Protumoral Effect of Angiotensin System.

Colorectal cancer (CRC) cells possess an angiotensin activation mechanism provided by the expression of renin and chymase. Renin expression is induced by a hyperglycemic condition. Since angiotensinogen is produced in the liver, CRC cells with angiotensin-activating machinery possess an advantage to metastasize to the liver. In human CRC cases, the diabetes-complicated patients show higher concentrations of renin and angiotensin-Ⅱ in the primary tumors, and a more progressed disease stage, especially, liver metastasis in association with HbA1c levels than those in the patients without diabetes. Concurrent treatment with anti-angiotensin and hypoglycemic agents shows a synergic effect of decreasing liver metastasis and improving the survival of diabetic mice in the CRC liver metastasis model. MAS1-angiotensin1-7 is a negative regulator of the AGTR1-angiotensin Ⅱ axis in breast cancer. Notably, MAS1 is overexpressed in triple negative breast cancer, which might be a novel molecular target for the treatment-refractory entity of breast cancer. Nuclear AGTR2 and intracellular angiotensin-Ⅱ play a role in anti-apoptotic and anti-oxidative stress properties. These functions of nuclear AGTR2 might mitigate "anti-tumoral side effects" of AGTR1 and angiotensin-Ⅱ system, which enhance mainly tumor progression. The effect of anti-angiotensin treatment such as ARB and blood sugar control as ab aseline management of many cancer patients needs to be examined in a clinical situation for prevention of RAS-induced tumor progression

Implant success remains high despite grafting voids in the maxillary sinus

ObjectivesGiven that the nature and presence of voids present within grafted sinuses following maxillary sinus elevation procedures were not known, nor was the contribution of these factors to implant success, the purpose of this study was to investigate these parameters and their relationship to implant success.Materials and MethodsThis study evaluated data from 25 subjects who had a lateral window maxillary sinus augmentation procedure. Cone‐beam computed tomography (CBCT) was performed at baseline and 4 months after surgery. CBCT images were used to evaluate grafted sites prior to implant placement. Using CBCT images, three examiners independently measured bone‐grafted areas (BG), void areas (V), and percentage of void areas (V%) from six different sections within grafted sites. The six sections were defined as a cross‐sectional (CS) midpoint, CS mesial point, CS distal point, horizontal section (HS) low point, HS midpoint, and HS high point. Implant success was also determined.ResultsThe calculated V% (V/BG) for the CS midpoint, CS mesial point, CS distal point, HS low point, HS midpoint, and HS high point were 5.30 ± 6.67%, 5.79 ± 8.51%, 6.67 ± 7.12%, 2.07 ± 2.56%, 5.30 ± 6.62%, and 4.92 ± 5.17% respectively. Implant success after 6 months of follow‐up approximated 100%.ConclusionsAlthough voids within grafts varied in terms of distribution and size, the V% within the HS low point were significantly smaller compared to those within the CS midpoint and CS distal point, which had the most intra‐subject V%. Thus, more attention should be given to the distal aspect of the sinus when compacting graft materials in the lateral wall sinus augmentation procedure. Implant success was not influenced by the existence of voids as implant success remained high.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110843/1/clr12386.pd

中鎖脂肪酸と糖質の併用摂取は癌関連骨格筋萎縮から保護する

Skeletal muscle volume is associated with prognosis of cancer patients. Maintenance of skeletal muscle is an essential concern in cancer treatment. In nutritional intervention, it is important to focus on differences in metabolism between tumor and skeletal muscle. We examined the influence of oral intake of glucose (0%, 10%, 50%) and 2% medium-chain fatty acid (lauric acid, LAA, C12:0) on tumor growth and skeletal muscle atrophy in mouse peritoneal metastasis models using CT26 mouse colon cancer cells and HT29 human colon cancer cells. After 2 weeks of experimental breeding, skeletal muscle and tumor were removed and analyzed. Glucose intake contributed to prevention of skeletal muscle atrophy in a sugar concentration-dependent way and also promoted tumor growth. LAA ingestion elevated the level of skeletal muscle protein and suppressed tumor growth by inducing tumor-selective oxidative stress production. When a combination of glucose and LAA was ingested, skeletal muscle mass increased and tumor growth was suppressed. Our results confirmed that although glucose is an important nutrient for the prevention of skeletal muscle atrophy, it may also foster tumor growth. However, the ingestion of LAA inhibited tumor growth, and its combination with glucose promoted skeletal muscle integrity and function, without stimulating tumor growth. These findings suggest novel strategies for the prevention of skeletal muscle atrophy.博士（医学）・甲第733号・令和2年3月16日© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License(https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

Development of a high-resolution two-dimensional detector-based dose verification system for tumor-tracking irradiation in the CyberKnife system

We aim to evaluate the basic characteristics of SRS MapCHECK (SRSMC) for CyberKnife (CK) and establish a dose verification system using SRSMC for the tumor-tracking irradiation for CK. The field size and angular dependence of SRSMC were evaluated for basic characterization. The output factors (OPFs) and absolute doses measured by SRSMC were compared with those measured using microDiamond and microchamber detectors and those calculated by the treatment planning system (TPS). The angular dependence was evaluated by comparing the SRSMC with a microchamber. The tumor-tracking dose verification system consists of SRSMC and a moving platform. The doses measured using SRSMC were compared with the doses measured using a microchamber and radiochromic film. The OPFs and absolute doses of SRSMC were within ±3.0% error for almost all field sizes, and the angular dependence was within ±2.0% for all incidence angles. The absolute dose errors between SRSMC and TPS tended to increase when the field size was smaller than 10 mm. The absolute doses of the tumor-tracking irradiation measured using SRSMC and those measured using a microchamber agreed within 1.0%, and the gamma pass rates of SRSMC in comparison with those of the radiochromic film were greater than 95%. The basic characteristics of SRSMC for CK presented acceptable results for clinical use. The results of the tumor-tracking dose verification system realized using SRSMC were equivalent to those of conventional methods, and this system is expected to contribute toward improving the efficiency of quality control in many facilities

Ultrasonography and 3D-CT Follow-Up of Extrahepatic Portal Vein Aneurysm: A Case Report

Extrahepatic portal vein aneurysm is a rare disorder. From 1956 to 2008, we found only 43 published English-language reports, including 67 cases, using Pub Med. We report a case of a 77-year-old woman who had complaints of lower abdominal fullness and residual urine. We performed ultrasonography (US), which demonstrated a congenital extrahepatic portal vein aneurysm. She had no obvious symptoms of the extrahepatic portal vein aneurysm. She had undergone gastrectomy without blood transfusion for gastric ulcer more than 20 years ago. Physical examination revealed no abnormal findings. US revealed a 2.2 × 1.8 cm, round shaped hypoechogenic lesion at the hepatic hilum. Color Doppler US showed bidirectional colors due to circular flow within this lesion. 3D-CT and CT angiography demonstrated that the saccular aneurysm at the hepatic hilum was 3.0 cm in diameter and was enhanced equal to that of portal vein.Twenty-six months after the diagnosis, the aneurysm had not grown in size. Since our patient had no serious complaints or liver disease, surgical procedures had not been employed. US and 3D-CT are noninvasive diagnostic techniques and are helpful in the diagnosis and follow-up of extrahepatic portal vein aneurysms

胃癌におけるクローディン4標的化によるシスプラチン化学療法感受性の向上

Claudins are major tight-junction proteins that mediate cellular polarity and differentiation. The present study investigated whether the 4D3 antibody to the human CLDN4 extracellular domain (that we previously established) is capable of modulating chemotherapeutic sensitivity in gastric cancer (GC). The results of the present study showed that CLDN4 was overexpressed in 137 of the 192 analyzed GC cases, and that CLDN4 expression was retained in tumors of a lower histological grade (more differentiated), and/or those that were caudal-type homeobox protein 2 (CDX2)-positive, but was reduced in more highly undifferentiated, and CDX2-negative GC cases. The study also compared the synergic effects of combining 4D3 with CDDP treatment and knocking down CLDN4 expression in MKN74 and TMK-1 human GC cells. Co-treatment with 4D3 increased anti-tumor effects of CDDP, whereas CLDN4 knockdown did not. In the TMK-1 cells, non-tight junction CLDN4 associated with integrin β1, increasing stem cell-associated proteins via FAK-c-SRC signals. The anti-tumoral effect of CDDP and 4D3 was examined in a nude mouse subcutaneous tumor model. In the two GC cell lines, concurrent treatment with 4D3 and CDDP synergistically inhibited cell proliferation and increased tumor necrosis and apoptosis to a greater degree than CDDP treatment alone. These findings suggest that 4D3 might increase chemotherapeutic sensitivity by evoking structural disintegration of tight-junction CLDN4 expressed in gastric cancer.博士（医学）・甲第713号・令和元年6月26日Copyright: Nishiguchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

酸化型HMGB-1は間葉系幹細胞/間葉系細胞を介して大腸癌の転移性を促進する

High mobility group box-1 (HMGB1) is known to be a chemotactic factor for mesenchymal stem/stromal cells (MSCs), but the effect of post-translational modification on its function is not clear. In this study, we hypothesized that differences in the oxidation state of HMGB1 would lead to differences in the function of MSCs in cancer. In human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three-fold fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM-MSCs) and induced differentiation into osteoblasts and vascular pericytes, whereas oxidized HMGB1 promoted proliferation and increased stemness, and no differentiation was observed. When BM-MSCs pretreated with oxidized HMGB1 were co-cultured with syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased, and tumorigenesis and drug resistance were promoted. In contrast, co-culture with reduced HMGB1-pretreated BM-MSCs did not enhance stemness. In an animal orthotopic transplantation colorectal cancer model, oxidized HMGB1, but not reduced HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore, oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized HMGB1–MSC axis may be an important target for cancer therapy.博士（医学）・甲第874号・令和5年3月15