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Amyloid β-protein (Aβ) oligomers are involved in the early stages of Alzheimer's disease (AD) and antibodies against these toxic oligomers could be useful for accurate diagnosis of AD. We identified the toxic conformer of Aβ42 with a turn at positions 22/23, which has a propensity to form toxic oligomers. The antibody 24B3, developed by immunization of a toxic conformer surrogate E22P-Aβ9-35 in mice, was found to be useful for AD diagnosis using human cerebrospinal fluid (CSF). However, it is not known how 24B3 recognizes the toxic conformation of wild-type Aβ in CSF. Here, we report the crystal structure of 24B3 Fab complexed with E22P-Aβ11-34, whose residues 16-26 were observed in electron densities, suggesting that the residues comprising the toxic turn at positions 22/23 were recognized by 24B3. Since 24B3 bound only to Aβ42 aggregates, several conformationally restricted analogs of Aβ42 with an intramolecular disulfide bond to mimic the conformation of toxic Aβ42 aggregates were screened by enzyme immunoassay. As a result, only F19C,A30homoC-SS-Aβ42 (1) bound significantly to 24B3. These data provide a structural basis for its low affinity to the Aβ42 monomer and selectivity for its aggregate form.

A precut procedure is sometimes required for difficult biliary cannulation during endoscopic retrograde cholangiopancreatography (ERCP). However, it is unclear whether the biliary access rate has improved for early precut procedures compared to conventional techniques. This study aimed to identify the benefit of early precut sphincterotomy in cases showing difficult biliary access.Between April 2017 and August 2021, consecutive patients who underwent precutting for difficult biliary cannulation were retrospectively enrolled. The outcomes of early (≤ 10 min from start of cannulation) and delayed ( 10 min) precut groups were evaluated. All adverse events were defined according to Cotton criteria.A total of 70 patients were enrolled in this study. The biliary cannulation rate for a first ERCP was significantly higher in the early compared to delayed precut group (95% vs. 73.3%; P = 0.015). A difference in overall cannulation rate between the two groups was not observed (97.5% vs. 83.3%; P 0.05). Significantly higher rates of prophylactic pancreatic stents were described in the delayed compared to early precut group (36.7% vs. 12.5%; P = 0.009). Significant differences in the frequency of pancreatitis, bleeding, penetration, and perforation were not noted between the two groups. Overall, the success rate was statistically significant between the experienced and less experienced endoscopists (87.2% vs. 63.9%; P = 0.017).Early precutting within 10 min from the start of cannulation in ERCP is safe and effective in cases with a difficult biliary cannulation, and can improve the biliary cannulation rate.

Supplementary Table 3 from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Supplementary Table 1 from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Supplementary Table 2 from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

CCR Translation for This Article from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Purpose: On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.Results: ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.Conclusions: ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer. Clin Cancer Res; 17(11); 3803–11. ©2011 AACR.

We herein report a case of atypical pseudo-Meigs' syndrome without pleural effusion. A 46-year-old woman was diagnosed with an ovarian tumor and sigmoid colon cancer with massive ascites. She underwent surgical resection of the sigmoid colon and bilateral salpingo-oophorectomy. The pathological diagnosis was sigmoid colon cancer with ovarian metastasis. A few days after the operation, the massive ascites disappeared. Immunostaining for vascular endothelial growth factor (VEGF) suggested its overproduction was involved in the development of the ascites. Although cases of pseudo-Meigs' syndrome without pleural effusion are rare, reporting such cases will facilitate the choice of more appropriate treatment strategies in future.

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP

Aberrant DNA methylation, induced by aging and accelerated by chronic inflammation, accumulates in normal tissue. Accumulation of DNA methylation in multiple genes, namely epimutation burden, is closely associated with cancer risk. Indeed, we demonstrated that the measurement of the methylation level of a marker gene in normal tissue is useful for cancer risk prediction of metachronous cancers, by a multicenter prospective study with gastric cancer patients (Asada, Gut, 64:388, 2015: Maeda, Gut, 66:1721, 2017). In this study, we attempted to predict the risk of primary gastric cancer by performing a new multicenter prospective study. We recruited 1,880 healthy people, after Helicobacter pylori eradication, with a clinically high risk of gastric cancer. Biopsy specimens were obtained from the antrum and body, and the methylation level of RIMS1, which is a preselected epigenomic risk marker for this study, was measured in 1,757 participants. The participants are annually being followed-up to detect primary gastric cancer, for 5-8 years. Currently, the median follow-up is 4.05 years, and 27 people have developed primary gastric cancers (as of September 2022). The results of statistical analysis are being determined. This study will establish the clinical utility of a cancer risk diagnosis by epimutation burden in normal tissue, and is promising for application in various inflammation-associated cancers. Citation Format: Harumi Yamada, Masahiro Maeda, Seiichiro Abe, Taichi Shimazu, Takayuki Ando, Kazunari Murakami, Shinji Tanaka, Takao Maekita, Osamu Inatomi, Ken Sugimoto, Tetsuro Kawagoe, Nobutake Yamamichi, Toshikazu Ushijima. Cancer risk diagnosis by epimutation burden: a multicenter prospective study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6014.

Background Situs inversus totalis (SIT) is a rare congenital condition in which the thoracic and abdominal organs are inverted like a mirror image. Case report We present a case of synchronous gastric cancer and gastrointestinal stromal tumor (GIST) associated with SIT in a 74-year-old man who was admitted to our department to treat gastric cancer. Esophagogastroduodenoscopy revealed a depressed lesion and a submucosal tumor (SMT) in the middle-third of the stomach. Abdominal contrast-enhanced computed tomography revealed complete inversion of the internal organs, and the common hepatic artery branched from the superior mesenteric artery. The patient underwent laparoscopic distal gastrectomy with regional lymph node dissection and Billroth I reconstruction. The macroscopic observation of the resected specimen revealed a depressed lesion measuring 2.0×1.5 cm in diameter and an SMT measuring 2.2×1.8 cm. Conclusion Careful preoperative anatomic evaluation is important in SIT because the situs anomalies may be accompanied by major vascular anomalies.

Background: This study aimed to investigate the efficacy of enteral supplementation of vitamin B12 for vitamin B12 deficiency in patients who underwent total gastrectomy for gastric cancer. Methods: The study enrolled 133 patients who underwent total gastrectomy for gastric cancer at Kochi Medical School. Clinical data were obtained to investigate associations between vitamin B12 supplementation and vitamin B12 levels. Vitamin B12 deficiency was defined as serum vitamin B12 less than 200 pg/mL. Baseline characteristics and changes in hematological variables, including vitamin B12 levels, were examined. Results: Vitamin B12 deficiency was present in 71.4% of the 133 patients. Vitamin B12 levels at 3, 6, and 12 months after enteral supplementation were 306 pg/mL, 294 pg/mL, and 367 pg/mL, respectively, which were all significantly higher than those before supplementation (p < 0.001 for all comparisons). The median red blood cell count at 3, 6, and 12 months after enteral supplementation were 380 × 104/mm3, 394 × 104/mm3, and 395 × 104/mm3, respectively, which were all significantly higher than those before supplementation (p = 0.020, p = 0.001, and p = 0.003, respectively). Vitamin B12 levels at 3, 6, and 12 months after supplementation were significantly higher in patients supplemented enterally than those supplemented parenterally (p < 0.001 for all comparisons). Conclusions: Vitamin B12 deficiency was found in 71.4% of postoperative patients who underwent total gastrectomy for gastric cancer, and enteral vitamin B12 supplements might be effective to improve anemia in these patients.

The performance of sunscreen products depends on their ultraviolet (UV) absorption ability through the film formed on the skin surface upon their application. Therefore, it is important that a uniform film is formed on the uneven skin surface for effective sunscreen performance. Because most UV filters are oil soluble, we hypothesized in this study that increasing the viscosity of the oil phase of a sunscreen product can improve the performance of the sunscreen. We first examined the association between the concentration of the oil thickener and the UV absorption ability of the sunscreen product using a skin-mimicking substrate (SMS). Among all thickeners examined (petrolatum, dextrin palmitate, silica silylate, and organoclay), organoclay and silica silylate significantly increased the UV absorbance of sunscreen on the SMS in a concentration-dependent manner. Thereafter, we examined film uniformity to elucidate the mechanism underlying the observed increase in UV absorption. The uniformity of film thickness on the SMS increased with increasing organoclay content, based on decreased standard deviations of film thickness. Our results showed that increasing the viscosity of the oil phase with organoclay resulted in the formation of a uniform film by preventing the sunscreen from flowing into the grooves when applied on the SMS, thereby increasing UV absorbance by more than two-fold that of sunscreen without organoclay. Thus, the use of thickeners, such as organoclay, increases the viscosity of the oil phase at a low shear rate after the high shear of application. This is an effective strategy for improving the overall quality and performance of sunscreen products.

Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the α8β1 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4+ T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4+ T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.

Background and aim The reliable method to stratify the gastric cancer risk after Helicobacter pylori eradication remains an elusive goal. Methods Mass eradication of H. pylori began in 2004 in a high-risk population. After eradication, a screening program involving first-stage serological tests (pepsinogen-I, pepsinogen-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018. Index lesions included gastric cancer or extensive premalignant lesions. We evaluated the performance of the serological tests to "rule in" and "rule out" the risk based on positive and negative likelihood ratios, respectively. The methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage. Results Among 6512 invited subjects, 3895 (59.6%) participated. Both gastrin-17 and pepsinogen tests were normal in 3560 (91.4%) subjects; 206 (5.3%) gastrin-17 and 129 (3.3%) pepsinogen tests were abnormal. Years after eradication, the severity of gastritis had fallen greatly, and extensive premalignant lesions or gastric cancer frequently occurred in newly non-atrophic-appearing mucosa. Pepsinogen testing could moderately predict atrophic gastritis (positive likelihood ratio: 4.11 [95% confidence interval: 2.92-5.77]; negative likelihood ratio: 0.14 [0.10-0.19]). Gastrin-17 was not useful (0.66 and 1.20, respectively). However, pepsinogen testing poorly predicted the index lesions (2.04 [1.21-3.42] and 0.57 [0.34-0.95]). DNA methylation levels in the post-eradication mucosa were more discriminative for predicting index lesions (3.89 [2.32-6.54] and 0.25 [0.15-0.42]). Conclusions After eradication, pepsinogen false-negative results become more frequent because histology is improved but genetic damage may persist. Direct testing for genetic damage offers better discrimination.

We investigated lipid metabolism in PXB-cells, which are human primary hepatocytes isolated from liver-humanized mice, and HepG2 and HuH-7 human hepatoma cell lines. Lipoprotein levels were higher in PXB-cells than in the 2 other cell lines, and PXB-cells mainly released triglycerides and cholesterol as very low density lipoprotein (VLDL), similar to actual liver tissue, whereas the major lipoprotein released from the 2 hepatoma cell lines was LDL. RT-PCR analysis demonstrated that the gene expression levels of apolipoprotein B100 (ApoB100), the apolipoprotein of VLDL/LDL, were similar in PXB-cells and HepG2 cells, while the overexpression of ApoC2, ApoC3, and ApoE, which are components of VLDL, but not LDL, was observed in PXBcells. A protein immunoassay revealed that ApoB100 levels secreted from PXB-cells and HuH-7 cells were similar; however, ApoC3 levels were higher in PXB-cells than in the two other cell lines. We also examined the anti-lipidemic activities of fenofibrate using this assay system. Fenofibrate suppressed lipoprotein production from PXB-cells in a dose-dependent manner mainly by activating the β-oxidation pathway. These results suggest that PXB-cells produce high levels of lipoproteins and are suitable for screening anti-lipidemic agents.

Aim: To determine whether markers of systemic inflammatory response and nutrition are a predictor of treatment response in patients with trastuzumab-treated unresectable advanced gastric cancer. Patients and Methods: Twenty-one patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2013 to 2020 were enrolled. Clinicopathological information and systemic inflammatory response data were obtained retrospectively to investigate associations between baseline cancer-related prognostic variables and survival outcomes. Results: The median overall survival (OS) and progression-free survival (PFS) for the whole cohort were 24.5 (range=1.9-88.4) months and 7.0 (range=2.0-23.4) months, respectively. The objective response rate and disease control rate were 52.4% and 81.0%, respectively. The median PFS for patients with a neutrophil to lymphocyte ratio (NLR)

Mesenteric lymph node metastasis of gastric cancer is extremely rare. We report the case of a patient with advanced gastric cancer having lymph node metastasis in the transverse mesocolon who underwent gastrectomy with lymph node dissection followed by chemotherapy. A 74-year-old male complaining of tarry stool was referred to our hospital for further examination following a diagnosis of gastric cancer by a local medical doctor. Esophagogastroduodenoscopy revealed an irregular and ulcerated lesion in the lower third of the stomach, and analyses of biopsy specimens revealed adenocarcinoma. Abdominal computed tomography revealed abdominal wall thickening in the lower third of the stomach, with enlarged lymph nodes in the perigastric area and the left side area of the middle colic artery. With a clinical diagnosis of gastric cancer, the patient underwent distal gastrectomy with lymph node dissection followed by Billroth Ⅰ reconstruction. During surgery, the enlarged lymph node along with the middle colic artery in the transverse mesocolon was dissected. The gross appearance of the resected specimen shows a large and ulcerated tumor measuring 6.0×5.5 cm in the lesser curvature side of the lower third of the stomach. The pathological examination of the resected specimen showed solid-type poorly-differentiated adenocarcinoma with lymph nodes metastases, which was detected in the perigastric area and transverse mesocolon. The final diagnosis according to the Japanese classification of gastric carcinoma by the Japanese Gastric Cancer Association was L, Less-Post-Ant, Type 2, 6.0×5.5 cm, T3(SS), N2(5/19), M1(LYM), P0, H0, CY0, por1, Ly0, V1a, Stage Ⅳ, R0. Subsequently, the patient received S-1 plus oxaliplatin chemotherapy; however, he developed para-aortic lymph node metastases 18 months after surgery. Therefore, the patient was treated with ramucirumab plus nab-paclitaxel and was alive 20 months after the operation. Although mesocolonic lymph node metastasis of gastric cancer is rare, future identification of risk factors and the development of novel treatments should be achieved through further investigations and the accumulation of 3 cases.

The extracellular matrix protein nephronectin (Npnt) is known to be critical for kidney development, but its function in inflammatory diseases is unknown. Here, we developed a new enzyme‐linked immunosorbent assay system to detect Npnt in various autoimmune diseases, which revealed that plasma Npnt levels are increased in various mouse autoimmune models. We also report that antibodies against the α8β1 integrin‐binding region of Npnt protect mice from anti‐type II collagen‐induced arthritis, suggesting that Npnt may be a potential therapeutic target molecule for the prevention of autoimmune arthritis., The role of extracellular matrix protein nephronectin (Npnt) in inflammatory diseases is unknown. In this study, we show that plasma Npnt levels are increased in various mouse autoimmune models and antibodies against the α8β1 integrin‐binding region attenuated the development of anti‐type II collagen‐induced arthritis in mice.

Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2′-deoxycytidine (5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs. Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis. The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC50 values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as RUNX3, PYCARD, TNF, FAS, and FASLG, was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of RUNX3 and PYCARD was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression. Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP.

Irie and colleagues identified a "toxic conformer", which possesses a turn structure at positions 22-23, among various conformations of Aβ and have been reporting its potent oligomeric capacity and neurotoxicity. This toxic conformer was detected in the brains of AD patients and AD model mice (Tg2576 line), and passive immunization targeting this conformer ameliorated the cognitive dysfunction in an AD model. In this study, we developed a novel AD mouse model (AppNL-P-F/NL-P-F) with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aβ, a mimic of the toxic conformer, utilizing the knock-in technique that well recapitulates the Aβ pathology of AD patients in mice and avoids the artificial phenotype observed in transgenic-type model mice. We confirmed that AppNL-P-F/NL-P-F mice produce Aβ by ELISA and accumulate senile plaques by immunohistochemistry at eight months of age. In WB, we observed a potential trimer band and high molecular-weight oligomer bands without a monomeric band in the TBS-soluble fraction of AppNL-P-F/NL-P-F mice at six months of age. In the novel object recognition test, cognitive impairment was observed at six months of age in these mice. These findings suggest that the toxic conformer of Aβ induces cognitive dysfunction mediated by its oligomer formation in this mouse brain. AppNL-P-F/NL-P-F mice may be a useful model for evaluating Aβ oligomer-induced cognitive impairment in AD and will aid in exploring therapeutic targets for AD pathology.

"Nutraceuticals" are well-tolerated natural dietary compounds with drug-like properties that make them attractive as Alzheimer's disease (AD) therapeutics. Combination therapy for AD has garnered attention following a recent National Institute on Aging mandate, but this approach has not yet been fully validated. In this report, we combined the two most promising nutraceuticals with complementary anti-amyloidogenic properties: the plant-derived phenolics (-)-epigallocatechin-3-gallate (EGCG, an α-secretase activator) and ferulic acid (FA, a β-secretase modulator). We used transgenic mice expressing mutant human amyloid β-protein precursor and presenilin 1 (APP/PS1) to model cerebral amyloidosis. At 12 months of age, we orally administered EGCG and/or FA (30 mg/kg each) or vehicle once daily for 3 months. At 15 months, combined EGCG-FA treatment reversed cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks. Moreover, EGCG- and FA-treated APP/PS1 mice exhibited amelioration of brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-proteins compared with either EGCG or FA single treatment. Combined treatment elevated nonamyloidogenic soluble APP-α and α-secretase candidate and down-regulated amyloidogenic soluble APP-β, β-C-terminal APP fragment, and β-secretase protein expression, providing evidence for a shift toward nonamyloidogenic APP processing. Additional beneficial co-treatment effects included amelioration of neuroinflammation, oxidative stress, and synaptotoxicity. Our findings offer preclinical evidence that combined treatment with EGCG and FA is a promising AD therapeutic approach.

Introduction Neuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. Methods We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results In monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42. Discussion Aging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.