drugs increased over the study period. Changes from MSA-C to MSA-P occurred, but not vice versa.
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http://dx.doi.org/10.1136/bmjopen-2020-045100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871682PMC
February 2021

Requirement of the exopolyphosphatase gene for cellular acclimation to phosphorus starvation in a cyanobacterium, Synechocystis sp. PCC 6803.

Biochem Biophys Res Commun 2021 02 9;540:16-21. Epub 2021 Jan 9.

School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo, 192-0392, Japan. Electronic address:

Polyphosphate, which is ubiquitous in cells in nature, is involved in a myriad of cellular functions, and has been recently focused on its metabolism related with microbial acclimation to phosphorus-source fluctuation. In view of the ecological importance of cyanobacteria as the primary producers, this study investigated the responsibility of polyphosphate metabolism for cellular acclimation to phosphorus starvation in a cyanobacterium, Synechocystis sp. PCC 6803, with the use of a disruptant (Δppx) as to the gene of exopolyphosphatase that is responsible for polyphosphate degradation. Δppx was similar to the wild type in the cellular content of polyphosphate to show no defect in cell growth under phosphorus-replete conditions. However, under phosphorus-starved conditions, Δppx cells were defective in a phosphorus-starvation dependent decrease of polyphosphate to show deleterious phenotypes as to their survival and the stabilization of the photosystem complexes. These results demonstrated some crucial role of exopolyphosphatase to degrade polyP in the acclimation of cyanobacterial cells to phosphorus-starved conditions. Besides, it was found that ppx expression is induced in Synechocystis cells in response to phosphorus starvation through the action of the two-component system, SphS and SphR, in the phosphate regulon. The information will be a foundation for a fuller understanding of the process of cyanobacterial acclimation to phosphorus fluctuation.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.095DOI Listing
February 2021

Negative regulation between the expression levels of receptor for hyaluronic acid-mediated motility and hyaluronan leads to cell migration in pancreatic cancer.

Oncol Lett 2020 Nov 4;20(5):199. Epub 2020 Sep 4.

Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.

Receptor for hyaluronic acid (HA)-mediated motility (RHAMM) expression is upregulated in pancreatic ductal adenocarcinoma (PDAC). In the present study, small interfering RNA knockdown was used to investigate the regulatory mechanism and function of RHAMM in PDAC cells. Reverse transcription-quantitative PCR was used to measure the mRNA expression levels of RHAMM, hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1, HYAL2 and HYAL3) in eight PDAC cell lines. Cell migration was assessed using a Transwell assay, while HA concentration was measured using an ELISA. The results revealed that RHAMM-knockdown significantly increased migration in two PDAC cell lines, significantly decreased migration in one cell line and did not affect migration in the other cell lines, and was positively associated with changes in HA production. There was a between RHAMM mRNA expression and HA concentration in PDAC cells and tissues. The negative correlation between RHAMM mRNA expression and HA concentration was demonstrated in other models, including SUIT2 cells treated with an HA inhibitor or stimulator and a system involving co-culture of SUIT2 cells and stromal fibroblasts. The present findings demonstrated a negative correlation between RHAMM mRNA expression and HA production in a subset of PDAC cell lines. The efficacy of a therapeutic strategy targeting RHAMM should be carefully evaluated in future studies.
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http://dx.doi.org/10.3892/ol.2020.12060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491089PMC
November 2020

A case of gallbladder adenocarcinoma arising in association with intracystic papillary neoplasm (ICPN) with abundant mucin production.

Clin J Gastroenterol 2021 Feb 19;14(1):319-324. Epub 2020 Sep 19.

Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.

Intracystic papillary neoplasm (ICPN) of the gallbladder is a rare clinicopathological entity with a wide range of malignant potentials. Here, we report a case of mucin-producing gallbladder carcinoma possibly derived from ICPN. A 78-year-old female patient was referred to our hospital for examination of jaundice. Abdominal CT showed dilated biliary trees and a contrast-enhanced large polypoid mass in the gallbladder. Duodenoscopy showed a large amount of mucin extravasating from the ampulla of Vater. Bile cytology showed no evidence of malignancy. Under the diagnosis of mucin-producing gallbladder tumor, we performed laparoscopic cholecystectomy. Macroscopically, there was a large papillary tumor throughout the entire gallbladder mucosa. Pathological examinations showed a gallbladder adenocarcinoma localized to the mucosa in association with ICPN. Immunohistochemical analysis of the tumor revealed positive staining for MUC2 and MUC5AC but negative for MUC1 and MUC6, suggestive of the intestinal type.
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http://dx.doi.org/10.1007/s12328-020-01233-1DOI Listing
February 2021

Overexpression of transmembrane protein 2 (TMEM2), a novel hyaluronidase, predicts poor prognosis in pancreatic ductal adenocarcinoma.

Pancreatology 2020 Oct 9;20(7):1479-1485. Epub 2020 Sep 9.

Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan.

Background: Abnormal metabolism of hyaluronan (HA), a major component of extracellular matrix, is a hallmark of cancer. Our previous studies have shown the importance of enzymes responsible for HA degradation in the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). In the present study, we investigated the expression and function of transmembrane protein 2 (TMEM2), a recently identified HA-degrading enzyme, in PDAC.

Materials & Methods: We used immunohistochemistry to investigate expression patterns of TMEM2 in archival tissues obtained from 100 patients with PDAC who underwent surgical resection from 1982 to 2012. The correlations between TMEM2 expression and clinicopathological variables, including survival, were determined using univariate and multivariate analyses. The effect of TMEM2 on proliferation and migratory ability (measured using transwell cell migration assay) of PDAC cells was determined by TMEM2 knockdown with small-interfering RNA (siRNA).

Results: Immunohistochemical analysis revealed high expression of TMEM2 in 22 (22%) of 100 patients. The overall survival was significantly shorter in patients with high TMEM2 expression than in those with low expression (P = 0.013). Multivariate analysis identified high TMEM2 expression as an independent factor predicting poor prognosis (P = 0.011). Unexpectedly, knockdown of TMEM2 resulted in increased migratory ability of PDAC cells, which was associated with increased expression of KIAA1199, a potent HA-degrading enzyme shown to enhance cell migration.

Conclusion: TMEM2 overexpression is associated with poor prognosis in PDAC patients. Targeted disruption of this molecule, however, could enhance the aggressiveness of PDAC cells through a possible interaction with KIAA1199.
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http://dx.doi.org/10.1016/j.pan.2020.08.026DOI Listing
October 2020

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency.

Brain Dev 2021 Feb 11;43(2):214-219. Epub 2020 Aug 11.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, Research and Development Division, Japan.

Background: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks.

Patients And Methods: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions.

Results: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment.

Conclusion: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
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http://dx.doi.org/10.1016/j.braindev.2020.07.019DOI Listing
February 2021

Gallbladder metastasis of renal cell carcinoma presenting as a hypervascular polypoid lesion: case report of two cases with immunohistochemical analysis.

Surg Case Rep 2020 Apr 28;6(1):86. Epub 2020 Apr 28.

Department of Surgery1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.

Background: Metastasis of renal cell carcinoma (RCC) to the gallbladder is rare, and its clinicopathological feature remains poorly understood. We here present two cases of gallbladder metastasis from RCC presenting as a hypervascular polypoid lesion.

Case Presentation: The first case was a 73-year-old man who had undergone right nephrectomy for clear cell RCC. Imaging studies detected a hypervascular polypoid lesion in the gallbladder 6 years after nephrectomy. Laparoscopic cholecystectomy was done. The pathological findings of the polypoid lesion showed proliferation of clear cells in the submucosal layer. Immunohistochemically, the tumor was positive for carbonic anhydrase 9 (CA9) but negative for cytokeratin 7 (CK7), suggestive of metastatic RCC. The second case was a 43-year-old man who had undergone right nephrectomy for clear cell RCC. Imaging studies revealed a hypervascular polypoid lesion of 20 mm in diameter in the gallbladder 1 year after nephrectomy. The patient underwent expanded cholecystectomy and extra-hepatic bile duct resection with lymphadenectomy. Microscopically, the polypoid lesion of the gallbladder was composed of clear cells in the submucosal layer. Immunohistochemical analysis showed positive staining for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) but negative staining for CK7, leading to the diagnosis of metastatic RCC.

Conclusions: Gallbladder metastasis from RCC is rare but should be considered when a hypervascular polypoid lesion in the gallbladder is detected during the follow-up period after RCC treatment.
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http://dx.doi.org/10.1186/s40792-020-00814-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188748PMC
April 2020

Open colectomy vs. laparoscopic colectomy in Japan: a retrospective study using real-world data from the diagnosis procedure combination database.

Surg Today 2020 Oct 25;50(10):1255-1261. Epub 2020 Apr 25.

Department of Surgery 1, University Hospital, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.

Purpose: To compare the short-term outcomes of conventional open colectomy with those of laparoscopic colectomy for colon cancer.

Methods: We retrieved data between January 2014 and March 2016 from the Diagnosis Procedure Combination database. A total of 69,418 patients who underwent colectomy for colon cancer were analyzed from among 15,901,766 cases of colorectal cancer. We applied a multilevel logistic regression model using a 2-level structure of individuals nested from 1065 hospitals.

Results: A total of 22,440 open colectomy and 46,978 laparoscopic colectomy procedures were performed. The in-hospital mortality rate was significantly lower in the laparoscopic group than in the open group (0.28% vs. 0.06%, odds ratio [OR] 0.40, p < 0.001). Similarly, the 30-day postoperative mortality rate (0.14% vs. 0.03%, OR 0.47, p = 0.019) and surgical morbidity rate (43.0% vs. 25.3%, OR 0.47, p < 0.001) were significantly lower in the laparoscopic group than in the open group. The postoperative length of stay was significantly longer in the open group (mean difference - 5.6 days, p < 0.001) than in the open group. The admission cost was significantly greater in the open group than in the laparoscopic group (mean difference - 95,080 yen, p < 0.001).

Conclusions: Laparoscopic colectomy is safe and effective in the short term.
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http://dx.doi.org/10.1007/s00595-020-02006-6DOI Listing
October 2020

Contribution of protein synthesis depression to poly-β-hydroxybutyrate accumulation in Synechocystis sp. PCC 6803 under nutrient-starved conditions.

Sci Rep 2019 12 27;9(1):19944. Epub 2019 Dec 27.

School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.

Poly-β-hydroxybutyrate (PHB) in cyanobacteria, which accumulates as energy and carbon sources through the action of photosynthesis, is expected to substitute for petroleum-based plastics. This study first demonstrated that PHB accumulation was induced, with the appearance of lipid droplets, in sulfur (S)-starved cells of a cyanobacterium, Synechocystis sp. PCC 6803, however, to a lower level than in nitrogen (N)- or phosphorus (P)-starved cells. Concomitantly found was repression of the accumulation of total cellular proteins in the S-starved cells to a similar level to that in N-starved cells, and a severer level than in P-starved cells. Intriguingly, PHB accumulation was induced in Synechocystis even under nutrient-replete conditions, upon repression of the accumulation of total cellular proteins through treatment of the wild type cells with a protein synthesis inhibitor, chloramphenicol, or through disruption of the argD gene for Arg synthesis. Meanwhile, the expression of the genes for PHB synthesis was hardly induced in S-starved cells, in contrast to their definite up-regulation in N- or P-starved cells. It therefore seemed that PHB accumulation in S-starved cells is achieved through severe repression of protein synthesis, but is smaller than in N- or P-starved cells, owing to little induction of the expression of PHB synthesis genes.
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http://dx.doi.org/10.1038/s41598-019-56520-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934822PMC
December 2019

Landiolol, an ultra-short acting beta-1 blocker, for preventing postoperative lung cancer recurrence: study protocol for a phase III, multicenter randomized trial with two parallel groups of patients.

Trials 2019 Dec 11;20(1):715. Epub 2019 Dec 11.

Hokkaido University Hospital, Sapporo, Hokkaido, Japan.

Background: Recurrence of cancer after curative surgery is a major problem after most cancer treatments. Increased sympathetic activity during the perioperative period could promote cancer cell invasion to blood vessels and angiogenesis, resulting in cancer metastasis. Recent studies showed that use of beta blockers can be associated with the prolonged survival of patients with cancer. The objective of this study is to evaluate the preventive effects of landiolol hydrochloride, which is an ultra-short-acting beta-1-selective blocker that has been developed in Japan, on reducing recurrence of cancer after curative surgery for patients with lung cancer.

Methods: The present study is a phase III, multicenter, randomized trial with two parallel groups of patients with lung cancer, comparing surgery alone and surgery with landiolol administration for three days during the perioperative period. A total of 400 patients will be enrolled from 12 Japanese institutions. The primary endpoint is two-year relapse-free survival and overall survival after curative surgery for lung cancer. The secondary endpoints are additional treatment after recurrence of cancer, safety events, and the incidence of postoperative complications.

Discussion: The principal question addressed in this trial is whether landiolol can reduce recurrence of cancer after curative surgery for lung cancer.

Trial Registration: Japan Registry of Clinical Trials, jRCT2011180004. Registered 17 January 2019.
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http://dx.doi.org/10.1186/s13063-019-3904-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907139PMC
December 2019

Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial.

Ann Rheum Dis 2020 01 19;79(1):94-102. Epub 2019 Oct 19.

Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Hokkaido, Japan.

Objectives: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year.

Methods: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106.

Results: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106.

Conclusion: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.
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http://dx.doi.org/10.1136/annrheumdis-2019-216169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937411PMC
January 2020

Hyaluronan activated-metabolism phenotype (HAMP) in pancreatic ductal adenocarcinoma.

Oncotarget 2019 Sep 24;10(54):5592-5604. Epub 2019 Sep 24.

Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is enhanced by its interactions with stromal extracellular matrix, notably with hyaluronan (HA). Our previous studies have demonstrated increased expression of genes involved in HA synthesis and degradation in PDAC, suggesting the presence of an autocrine mechanism which accelerates the production of low-molecular-weight HA. A subset of PDAC (20% of cell lines and 25% of tissues) showed overexpression of multiple genes encoding both HA-synthesizing and HA-degrading enzymes, displaying a phenotype defined as an HA activated-metabolism phenotype (HAMP). Interestingly, HAMP+ cells were more susceptible to the treatment with an HA synthesis inhibitor and HA degradation inhibitor than HAMP- cells. Patients with HAMP+ tumors were significantly associated with shorter survival than those with HAMP- tumors (P = 0.049). We investigated transcriptional profiling of genes involved in HA synthesis (including and ) and degradation (including and ) in a panel of PDAC cell lines and primary tissues. Response of PDAC cells to treatment with an HA synthesis inhibitor (4-methylumbelliferone) or HA degradation inhibitor (dextran sulfate) was examined by cell migration assay. Survival was determined by Kaplan-Meier curve and compared by log-rank test. The present study identified a novel phenotype, HAMP, characterized by activation of HA metabolism pathways, in PDAC. HAMP should be further investigated as a prognostic marker as well as a target for personalized medicine.
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http://dx.doi.org/10.18632/oncotarget.27172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771457PMC
September 2019

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey.

Mol Genet Metab Rep 2019 Sep 25;20:100496. Epub 2019 Jul 25.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, North 14, West 5, Kita-ku, Sapporo 060-8648, Japan.

Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate.

Materials And Methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9 years; range, 5.8-26.4 years). The bezafibrate administration was continued for a further 102-174 weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health.

Results: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20 years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases.

Conclusion: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661278PMC
September 2019

Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II Japanese trial.

BMJ Open 2019 07 9;9(7):e026403. Epub 2019 Jul 9.

Laboratory of Medical Innovation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.

Introduction: Regenerative medicine and cell therapies have been gaining much attention among clinicians. Therapeutic infusion of mesenchymal stromal cells (MSCs) is now a leading investigational strategy for the treatment of acute graft-versus-host disease (aGVHD). Bone marrow MSCs are approved for manufacture and marketing as a cell therapy for aGVHD. Our non-clinical studies confirmed that human amnion-derived MSCs had immunomodulatory activity equal to or higher than that of human bone marrow MSCs. This study will aim to evaluate the safety and efficacy of amnion-derived MSCs (AM01) in patients with steroid-refractory aGVHD.

Methods And Analysis: This study will be a multicentre, single-arm, open-label trial (an interventional study). This clinical trial will begin with a low-dose group, and when safety has been confirmed in at least three cases in the low-dose group, treatment will begin for the high-dose group, for which the safety will also be verified. The primary endpoint is to assess the safety of intravenous infusion therapy of AM01 within 24 hours after intravenous infusion of AM01. The secondary endpoint is to explore the efficacy of intravenous infusion therapy with AM01.

Ethics And Dissemination: The institutional review boards of all participating hospitals approved this study protocol (latest V3.3.0, 3 August 2018). Final data will be publicly announced. A report releasing the study results will be submitted for publication to an appropriate peer-reviewed journal.

Trial Registration Number: UMIN000029945.
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http://dx.doi.org/10.1136/bmjopen-2018-026403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615811PMC
July 2019

The Global academic research organization network: Data sharing to cure diseases and enable learning health systems.

Learn Health Syst 2019 Jan 3;3(1):e10073. Epub 2018 Dec 3.

Translational Research Center for Medical Innovation Kobe Japan.

Introduction: Global data sharing is essential. This is the premise of the Academic Research Organization (ARO) Council, which was initiated in Japan in 2013 and has since been expanding throughout Asia and into Europe and the United States. The volume of data is growing exponentially, providing not only challenges but also the clear opportunity to understand and treat diseases in ways not previously considered. Harnessing the knowledge within the data in a successful way can provide researchers and clinicians with new ideas for therapies while avoiding repeats of failed experiments. This knowledge transfer from research into clinical care is at the heart of a learning health system.

Methods: The ARO Council wishes to form a worldwide complementary system for the benefit of all patients and investigators, catalyzing more efficient and innovative medical research processes. Thus, they have organized Global ARO Network Workshops to bring interested parties together, focusing on the aspects necessary to make such a global effort successful. One such workshop was held in Austin, Texas, in November 2017. Representatives from Japan, Taiwan, Singapore, Europe, and the United States reported on their efforts to encourage data sharing and to use research to inform care through learning health systems.

Results: This experience report summarizes presentations and discussions at the Global ARO Network Workshop held in November 2017 in Austin, TX, with representatives from Japan, Korea, Singapore, Taiwan, Europe, and the United States. Themes and recommendations to progress their efforts are explored. Standardization and harmonization are at the heart of these discussions to enable data sharing. In addition, the transformation of clinical research processes through disruptive innovation, while ensuring integrity and ethics, will be key to achieving the ARO Council goal to overcome diseases such that people not only live longer but also are healthier and happier as they age.

Conclusions: The achievement of global learning health systems will require further exploration, consensus-building, funding aligned with incentives for data sharing, standardization, harmonization, and actions that support global interests for the benefit of patients.
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http://dx.doi.org/10.1002/lrh2.10073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508835PMC
January 2019

Regulatory carbon metabolism underlying seawater-based promotion of triacylglycerol accumulation in Chlorella kessleri.

Bioresour Technol 2019 Oct 19;289:121686. Epub 2019 Jun 19.

School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan. Electronic address:

Chlorella kessleri accumulates triacylglycerol usable for biodiesel-fuel production to >20% dry cell weight in three days when cultured in three-fold diluted seawater, which imposes the combinatory stress of hyperosmosis and nutrients limitation. The quantitative behavior of major C-compounds, and related-gene expression patterns were investigated in Chlorella cells stressed with hyperosmosis, nutrients limitation, or their combination, to elucidate the C-metabolism for economical seawater-based triacylglycerol accumulation. Combinatory-stress cells showed repressed protein synthesis with initially accumulated starch being degraded later, the C-metabolic flow thereby being diverted to fatty acid and subsequent triacylglycerol accumulation. This C-flow diversion was induced by cooperative actions of nutrients-limitation and hyperosmosis. Semi-quantitative PCR analysis implied positive rewiring of the diverted C-flow into triacylglycerol in combinatory-stress cells through upregulation of gene expression concerning fatty acid and triacylglycerol synthesis, and starch synthesis and degradation. The information of regulatory C-metabolism will help reinforce the seawater-based triacylglycerol accumulation ability in algae including Chlorella.
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http://dx.doi.org/10.1016/j.biortech.2019.121686DOI Listing
October 2019

Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids.

Nucleic Acids Res 2019 07;47(13):6578-6589

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan.

Higher-ordered structure motifs of nucleic acids, such as the G-quadruplex (G-4), mismatched and bulge structures, are significant research targets because these structures are involved in genetic control and diseases. Selective alkylation of these higher-order structures is challenging due to the chemical instability of the alkylating agent and side-reactions with the single- or double-strand DNA and RNA. We now report the reactive OFF-ON type alkylating agents, vinyl-quinazolinone (VQ) precursors with a sulfoxide, thiophenyl or thiomethyl group for the OFF-ON control of the vinyl reactivity. The stable VQ precursors conjugated with aminoacridine, which bind to the G-4 DNA, selectively reacted with a T base on the G-4 DNA in contrast to the single- and double-strand DNA. Additionally, the VQ precursor reacted with the T or U base in the AP-site, G-4 RNA and T-T mismatch structures. These VQ precursors would be a new candidate for the T or U specific alkylation in the higher-ordered structures of nucleic acids.
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http://dx.doi.org/10.1093/nar/gkz512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649768PMC
July 2019

[(3)Overview of the Clinical Trials Act].

Authors:
Norihiro Sato

No Shinkei Geka 2019 Apr;47(4):481-489

Hokkaido University Hospital Clinical Research and Medical Innovation Center.

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http://dx.doi.org/10.11477/mf.1436203966DOI Listing
April 2019

Cultured Epidermal Autografts from Clinically Revertant Skin as a Potential Wound Treatment for Recessive Dystrophic Epidermolysis Bullosa.

J Invest Dermatol 2019 10 2;139(10):2115-2124.e11. Epub 2019 May 2.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Inherited skin disorders have been reported recently to have sporadic normal-looking areas, where a portion of the keratinocytes have recovered from causative gene mutations (revertant mosaicism). We observed a case of recessive dystrophic epidermolysis bullosa treated with cultured epidermal autografts (CEAs), whose CEA-grafted site remained epithelized for 16 years. We proved that the CEA product and the grafted area included cells with revertant mosaicism. Based on these findings, we conducted an investigator-initiated clinical trial of CEAs from clinically revertant skin for recessive dystrophic epidermolysis bullosa. The donor sites were analyzed by genetic analysis, immunofluorescence, electron microscopy, and quantification of the reverted mRNA with deep sequencing. The primary endpoint was the ulcer epithelization rate per patient at 4 weeks after the last CEA application. Three patients with recessive dystrophic epidermolysis bullosa with 8 ulcers were enrolled, and the epithelization rate for each patient at the primary endpoint was 87.7%, 100%, and 57.0%, respectively. The clinical effects were found to persist for at least 76 weeks after CEA transplantation. One of the three patients had apparent revertant mosaicism in the donor skin and in the post-transplanted area. CEAs from clinically normal skin are a potentially well-tolerated treatment for recessive dystrophic epidermolysis bullosa.
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http://dx.doi.org/10.1016/j.jid.2019.03.1155DOI Listing
October 2019

Quantitative detection of IKZF1 deletion by digital PCR in patients with acute lymphoblastic leukemia.

Int J Lab Hematol 2019 04 20;41(2):e38-e40. Epub 2018 Nov 20.

Department of Hematology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

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http://dx.doi.org/10.1111/ijlh.12945DOI Listing
April 2019

Predictive factors for hyperglycaemic progression in patients with schizophrenia or bipolar disorder.

BJPsych Open 2018 Nov 30;4(6):454-460. Epub 2018 Oct 30.

Professor, Hokkaido University Hospital Clinical Research and Medical Innovation Center, Japan.

Background: Patients with schizophrenia or bipolar disorder have a high risk of developing type 2 diabetes.

Aims: To identify predictive factors for hyperglycaemic progression in individuals with schizophrenia or bipolar disorder and to determine whether hyperglycaemic progression rates differ among antipsychotics in regular clinical practice.

Method: We recruited 1166 patients who initially had normal or prediabetic glucose levels for a nationwide, multisite, l-year prospective cohort study to determine predictive factors for hyperglycaemic progression. We also examined whether hyperglycaemic progression varied among patients receiving monotherapy with the six most frequently used antipsychotics.

Results: High baseline serum triglycerides and coexisting hypertension significantly predicted hyperglycaemic progression. The six most frequently used antipsychotics did not significantly differ in their associated hyperglycaemic progression rates over the 1-year observation period.

Conclusions: Clinicians should carefully evaluate baseline serum triglycerides and coexisting hypertension and perform strict longitudinal monitoring irrespective of the antipsychotic used.

Declaration Of Interest: The authors report no financial or other relationship that is relevant to the subject of this article. Relevant financial activities outside the submitted work are as follows. I.K. has received honoraria from Astellas, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Nippon Chemiphar, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; has received research/grant support from AbbVie GK, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; and is a member of the advisory boards of Dainippon Sumitomo Pharma and Tanabe Mitsubishi Pharma. Y.T. has received speaker's honoraria from Dainippon-Sumitomo Pharma, Otsuka, Meiji-Seika Pharma, Janssen Pharmaceutical, Daiichi-Sankyo Company, UCB Japan and Ono Pharmaceutical. K.U. has received honoraria from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin. B.Y. has received speaker's honoraria from Otsuka Pharmaceutical and Janssen Pharmaceutical. J. I. has received honoraria from Dainippon Sumitomo Pharma, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical and Mochida Pharma.
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http://dx.doi.org/10.1192/bjo.2018.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235992PMC
November 2018

Evaluation of amnion-derived mesenchymal stem cells for treatment-resistant moderate Crohn's disease: study protocol for a phase I/II, dual-centre, open-label, uncontrolled, dose-response trial.

BMJ Open Gastroenterol 2018 31;5(1):e000206. Epub 2018 May 31.

Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Introduction: The medical treatment options for patients with Crohn's disease (CD) are limited and patients resistant to those therapies are left requiring surgical operations that usually only achieve some symptomatic relief. Mesenchymal stem cells (MSC) have been shown to be effective for the treatment of CD, and we have demonstrated in animal experiments that human amnion-derived MSCs (AMSC) are a potential new therapeutic strategy. Therefore, we designed this study to investigate the safety and efficacy of AMSCs in patients with treatment-resistant CD.

Methods And Analysis: This is the protocol for an ongoing phase I/II, dual-centre, open-label, uncontrolled, dose-response study. The estimated enrolment is 6-12 patients with treatment-resistant, moderate CD. A dose of 1.0×10 cells/kg will be administered intravenously in the low-dose group at days 0 and 7. After confirming the safety of low-dose administration, a dose of 4.0×10 cells/kg will be administered intravenously in the high-dose group on days 0 and 7. The primary endpoint will measure the occurrence of adverse events related to acute infusion toxicity, and secondary endpoints will include long-term adverse events and efficacy of AMSC administration.

Ethics And Dissemination: The Institutional Review Board of Hokkaido University Hospital approved this study protocol (approval number H29-6). A report releasing study results will be submitted to an appropriate journal.

Discussion: This study is the first to investigate the safety and efficacy of AMSC use for CD treatment. Our results will advance studies on more efficient and convenient methods to overcome the limits of available CD treatments.

Trial Registration Number: UMIN000029841.
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http://dx.doi.org/10.1136/bmjgast-2018-000206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001910PMC
May 2018

Vinyldiaminotriazine-acridine conjugate as G-quadruplex alkylating agent.

Bioorg Med Chem 2018 07 19;26(12):3551-3558. Epub 2018 May 19.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan. Electronic address:

Higher-order structures of nucleic acids have become widely noted for their biological consequences and the discovery of an alkylating small molecule for these structures has been of interest due to its therapeutic potential. We previously developed the vinyldiaminotriazine (VDAT)-acridine conjugate as a T-T mismatch alkylating agent. In this report, we focused on the finding of the alkylation to the G-quadruplex (G4) DNA with VDAT-acridine conjugates. The VDAT-acridine conjugates exhibited a considerable alkylation ability to G4 under mild conditions. Moreover, the investigation of properties with the alkylated G4 revealed that alkylation by this conjugate significantly increased the stability of the G4 structure. This study provides a starting point in the further development of selective G4 alkylating small molecules.
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http://dx.doi.org/10.1016/j.bmc.2018.05.030DOI Listing
July 2018

4-Methylumbelliferone inhibits enhanced hyaluronan synthesis and cell migration in pancreatic cancer cells in response to tumor-stromal interactions.

Oncol Lett 2018 May 1;15(5):6297-6301. Epub 2018 Mar 1.

Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.

Hyaluronic acid (HA) in tumor stroma promotes tumor invasion and progression. 4-Methylumbelliferone (4-MU) is a potent HA synthesis inhibitor. In the present study, the effects of 4-MU on enhanced HA synthesis and cell migration in pancreatic ductal adenocarcinoma (PDAC) cells, in response to co-culture with stromal fibroblasts, was investigated. The HA concentration was determined using ELISA and a Transwell migration assay was used to analyze cell migratory capability. The mRNA expression levels of hyaluronan synthases ( and ) were determined using the quantitative polymerase chain reaction. Co-culture between Panc-1 cells and stromal fibroblasts markedly increased cell migration in association with increasing HA production, which was markedly associated with an increase in mRNA expression. Treatment with 4-MU markedly decreased the HA production and cell migration of Panc-1 cells in the co-culture system. The results of the present study suggested that interactions between PDAC cells and stromal fibroblasts increased HA production, resulting in a marked increase in migration of PDAC cells, and 4-MU may be used as a chemotherapeutic agent to inhibit the enhanced migration of PDAC cells in response to tumor-stromal interactions.
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http://dx.doi.org/10.3892/ol.2018.8147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920249PMC
May 2018

Remission induction by Raising the dose of Remicade in RA (RRRR) study: Rationale and study protocol for a randomized controlled trial comparing for sustained clinical remission after discontinuation of infliximab in patients with rheumatoid arthritis.

Contemp Clin Trials Commun 2017 Dec 17;8:49-54. Epub 2017 Aug 17.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahata-nishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.

Infliximab, an inhibitor of TNF-α, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-α could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naïve patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017.
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http://dx.doi.org/10.1016/j.conctc.2017.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898537PMC
December 2017

Effect of combined treatment with bisphosphonate and vitamin D on atherosclerosis in patients with systemic lupus erythematosus: a propensity score-based analysis.

Arthritis Res Ther 2018 04 17;20(1):72. Epub 2018 Apr 17.

Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Background: Premature atherosclerosis is one of the major complications of systemic lupus erythematosus (SLE). Recently, the biological linkage between atherosclerosis and osteoporosis has garnered much attention. The aim of this study is to explore correlation between the development of atherosclerosis and anti-osteoporotic treatment.

Methods: Consecutive patients with SLE (n = 117) who underwent carotid ultrasonography were retrospectively analyzed using propensity scoring.

Results: Of the 117 patients, 42 (36%), 27 (23%), and 30 (26%) were receiving bisphosphonates and vitamin D (BP + VD), bisphosphonates alone, or vitamin D alone, respectively. Low bone mineral density was more frequent, and carotid plaque was less prevalent in the BP + VD group compared with other treatment groups. Age (OR = 1.57) and BP + VD treatment (OR = 0.24) were shown by multivariate analysis to be associated with the presence of carotid plaque. In all strata divided using the propensity score, carotid plaque was statistically significantly less prevalent (p = 0.015, Mantel-Haenszel test) in the BP + VD group relative to the other treatment groups.

Conclusion: Combined treatment with bisphosphonate and vitamin D may have a role in preventing atherosclerosis in patients with SLE.
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http://dx.doi.org/10.1186/s13075-018-1589-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905171PMC
April 2018
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