Publications by authors named "Shiho Arima"

69 Publications

Gemcitabine Plus Nanoparticle Albumin-bound Paclitaxel FOLFIRINOX for Recurrent Pancreatic Cancer After Resection.

Anticancer Res 2021 Jul;41(7):3573-3582

Department of Medical Oncology, Fukuoka Wajiro Hospital, Fukuoka, Japan.

Background/aim: The aim of the study was to evaluate gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP) and FOLFIRINOX for recurrent pancreatic cancer (rPC) after resection.

Patients And Methods: Forty-four patients with rPC and 211 with de novo metastatic pancreatic cancer (mPC) who received GnP or FOLFIRINOX as first-line chemotherapy were retrospectively analyzed.

Results: On crude analysis, the median overall survival (OS) was significantly longer in the rPC group than in the mPC group (14.0 vs. 10.6 months, respectively; p=0.02). However, the difference was not significant on adjusted analysis using the Cox proportional hazards model (adjusted p=0.90). Patients receiving FOLFIRINOX (n=10) and GnP (n=34) in the rPC group had comparable OS (medians, 12.2 vs. 14.4 months, respectively; p=0.82) even after adjusting for covariates using the Cox model (adjusted p=0.18).

Conclusion: The outcomes of patients in the rPC and mPC groups were comparable following chemotherapy. Both FOLFIRINOX and GnP may be reasonable options for treating rPC.
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http://dx.doi.org/10.21873/anticanres.15145DOI Listing
July 2021

Gemcitabine plus nab-paclitaxel in older patients with metastatic pancreatic cancer: A post-hoc analysis of the real-world data of a multicenter study (the NAPOLEON study).

J Geriatr Oncol 2021 Jun 29. Epub 2021 Jun 29.

Department of Medical Oncology, Hamanomachi Hospital, 3-3-1 Nagahama, Chuo-ku, Fukuoka-shi, Fukuoka, 810-8539, Japan.

Objectives: This study aimed to examine the efficacy and safety of gemcitabine plus nab-paclitaxel (GnP) in older patients with metastatic pancreatic cancer (MPC), especially those ≥75 years old.

Materials And Methods: This study retrospectively enrolled 153 patients with MPC who received GnP as first-line chemotherapy. Patients ≥75 years old were allocated to the older group, and those <75 years old were assigned to the non-older group. We compared safety, antitumor efficacy, and survival between the two groups. In the older group, prognostic indicators of survival were also assessed.

Results: The pretreatment characteristics of the two groups were not significantly different excluding age, history of malignancy, and C-reactive protein levels. The initial dose and relative dose intensities of GnP were significantly lower in the older group. There were no significant differences in the adverse event and antitumor response rates between the two groups. Median progression-free survival and overall survival were 5.5 and 12.0 months, respectively, in the older group, versus 6.0 and 11.1 months, respectively, in the non-older group. In the older group, a Geriatric Nutrition Risk Index (GNRI) of less than 86 was associated with poor prognosis.

Conclusion: GnP exhibited acceptable efficacy and safety in patients ≥75 years old with MPC. GNRI might be helpful for identifying older individuals at higher risk of unfavorable outcomes.
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http://dx.doi.org/10.1016/j.jgo.2021.06.011DOI Listing
June 2021

Impairment of endothelium-dependent vasodilator function of retinal blood vessels in adult rats with a history of retinopathy of prematurity.

J Pharmacol Sci 2021 Aug 7;146(4):233-243. Epub 2021 May 7.

Department of Molecular Pharmacology, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address:

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease, initiated by delayed retinal vascular growth after premature birth. In the majority of cases, ROP resolves spontaneously; however, a history of ROP may increase the risk of long-term visual problems. In this study, we evaluated the endothelial function of retinal blood vessels in adult rats with a history of ROP. ROP was induced in rats by subcutaneous injection of a vascular endothelial growth factor receptor tyrosine kinase inhibitor (KRN633) on postnatal day (P) 7 and P8. On P56, vasodilator responses to acetylcholine, GSK1016790A (an activator of transient receptor potential vanilloid 4 channels), NOR3 (a nitric oxide [NO] donor), and salbutamol (a β-adrenoceptor agonist) were assessed. Compared to age-matched controls, retinal vasodilator responses to acetylcholine and GSK1016790A were attenuated in P56 rats with a history of ROP. No attenuation of acetylcholine-induced retinal vasodilator response was observed under inhibition of NO synthase. Retinal vasodilator responses to NOR3 and salbutamol were unaffected. These results suggest that the production of and/or release of NO is impaired in retinal blood vessels in adult rats with a history of ROP. A history of ROP might increase the risk of impaired retinal circulation in adulthood.
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http://dx.doi.org/10.1016/j.jphs.2021.04.008DOI Listing
August 2021

A case of immunoglobulin G4-related sclerosing mesenteritis without other organ involvement.

Clin J Gastroenterol 2021 Jun 7. Epub 2021 Jun 7.

Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.

A 64-year-old man presented to our hospital with abdominal pain and 4-5 episodes of watery diarrhea per day for 2 months. Abdominal ultrasound examination revealed a mass in the peritoneal cavity, and computed tomography showed a 13.4 cm mass in the mesentery and a 3 cm mass in the mesocolon. The patient underwent laparoscopic partial resection for diagnosis. Microscopically, abundant fibrosis and numerous immunoglobulin (Ig) G4-positive plasma cells were observed. The serum level of IgG4 was 665 mg/dl postoperatively. These findings suggested that the lesion was consistent with IgG4-related sclerosing mesenteritis. Oral steroids resulted in rapid disappearance of symptoms and a decrease in masses. Recently, sclerosing mesenteritis are reported as IgG4-related disease or mimicking IgG4-related disease but multiple lesions rarely occur in the same organ. We report a case of IgG4-related sclerosing mesenteritis with multiple lesions without involvement of other organs, such as the pancreas and salivary glands.
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http://dx.doi.org/10.1007/s12328-021-01451-1DOI Listing
June 2021

Acetaldehyde breath test as a cancer risk marker in patients with esophageal and hypopharyngeal squamous cell carcinoma.

PLoS One 2021 19;16(5):e0251457. Epub 2021 May 19.

Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Patients with inactive acetaldehyde dehydrogenase 2 (ALDH2) are at high risk for esophageal squamous cell carcinoma (ESCC) and hypopharyngeal squamous cell carcinoma (HPSCC). The acetaldehyde breath test (ABT) may demonstrate ALDH2 gene polymorphisms. We evaluated the usefulness of the ABT in patients with ESCC and HPSCC. The squamous cell carcinoma (SCC) group consisted of 100 patients who were treated with endoscopic submucosal dissection (ESD) for ESCC or HPSCC, and the control group (HC) consisted of 275 healthy subjects. The SCC group comprised the "single subgroup" (n = 63), in which a single lesion was initially treated with ESD, and the "multiple subgroup" (n = 31), in which multiple lesions were initially treated with ESD. First, we compared the groups' risk factors for carcinogenesis and measured the acetaldehyde-to-ethanol (A/E) ratio. Then we tested the groups' differences in the abovementioned carcinogenic risk factors. We found that the proportion of individuals in the SCC group with inactive ALDH2 (A/E ratio ≥ 23.3) was significantly higher than that in the HC group (p = 0.035), as was the A/E ratio (p < 0.001). Also, the proportion of individuals with inactive ALDH2 in the multiple subgroup was significantly higher than that in single subgroup (p = 0.015), as was the A/E ratio (p = 0.008). In conclusion, ABT may be a potential screening tool for detecting people at risk of ESCC and HPSCC. In addition, it could be a useful tool in detecting patients at risk of multiple or double carcinomas among patients with ESCC and HPSCC. Trial registration: Trial Registration number: UMIN000040615 [https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000040615], Data of Registration: 01 46 June 2020, retrospectively registered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251457PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133406PMC
May 2021

Analysis of factors affecting progression-free survival of first-line chemotherapy in older patients with advanced gastrointestinal cancer.

J Geriatr Oncol 2021 May 11. Epub 2021 May 11.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima city, Kagoshima 890-8520, Japan. Electronic address:

Objectives: Few studies have investigated factors influencing the efficacy of chemotherapy in older patients with cancer. This study aimed to evaluate the usefulness of G8, geriatric assessment (GA), and factors measured in general clinical practice for evaluating progression-free survival (PFS) of first-line palliative chemotherapy in older patients with advanced gastrointestinal cancer.

Materials And Methods: This was a prospective observational study of older patients (age ≥ 70 years) with advanced gastrointestinal cancer. The modified cut-off value of G8 was determined by referring to two or more abnormal GA conditions. The usefulness of baseline GA and G8 (conventional and modified cut-off value) was assessed according to the efficacy (PFS and disease control rate) of the administered first-line palliative chemotherapy.

Results: Overall, 93 patients were evaluated between March 2017 and February 2019. A modified G8 cut-off value of ≤12 had a sensitivity and specificity of 68.9% and 46.9%, respectively. PFS was significantly prolonged in the patients with G8 > 12, serum albumin ≥3.5 g/dl, and in whom grade ≥ 3 adverse events occurred. There was no significant difference in the PFS between monotherapy and combination therapy. GA was not useful for predicting PFS prolongation or the occurrence of serious adverse events in first-line treatment.

Conclusion: Among older patients with advanced gastrointestinal cancer who receive first-line chemotherapy, a modified G8 cut-off value of 12 points, occurrence of grade 3 or higher adverse events, albumin levels, rather than age or performance status were predictors of PFS prolongation.
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http://dx.doi.org/10.1016/j.jgo.2021.05.006DOI Listing
May 2021

Mixture of clopidogrel bisulfate and magnesium oxide tablets reduces clopidogrel dose administered through a feeding tube.

J Pharm Health Care Sci 2021 May 4;7(1):18. Epub 2021 May 4.

Department of Clinical Pharmacy, Research and Education Center for Clinical Pharmacy, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

Background: In clinical practice, a mixed suspension of clopidogrel bisulfate and magnesium oxide (MgO) tablets is administered frequently via a feeding tube. However, there is no report on the changes occurring when suspensions of these two drugs are combined, including the effects or potential decrease in dose following tube administration. Thus, the purpose of our study was to investigate the (i) changes caused by mixing clopidogrel bisulfate (ion form) and MgO tablets and (ii) effects on the administered clopidogrel dose after passing through a feeding tube.

Methods: The molecular structure of clopidogrel generated in a mixture of clopidogrel bisulfate and a basic compound, such as sodium bicarbonate or MgO tablet, was determined by H-NMR after extraction and purification. The suspension of clopidogrel bisulfate tablet alone and the mixed suspension of clopidogrel bisulfate tablet and MgO tablet were passed through a feeding tube. We compared the yield of the molecular form of clopidogrel from each passed fraction.

Results: The substance obtained from the mixture of clopidogrel bisulfate tablet and sodium bicarbonate or MgO tablet was identified as the molecular form of clopidogrel, and chemical degradation did not occur under these conditions. In the tube passage test, the yield of clopidogrel (molecular form) from the mixture of clopidogrel bisulfate and MgO tablets was lower than that from the suspension of clopidogrel bisulfate tablet alone.

Conclusions: The mixture of clopidogrel bisulfate and MgO tablets caused a considerable reduction in the administered dose passed through the feeding tube. Therefore, it is recommended to administer the suspensions of clopidogrel bisulfate and MgO tablets separately for safe and effective pharmacotherapy.
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http://dx.doi.org/10.1186/s40780-021-00202-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094535PMC
May 2021

Prognostic significance of extracellular volume fraction with equilibrium contrast-enhanced computed tomography for pancreatic neuroendocrine neoplasms.

Pancreatology 2021 Jun 3;21(4):779-786. Epub 2021 Mar 3.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, 890-8520, Japan.

Background: /Objectives: Identifying reliable pretreatment imaging biomarkers for pancreatic neuroendocrine neoplasm (PanNEN) is a key imperative. Extracellular volume (ECV) fraction quantified with equilibrium contrast-enhanced CT can be easily integrated into routine examinations. This study aimed to determine whether ECV fraction with equilibrium contrast-enhanced computed tomography (CECT) could predict long-term outcomes in patients with PanNEN.

Methods: This study was a retrospective observational study of 80 patients pathologically diagnosed with PanNEN at a single institution. ECV fraction of the primary lesion was calculated using region-of-interest measurement within PanNEN and the aorta on unenhanced and equilibrium CECT. The impact of clinical factors and tumor ECV fraction on progression-free survival (PFS) and overall survival (OS) was assessed with univariate and multivariate analyses using Cox proportional hazards models. The correlation between WHO classification and tumor ECV fraction was evaluated using Kendall rank correlation coefficients.

Results: PFS and OS rates were estimated as 93.4% and 94.6%, 78.7% and 86.2%, 78.7% and 77.0%, and 78.7% and 66.6% at 1, 3, 5, and 10 years, respectively. Multivariate analysis revealed that Union for International Cancer Control (UICC) stage (hazard ratio [HR] = 3.95, P = 0.003), WHO classification (HR = 12.27, P = 0.003), and tumor ECV fraction (HR = 11.93, P = 0.039) were independent predictors of PFS. Patient age (HR = 1.11, P < 0.001), UICC stage (HR = 3.14, P = 0.001), and tumor ECV fraction (HR = 5.27, P = 0.024) were independent significant variables for predicting OS. Tumor ECV fraction had a weak inverse relationship with WHO classification (P = 0.045, τ = -0.178).

Conclusions: ECV fraction determined by equilibrium CECT and UICC stage may predict survival in patients with PanNEN.
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http://dx.doi.org/10.1016/j.pan.2021.02.020DOI Listing
June 2021

A multicenter propensity score analysis of FOLFIRINOX vs gemcitabine plus nab-paclitaxel administered to patients with metastatic pancreatic cancer: results from the NAPOLEON study.

Int J Clin Oncol 2021 May 23;26(5):941-950. Epub 2021 Jan 23.

Department of Medical Oncology, Saga Medical Center Koseikan, 400 Kase-machi, Saga-shi, Saga, 840-8571, Japan.

Purpose: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX, FFX) and gemcitabine plus nab-paclitaxel (GnP) are considered standard treatments for patients with metastatic pancreatic cancer. Direct comparisons are not available that establish which is optimal.

Methods: We conducted a propensity score-adjusted analysis of patients with metastatic pancreatic cancer to identify the therapeutic advantages of these standard therapies. We used clinical data as part of a multicenter retrospective study of patients with unresectable or recurrent pancreatic cancer treated with FFX or GnP (NAPOLEON study).

Results: FFX and GnP were initially administered to 102 and 153 patients, respectively. The GnP group comprised more patients of advanced age, worse performance status, lower body mass index, recurrence, and lower albumin concentrations. Median overall survival (OS) and progression-free survival (PFS) were 11.5 months and 5.8 months in the FFX group and 11.1 months and 5.9 months in the GnP group, respectively. Propensity score-adjusted analysis indicated that the administration of FFX or GnP was not independently associated with OS (adjusted hazard ratio [HR] 1.06; 95% confidence interval [CI] 0.76-1.47; P = 0.73). Similarly, the difference in PFS was not significant between groups (adjusted HR 0.93; 95% CI 0.68-1.26; P = 0.62). Gastrointestinal disorders were more common in the FFX group, whereas the frequencies of hematological, nervous system, and skin disorders were higher in the GnP group.

Conclusion: The efficacies of FFX and GnP were comparable, although safety profiles differed and should be considered in selecting treatment.
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http://dx.doi.org/10.1007/s10147-021-01859-2DOI Listing
May 2021

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus.

Dev Dyn 2021 Apr 2;250(4):497-512. Epub 2020 Nov 2.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.

Background: In mice, a tri-layered (superficial, intermediate, and deep) vascular structure is formed in the retina during the third postnatal week. Short-term treatment of newborn mice with vascular endothelial growth factor (VEGF) receptor inhibitors delays the formation of superficial vascular plexus and this allows us to investigate the developmental process of superficial and deep vascular plexuses at the same time. Using this model, we examined the effect of pharmacological depletion of retinal neurons on the formation of superficial and deep vascular plexuses.

Results: Neuronal cell loss induced by an intravitreal injection of N-methyl-d-aspartic acid on postnatal day (P) 8 delayed vascular development in the deep layer but not in the superficial layer in mice treated with KRN633, a VEGF receptor inhibitor, on P0 and P1. In KRN633-treated mice, neuronal cell loss decreased the number of vertical sprouts originating from the superficial plexus without affecting the number of angiogenic sprouts growing in front. Neuronal cell loss did not impair networks of fibronectin and astrocytes in the superficial layer.

Conclusions: Our results suggest that inner retinal neurons play a crucial role in forming the deep vascular plexus by directing the sprouts from the superficial blood vessels to the deep layer.
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http://dx.doi.org/10.1002/dvdy.263DOI Listing
April 2021

Endoscopic ultrasonography-guided hybrid rendezvous technique for pancreatic stenting in a patient with pancreatoduodenectomy.

Endoscopy 2021 06 11;53(6):E213-E214. Epub 2020 Sep 11.

Department of Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan.

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http://dx.doi.org/10.1055/a-1244-9482DOI Listing
June 2021

The process of revascularization in the neonatal mouse retina following short-term blockade of vascular endothelial growth factor receptors.

Cell Tissue Res 2020 Dec 8;382(3):529-549. Epub 2020 Sep 8.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

Misdirected vascular growth frequently occurs in the neovascular diseases in the retina. However, the mechanisms are still not fully understood. In the present study, we created capillary-free zones in the central and peripheral retinas in neonatal mice by pharmacological blockade of vascular endothelial growth factor (VEGF) signaling. Using this model, we investigated the process and mechanisms of revascularization in the central and peripheral avascular areas. After the completion of a 2-day treatment with the VEGF receptor tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5, revascularization started on P8 in the central avascular area where capillaries had been dropped out. The expression levels of VEGF were higher in the peripheral than in the central avascular area. However, the expansion of the vasculature in the peripheral avascular retina remained suppressed until revascularization had been completed in the central avascular area. Additionally, we found disorganized endothelial cell division, misdirected blood vessels with irregular diameters, and abnormal fibronectin networks at the border of the vascular front and the avascular retina. In the central avascular area, a slight amount of fibronectin as non-vascular component re-formed to provide a scaffold for revascularization. Mechanistic analysis revealed that higher levels of VEGF attenuated the migratory response of endothelial cells without decreasing the proliferative activity. These results suggest that the presence of concentration range of VEGF, which enhances both migration and proliferation of the endothelial cells, and the structurally normal fibronectin network contribute to determine the proper direction of angiogenesis.
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http://dx.doi.org/10.1007/s00441-020-03276-9DOI Listing
December 2020

Visual enhancement pattern during the delayed phase of enhanced CT as an independent prognostic factor in stage IV pancreatic ductal adenocarcinoma.

Pancreatology 2020 Sep 28;20(6):1155-1163. Epub 2020 Jul 28.

Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background: Pancreatic ductal adenocarcinoma (PDAC) has substantial heterogeneity in biophysical features and in outcomes of patients. Identifying reliable pretreatment imaging biomarkers for PDAC with distant metastases (stage IV) is a key imperative. Our objective was to determine whether visual tumor enhancement pattern on enhanced computed tomography (CT) can be used as a prognostic factor in stage IV PDAC treated with chemotherapy.

Methods: This is a retrospective cohort study of 133 patients with stage IV PDAC who underwent multiphasic enhanced CT before systemic chemotherapy. The enhancement pattern of PDAC was qualitatively categorized as hypoattenuation, isoattenuation, or hyperattenuation on each of the pancreatic, portal venous, and delayed phases. The effects of clinical prognostic factors and the visual tumor enhancement pattern on progression-free survival (PFS) and overall survival (OS) were assessed in univariate and multivariate analyses using Cox proportional hazards models.

Results: On univariate analysis, the number of metastatic organs and the visual tumor enhancement pattern during the delayed phase were significantly associated with PFS (p = 0.003 and < 0.001, respectively) and OS (p = 0.005 and < 0.001, respectively). Multivariate analysis identified the number of metastatic organs (PFS, p = 0.021; OS, p = 0.041) and visual tumor enhancement pattern during the delayed phase (PFS, p < 0.001; OS, p < 0.001) as independent predictors of PFS and OS.

Conclusion: Visual enhancement pattern of PDAC on delayed phase enhanced CT appears to be associated with outcomes and could be a useful prognostic factor in stage IV PDAC, despite the need to add the delayed phase to CT protocol for pancreatic disease.
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http://dx.doi.org/10.1016/j.pan.2020.07.009DOI Listing
September 2020

Salvage endoscopic ultrasound-guided rendezvous technique for disconnected pancreatic duct syndrome in a patient with severe acute pancreatitis.

Endoscopy 2021 Apr 24;53(4):450-451. Epub 2020 Jul 24.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan.

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http://dx.doi.org/10.1055/a-1216-0809DOI Listing
April 2021

Covering Post-Endoscopic Submucosal Dissection Ulcers in Miniature Swine with Hexanoyl (Hx:C6) Group-Modified Alkaline-Treated Gelatin Porous Film (HAG) Induces Proper Healing by Decreasing Inflammation and Fibrosis.

Digestion 2021 22;102(3):415-427. Epub 2020 Jul 22.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background And Aims: Hexanoyl (Hx:C6) group-modified alkaline-treated gelatin porous film (HAG) is a newly developed degradable hydrogel characterized by strong adhesiveness and high affinity for vascular endothelial growth factor (VEGF). The aim of this study was to clarify the effect of HAG sheets on the healing process of post-endoscopic submucosal dissection (ESD) porcine gastric artificial ulcers.

Methods: (1) To evaluate the adhesiveness of HAG sheets over time, we performed ESD to create 1 artificial ulcer and covered the lesion with 1 HAG sheet using 1 miniature swine. We observed 2 ulcers by endoscopic and microscopic examinations. (2) To examine the effect of HAG sheets on post-ESD ulcer healing, we performed ESD using 5 miniature swine. The artificial ulcers were covered with HAG sheets, or left uncovered after ESD (day 0), followed by macroscopic and microscopic examinations. On days 7 and 14, we observed 2 ulcers by endoscopic examinations. On day 14, the animals were sacrificed, and histological examination was performed on the 3 stomachs that could be extirpated.

Results: (1) On day 7, adhesion of HAG sheets was observed. (2) Gastric ulcer area on day 7 was significantly larger in the covered ulcers than in the non-covered ulcers (p = 0.046). On day 14, although there was no significant difference in ulcer area irrespective of covering (p = 0.357), the covered ulcers tended to repair less fold convergence than non-covered ulcers. The covered ulcer sheets significantly decreased inflammatory cell infiltration (p = 0.011), but significantly increased the abundance of macrophages (p = 0.033), in submucosal layers. Also, the abundance of alpha-smooth muscle actin-positive cells in submucosal layers of the covered ulcers was significantly reduced (p = 0.044), leading to a decrease in collagen accumulation. In addition, fibrosis and atrophy of the muscularis propria were significantly lower for covered ulcers than for non-covered ulcers. Furthermore, microvessels and VEGF-positive cells were significantly more abundant in the submucosal layers of the covered ulcers (p < 0.001 and p = 0.024, respectively).

Conclusions: HAG sheets induced post-ESD ulcer healing with less submucosal inflammation and muscularis propria injury and have the potential to decrease excess scarring.
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http://dx.doi.org/10.1159/000509056DOI Listing
July 2020

Synthesis and Absolute Configuration of Habiterpenol.

Org Lett 2020 07 17;22(13):5131-5134. Epub 2020 Jun 17.

Laboratory of Synthetic Natural Products Chemistry and Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.

The synthesis of habiterpenol, a G2 checkpoint inhibitor, was achieved through the stereoselective Ti(III)-mediated radical cyclization of a β-epoxide as the key reaction. Moreover, the absolute configuration of habiterpenol was determined.
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http://dx.doi.org/10.1021/acs.orglett.0c01736DOI Listing
July 2020

Abnormal Vascular Phenotypes Associated with the Timing of Interruption of Retinal Vascular Development in Rats.

Biol Pharm Bull 2020 ;43(5):859-863

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

Pathological angiogenesis is a leading cause of blindness in several retinal diseases. The key driving factor inducing pathological angiogenesis is the pronounced hypoxia leading to a marked, increased production of vascular endothelial growth factor (VEGF). The aim of this study was to determine whether the abnormal vascular growth occurs in a manner dependent on the degree of the vascular defects. Vascular defects of two different degrees were created in the retina by subcutaneously treating neonatal rats with the VEGF receptor (VEGFR) tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5 (P4/5) or P7 and P8 (P7/8). The structure of the retinal vasculature changes was examined immunohistochemically. Prevention of vascular growth and regression of some preformed capillaries were observed on the next day, after completion of each treatment (i.e., P6 and P9). The vascular regrowth occurred as a result of eliminating the inhibitory effect on the VEGFR signaling pathway. KRN633 (P4/5)-treated rats exhibited a retinal vasculature with aggressive intravitreal neovascularization on P21. On the other hand, the appearance of tortuous arteries is a representative vascular pathological feature in retinas of KRN633 (P7/8)-treated groups. These results suggest that an interruption of the retinal vascular development at different time points induces different vascular pathological features in the retina. Pharmacological agents targeting the VEGF signaling pathway are useful for creating an abnormal retinal vasculature with various pathological features in order to evaluate the efficacy of anti-angiogenic compounds.
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http://dx.doi.org/10.1248/bpb.b19-01065DOI Listing
January 2021

Significance of Linked Color Imaging for Predicting the Risk of Clinical Relapse in Ulcerative Colitis.

Gastroenterol Res Pract 2020 6;2020:3108690. Epub 2020 Mar 6.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with unknown etiology. Recently, mucosal healing has emerged as an important therapeutic endpoint in UC. Linked color imaging (LCI) is a novel endoscopic system that enhances the color differences of the gastrointestinal mucosa. Our previous study emphasized the redness and yellowness of the lesion using LCI observation, which was useful for the evaluation of histological mucosal activity in UC. In this study, we aimed to evaluate the correlation between LCI observation and clinical relapse rate in UC patients. We retrospectively analyzed UC patients who underwent total colonoscopy between August 2016 and October 2018 at our facility with Mayo endoscopic scores of 0 or 1. We assessed the correlation between orange-like color lesion (defined as LCI-scarlet color lesions) and clinical relapse rate (requiring additional treatment for UC) during the 1-year follow-up period. Fifty-eight patients (22 female, 36 male; median age at diagnosis, 47.2 (18-80) years) who underwent colonoscopy were analyzed. During the 1-year follow-up period, clinical relapse was observed in 12 patients (20.1%) among which ten patients (83.3%) had an LCI-scarlet color lesions recognized by LCI. By contrast, 29 patients (63%) had no LCI-scarlet color lesions in the clinical remission group ( = 46). There was a significant difference in LCI-scarlet color between the clinical relapse and remission groups, remaining significantly associated with clinical relapse. LCI findings, including an orange-like color lesion, have diagnostic implications for predicting the risk of clinical relapse in UC during the 1-year follow-up period.
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http://dx.doi.org/10.1155/2020/3108690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079245PMC
March 2020

Oral administration of Lactobacillus plantarum 06CC2 prevents experimental colitis in mice via an anti‑inflammatory response.

Mol Med Rep 2020 Mar 9;21(3):1181-1191. Epub 2020 Jan 9.

Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8544, Japan.

Dysbiosis of the enteric microbiota causes gastrointestinal diseases, including colitis. The present study investigated the beneficial effect of Lactobacillus plantarum 06CC2 in experimental colitis in mice. An experimental colitis model in C57BL6 mice was induced using dextran sulfate sodium. Mice were orally administered 06CC2 (06CC2 group) or PBS only (control group) by gavage. The disease activity index (DAI), histological grading, and colon tissue and colonic lamina propria mononuclear cells (LPMCs) were examined macroscopically and histopathologically, and the expression levels of inflammation‑associated cytokines (IL‑6, IL‑12, TNF‑α and IL‑10) in these samples were determined. Compared with the control group, the 06CC2 group exhibited a significantly lower DAI (1.5±0.8 vs. 0.2±0.3, respectively; P<0.05) and pathology score (6.3±1.5 vs. 3.8±1.3, respectively; P<0.05). IL‑10 expression in colonic LPMCs was higher in the 06CC2 group than in the control group, although there was no significant difference in IFN‑γ, IL‑6 or IL‑12 expression in colonic LPMCs between the two groups. In addition, 06CC2 stimulated the production of IL‑10 from CD11b‑positive cells and CD11c‑positive cells in the colon. The 06CC2 strain induced IL‑10 production in the colon and attenuated colon inflammation.
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http://dx.doi.org/10.3892/mmr.2020.10925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002978PMC
March 2020

A case of gallbladder neuroendocrine carcinoma diagnosed preoperatively using somatostatin receptor scintigraphy.

Oncol Lett 2020 Jan 14;19(1):247-254. Epub 2019 Nov 14.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.

Gallbladder neuroendocrine carcinoma (NEC) is a rare gallbladder tumor. The current report is a case of a patient preoperatively diagnosed with gallbladder NEC using somatostatin receptor scintigraphy (SRS). A 63-year-old man was admitted to our hospital by a family doctor after abdominal ultrasonography revealed thickened walls of the neck of his gallbladder. At Kagoshima University Hospital, CT and MRI of the abdomen and endoscopic ultrasonography confirmed the thickening of the walls of the neck of the gallbladder. However, it did not resemble a typical gallbladder cancer or tumor, such as a neuroendocrine tumor or malignant lymphoma. Positron emission tomography and SRS showed abnormal accumulation at the tumor site. Endoscopic retrograde cholangiopancreatography was performed, adenocarcinoma was suspected based on intra-gallbladder bile cytology, and a cholecystectomy with lymphadenectomy was performed. The postoperative pathological diagnosis was small cell NEC (pT3a, N0, M0, stage II). Immunohistochemistry indicated that the gallbladder tumor cells were positive for synaptophysin, chromogranin A, and cluster of differentiation (CD) 56, and negative for somatostatin receptors (SSTR) 2 and 5. Gene expression assays revealed the expression of all SSTR subtypes (SSTR1-5) in the tumor. Generally, NECs exhibit poor accumulation in SRS, however, the results of the current case suggest that SRS may be useful in the preoperative diagnosis of NEC.
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http://dx.doi.org/10.3892/ol.2019.11101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924094PMC
January 2020

Changes in components of the neurovascular unit in the retina in a rat model of retinopathy of prematurity.

Cell Tissue Res 2020 Mar 2;379(3):473-486. Epub 2019 Dec 2.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

An impairment of cellular interactions between the elements of the neurovascular unit contributes to the onset and/or progression of retinal diseases. The present study aims to examine how elements of the neurovascular unit are altered in a rat model of retinopathy of prematurity (ROP). Neonatal rats were treated subcutaneously with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8 to induce ROP. Morphological assessments were performed of blood vessels, astrocytes and neuronal cells in the retina. Aggressive angiogenesis, tortuous arteries and enlarged veins were observed in the retinal vasculature of KRN633-treated (ROP) rats from P14 to P28, compared to age-matched control (vehicle-treated) animals. Morphological abnormalities in the retinal vasculature showed a tendency toward spontaneous recovery from P28 to P35 in ROP rats. Immunofluorescence staining for glial fibrillary acidic protein and Pax2 (astrocyte markers) revealed that morphological changes to and a reduction in the number of astrocytes occurred in ROP rats. The developmental cell death was slightly accelerated in ROP rats; however, no visible changes in the morphology of retinal layers were observed on P35. The abnormalities in astrocytes might contribute, at least in part, to the formation of abnormal retinal blood vessels and the pathogenesis of ROP.
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http://dx.doi.org/10.1007/s00441-019-03112-9DOI Listing
March 2020

An Unusual Extender Unit Is Incorporated into the Modular Polyketide Synthase of Scopranones Biosynthesis.

Biochemistry 2019 12 6;58(50):5066-5073. Epub 2019 Dec 6.

Kitasato Institute for Life Sciences , Kitasato University , 1-15-1 Kitasato, Minami-ku , Sagamihara , Kanagawa 252-0373 , Japan.

Scopranones, produced by sp. BYK-11038, are the novel bone morphogenetic protein inhibitors characterized by atypical two scoop-like moieties and a 3-furanone moiety. Two scoop-like moieties connected to a 3-furanone have not previously been reported in natural products, and their biosynthesis must occur via a unique pathway. Feeding experiments using C-labeled precursors indicated that scopranones were synthesized from three acetates and three butyrates in polyketide-type biosynthesis. Genome mining of sp. BYK-11038 revealed that the candidate biosynthetic gene cluster contains 21 open reading frames (ORFs), including three modular polyketide synthases (PKSs; SprA, SprB, and SprC), which were composed of 4 modules with one loading module and 18 additional ORFs (SprD to SprU) spanning a distance of 55 kbp. The characterization of in-frame deletion mutants and feeding experiments with the predicted extender units indicated that two genes, and , encoding discrete 3-oxoacyl-ACP synthases, and a gene, , encoding crotonyl-CoA reductase, were involved in assembling an unusual C branched extender unit, 2-(2-ethylbutyl)malonyl-CoA. Additionally, three ORFs, , , and , encoding cytochrome P450s and a monooxygenase, are important tailoring enzymes in post-PKS modification. SprT is an essential enzyme for decarboxylative ring contraction via oxidation, which converts the 2-pyranone to a 3-furanone.
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http://dx.doi.org/10.1021/acs.biochem.9b00908DOI Listing
December 2019

Extracellular volume fraction determined by equilibrium contrast-enhanced dual-energy CT as a prognostic factor in patients with stage IV pancreatic ductal adenocarcinoma.

Eur Radiol 2020 Mar 14;30(3):1679-1689. Epub 2019 Nov 14.

Department of Radiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, 890-8544, Japan.

Objectives: To evaluate the feasibility of equilibrium contrast-enhanced dual-energy CT (DECT), as compared with single-energy CT (SECT) and to calculate extracellular volume (ECV) fraction to predict the survival outcomes of pancreatic ductal adenocarcinoma (PDAC) patients with distant metastases (stage IV) treated with chemotherapy.

Methods: The study cohort included a total of 66 patients with stage IV PDAC who underwent DECT before systemic chemotherapy between July 2014 and March 2017. Unenhanced and 120-kVp equivalent images during the equilibrium phase were used to calculate tumor SECT-derived ECV fractions, and iodine density images were obtained from equilibrium-phase DECT for DECT-derived ECV fractions. Correlations between SECT- and DECT-derived ECV fractions were identified using the Pearson correlation coefficient and Bland-Altman analysis. The effects of clinical prognostic factors and tumor SECT- and DECT-derived ECV fractions on progression-free survival (PFS) and overall survival (OS) were assessed by univariate and multivariate analyses using Cox proportional hazards models.

Results: The correlation between SECT- and DECT-derived ECV fractions was strong (r = 0.965; p < 0.001). The Bland-Altman plot between SECT- and DECT-derived ECV fractions showed a small bias (- 3.4%). Increasing tumor SECT- and DECT-derived ECV fractions were associated with a positive effect on PFS (SECT, p = 0.002; DECT, p = 0.007) and OS (DECT, p = 0.014; DECT, p = 0.015). Only tumor DECT-derived ECV fraction was an independent predictor of PFS (p = 0.018) and OS (p = 0.022) in patients with stage IV PDAC treated with chemotherapy on multivariate analysis.

Conclusions: The ECV fraction determined by equilibrium contrast-enhanced DECT can potentially predict the survival of patients with stage IV PDAC treated with chemotherapy.

Key Points: • Extracellular volume fraction of stage IV pancreatic ductal adenocarcinoma determined by dual-energy CT was strongly correlated to that with single-energy CT (r = 0.965, p < 0.001). • Tumor extracellular volume fraction was an independent predictor of progression-free survival (p = 0.018) and overall survival (p = 0.022). • Extracellular volume fraction determined by dual-energy CT could be a useful imaging biomarker to predict the survival of patients with stage IV pancreatic ductal adenocarcinoma treated with chemotherapy.
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http://dx.doi.org/10.1007/s00330-019-06517-wDOI Listing
March 2020

Estimation of Extracellular Volume Fraction With Routine Multiphasic Pancreatic Computed Tomography to Predict the Survival of Patients With Stage IV Pancreatic Ductal Adenocarcinoma.

Pancreas 2019 Nov/Dec;48(10):1360-1366

From the Departments of Radiology.

Objective: This study aimed to determine whether extracellular volume (ECV) fraction with routine equilibrium contrast-enhanced computed tomography (CT) can predict outcomes in patients with stage IV pancreatic ductal adenocarcinoma (PDAC) treated with chemotherapy.

Methods: This is a retrospective cohort study of 128 patients with stage IV PDAC who underwent multiphasic pancreatic CT before systemic chemotherapy. Contrast enhancement and ECV fraction of the primary lesion were calculated using region-of-interest measurement within the PDAC and aorta on unenhanced and equilibrium phase-enhanced CT. The effects of clinical prognostic factors and ECV fractions on progression-free survival (PFS) and overall survival (OS) were assessed by univariate and multivariate analyses using Cox proportional hazards models.

Results: The number of metastatic organs and tumor ECV fraction were significant for PFS (P = 0.005 and 0.001, respectively) and OS (P = 0.012 and 0.007, respectively). On the multivariate analysis, multiple metastatic organs (PFS, P = 0.046; OS, P = 0.047) and lower tumor ECV fraction (PFS, P = 0.010; OS, P = 0.026) were identified as independent predictors of poor PFS and OS.

Conclusion: Extracellular volume fraction with routine equilibrium contrast-enhanced CT may potentially predict survival in patients with stage IV PDAC treated with chemotherapy.
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http://dx.doi.org/10.1097/MPA.0000000000001427DOI Listing
September 2020

Extract of strain 06CC2 induces JNK/p38 MAPK pathway-mediated apoptosis through endoplasmic reticulum stress in Caco2 colorectal cancer cells.

Biochem Biophys Rep 2019 Dec 3;20:100691. Epub 2019 Oct 3.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8544, Japan.

Colorectal cancer is a multi-factorial disease involving genetic, environmental and lifestyle risk factors. In recent years, many changes in the bacterial composition of the intestinal microflora have been reported in colorectal cancer, suggesting the involvement of the intestinal microflora in the development and progression of colorectal cancer. Along with these reports, research on lactic acid bacteria that have a beneficial effect on the human body for the purpose of improving the intestinal environment and treating intestinal diseases has advanced. Among these studies, biogenics (defined as a component derived from lactic acid bacteria that acts directly on diseases regardless of the state of intestinal microflora) is a recent concept derived from the work on probiotics. Based on this concept, it is important to evaluate the effectiveness of various components derived from lactic acid bacteria in the treatment to diseases from and apply them in prevention and treatment. In this study, we investigated the antitumor effect of an extract obtained from strain 06CC2 on colorectal cancer cells. In in vitro experiments, the extract derived from 06CC2 significantly suppressed the proliferation of Caco2 colorectal cancer cells in comparison to control and non-cancer cells. Furthermore, we found that endoplasmic reticulum stress and the JNK/p38 MAPK signaling system are involved in the induction of apoptosis. These findings indicate the direct antitumor effect of the 06CC2 extract on Caco2 colorectal cancer cells, and that this extract may have potential application as a biogenics.
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http://dx.doi.org/10.1016/j.bbrep.2019.100691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804738PMC
December 2019

Factors Associated with the Technical Success of Bilateral Endoscopic Metallic Stenting with Partial Stent-In-Stent Placement in Patients with Malignant Hilar Biliary Obstruction.

Gastroenterol Res Pract 2019 16;2019:5928040. Epub 2019 Sep 16.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.

Background: Bilateral biliary drainage decreases the risk of cholangitis, but bilateral endoscopic metallic stenting is technically challenging.

Aim: We retrospectively evaluated the factors associated with successful bilateral self-expanding metal stent (SEMS) placement using the partial stent-in-stent (PSIS) method for malignant hilar biliary obstruction and also assessed the safety and efficacy of this technique.

Methods: From April 2010 to February 2016, 47 consecutive patients (mean age, 73.0 ± 8.6 years; 32 males and 15 females) underwent PSIS placement for malignant hilar biliary obstruction in our hospital. The technical success of PSIS, clinical response, and complications were investigated. Factors associated with the technical success of PSIS were assessed. Using a propensity score-matched analysis, we compared the procedure time, clinical response, complications, stent patency, and survival time in 17 matched patients treated with bilateral SEMS placement using a SEMS delivery system of <6.0 or ≥6.0 Fr.

Results: The technical success rate was 77%. The clinical response rate was 91%, and the complication rate was 26%. Regarding complications, pancreatitis occurred in 5 patients (11%), cholangitis in 6 (13%), and cholecystitis in 1 (2%). A multiple logistic regression analysis identified the use of a SEMS with a delivery system < 6.0 Fr as a factor associated with technical success ( = 0.033; odds ratio, 10.769; 95% confidence interval, 1.205-96.212). In the 17 matched patients assigned according to the SEMS delivery system size, the procedure time was significantly shorter in those with a delivery system size < 6.0 Fr than in those with ≥6.0 Fr ( < 0.01). There were no significant differences in the clinical response, complication rate, stent patency, or survival time between the two groups.

Conclusion: Using a delivery system < 6.0 Fr in size helped improve the technical success and reduced the procedure time for the placement of a SEMS by the PSIS method.
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http://dx.doi.org/10.1155/2019/5928040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766084PMC
September 2019

Diagnostic utility of linked color imaging in the evaluation of colonic mucosal inflammation in ulcerative colitis: a pilot study.

Endosc Int Open 2019 Aug 24;7(8):E937-E943. Epub 2019 Jul 24.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

 Recent studies recommend histological mucosal healing of intestinal tissue as a treatment goal in ulcerative colitis (UC). Linked-color imaging (LCI) is a new endoscopy system that enhances the color differences of the gastrointestinal mucosa. We investigated the efficacy of LCI in the evaluation of intestinal activity, including the histological activity in UC.  A total of 21 UC patients who were evaluated by the LASEREO system (FUJIFILM Co., Tokyo, Japan) were enrolled from August to December in 2016. All of the target points were observed by conventional white-light imaging (WLI) and LCI and biopsied from the region of interest in each view. We quantified the color tones of 73 biopsied points on WLI and LCI using the L*a*b* color value (WLI-L, WLI-a, WLI-b, and LCI-L, LCI-a, LCI-b). We then investigated the relationships among the L*a*b* color values, endoscopic findings, and histological healing.  The average LCI-a and LCI-b values of patients with high mucosal activity disease were significantly higher than in those with mucosal healing (  < 0.01), and only LCI-a was significantly correlated with the score for histological healing. With regard to the other color values (LCI-L and all WLI values), there were no statistically significant differences in terms of average color value and correlation between patients with high mucosal activity and those with mucosal healing. In addition, the difference in the average color values with LCI and WLI was 7.1 and 3.1, respectively.  LCI is more useful than WLI for the visualization and evaluation of mucosal inflammation in UC.
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http://dx.doi.org/10.1055/a-0810-0398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656553PMC
August 2019

Attenuation of Retinal Endothelial Vasodilator Function in a Rat Model of Retinopathy of Prematurity.

Curr Eye Res 2019 12 18;44(12):1360-1368. Epub 2019 Jul 18.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.

: Retinopathy of prematurity (ROP) is characterized by morphological abnormalities in retinal blood vessels, but how an episode of ROP affects vascular function remains to be fully elucidated. The purpose of the present study was to assess the distribution of pericyte/smooth muscle in retinal blood vessels and retinal vasodilator responses in a rat model of ROP.: ROP was induced in rats by the subcutaneous injection of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8. The distribution of pericyte/smooth muscle in retinal blood vessels was examined on P14 and P35 by immunohistochemistry. Retinal vasodilator responses were assessed on P35 by measuring the diameter of retinal arterioles in fundus images.: In retinas of KRN633-treated (ROP) rats, progressive angiogenesis, tortuous arteries, enlarged veins, and enhanced expression of α-smooth muscle actin in pericytes on capillaries and veins were observed on P14. These abnormalities in retinal vasculature showed a tendency to normalize by P35. Vasodilation of retinal arterioles induced by acetylcholine, an endothelium-dependent vasodilator, was smaller in P35 ROP rats than age-matched controls, whereas retinal vasodilator responses to the nitric oxide (NO) donor NOR3 were unaltered.: Phenotypic changes in pericytes occur in the ROP model rats and endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired. The impaired vasodilator function may contribute to the progression and pathogenesis of ROP.
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http://dx.doi.org/10.1080/02713683.2019.1641825DOI Listing
December 2019

Cola Dissolution Therapy via Ileus Tube Was Effective for Ileus Secondary to Small Bowel Obstruction Induced by an Enterolith.

Intern Med 2019 Sep 22;58(17):2473-2478. Epub 2019 May 22.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Japan.

An 87-year-old bedridden woman developed intestinal obstruction caused by an enterolith or bezoar. Since the patient refused surgery, we administered 1,000 mL/day of cola via an ileus tube to dissolve the stone. Occlusion of the small intestine disappeared on day 6. The excreted stones contained calcium phosphate, which is typical of enteroliths. We later confirmed that the retrieved stones could be dissolved in cola (Coca-Cola, pH 1.9) as well as 0.10 and 0.010 mol/L hydrochloric acid (pH 1.0 and 2.0, respectively) and food-grade vinegar (pH 2.6). These findings suggest that the enteroliths were dissolved by an acid-base reaction.
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http://dx.doi.org/10.2169/internalmedicine.2745-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761349PMC
September 2019
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