Age-Stratified Seroprevalence of SARS-CoV-2 Antibodies before and during the Vaccination Era, Japan, February 2020-March 2022.

Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARS-CoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020-March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children <5 years of age was as low as 10% as of March 2022. Our study underscores the low incidence of SARS-CoV-2 infection in Japan and the effects of vaccination on immunity at the population level.

Potential use of EGFR-targeted molecular therapies for tumor suppressor CYLD-negative and poor prognosis oral squamous cell carcinoma with chemoresistance.

BACKGROUND: Tumor suppressor CYLD dysfunction by loss of its expression, triggers malignant transformation, especially drug resistance and tumor invasion/metastasis. Although loss of CYLD expression is significantly associated with poor prognosis in a large variety of tumors, no clinically-effective treatment for CYLD-negative cancer patients is available. METHODS: We focused on oral squamous cell carcinoma (OSCC), and sought to develop novel therapeutic agents for CYLD-negative cancer patients with poor prognosis. CYLD-knockdown OSCC cells by using CYLD-specific siRNA, were used to elucidate and determine the efficacy of novel drug candidates by evaluating cell viability and epithelial-mesenchymal transition (EMT)-like change. Therapeutic effects of candidate drug on cell line-derived xenograft (CDX) model and usefulness of CYLD as a novel biomarker using patient-derived xenograft (PDX) model were further investigated. RESULTS: CYLD-knockdown OSCC cells were resistant for all currently-available cytotoxic chemotherapeutic agents for OSCC, such as, cisplatin, 5-FU, carboplatin, docetaxel, and paclitaxel. By using comprehensive proteome analysis approach, we identified epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, played key roles in CYLD-knockdown OSCC cells. Indeed, cell survival rate in the cisplatin-resistant CYLD-knockdown OSCC cells was markedly inhibited by treatment with clinically available EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib. In addition, gefitinib was significantly effective for not only cell survival, but also EMT-like changes through inhibiting transforming growth factor-ß (TGF-ß) signaling in CYLD-knockdown OSCC cells. Thereby, overall survival of CYLD-knockdown CDX models was significantly prolonged by gefitinib treatment. Moreover, we found that CYLD expression was significantly associated with gefitinib response by using PDX models. CONCLUSIONS: Our results first revealed that EGFR-targeted molecular therapies, such as EGFR-TKIs, could have potential to be novel therapeutic agents for the CYLD-negative OSCC patients with poor prognosis.

Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades.

Lenvatinib inhibits VEGF- and FGF-driven angiogenesis, and proliferation of tumor cells with activated FGF signaling pathways in preclinical models, and we previously demonstrated antitumor activity in human HCC xenograft tumor models. Here, we examined the inhibitory activity of lenvatinib against FGF-driven survival of human HCC cell lines. First, we conducted a histological analysis of FGF19-overexpressing Hep3B2.1-7 xenograft tumors collected from mice treated with lenvatinib. Second, we examined the effects of pharmacological inhibition on survival of cultured HCC cells with an activated FGF signaling pathway under nutrient-starved culture condition to mimic tumor microenvironments induced by angiogenesis inhibition. In the first analysis, area of histological focal necrosis was greater in Hep3B2.1-7 xenograft tumors with the lenvatinib treatment than that after the treatment with sorafenib, which does not inhibit FGFRs. Lenvatinib and E7090 (a selective FGFR1-3 inhibitor), but not sorafenib, induced death of Hep3B2.1-7, and another FGF19 overexpressing HuH-7 cells. Lenvatinib and E7090 decreased phosphorylation of downstream molecules of the FGF signaling pathway (such as FRS2, Erk, and p38 MAPK), and induced PARP cleavage, even under limited nutrients. PD0325901, MEK inhibitor, caused the same changes in HCC cells as those described above for lenvatinib and E7090. These results reveal that the FGF signaling pathway through MAPK cascades plays an important role in survival of HCC cell lines with an activated FGF signaling pathway under limited nutrients, and FGFR-MAPK cascades likely contribute to survival of HCC cells with an activated FGF signaling pathway under tumor microenvironments with limited nutrients, where tumor angiogenesis is inhibited.

Histopathologic Characterization of Mifepristone-induced Ovarian Toxicity in Cynomolgus Monkeys.

Mifepristone, which is an orally active synthetic steroid with antiprogesterone activity, is known as an ovarian toxicant. Because the available data regarding the histopathologic characteristics of ovarian toxicity in nonhuman primates are limited, the present study was undertaken in order to investigate detailed histopathologic changes accompanying mifepristone-induced ovarian toxicity and its relationship to changes in menstrual cycle and circulating sex steroid hormone. Twenty mg/kg of mifepristone was orally administered daily to 4 cynomolgus monkeys for 2 months. Mifepristone inhibited the cyclic increases in circulating estradiol-17ß and progesterone levels with associated absence of menstruation. Histopathologically, the ovary in the treated animals showed follicular phase without changes in the percentage of atretic antral follicles, and reduced endometrial thickness was noted in the uterus. These changes indicated that a certain degree of antral follicle development had been retained in spite of the menstrual cycle having been arrested in mifepristone-treated animals. Our investigation suggested that it is important to perform detailed histopathologic examination of reproductive organs with precise knowledge of the characteristics of each menstrual stage to detect ovarian toxicity in nonhuman primates. Monitoring menstrual signs and circulating sex steroid hormone levels provides additional evidence for the investigation of the mechanism of ovarian toxicity.

Influenza vaccine showed a good preventive effect against influenza-associated hospitalization among elderly patients, during the 2016/17 season in Japan.

The 2016/17 influenza season in Japan was characterized by a predominance of influenza A (H3N2) activity; with H3N2 accounting for 85% of all detected influenza virus infections. We assessed the vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine (IIV4) in adult patients, using a test-negative case-control design study based on the results of a rapid influenza diagnostic test (RIDT). Between November 2016 and March 2017, a total of 1048 adult patients were enrolled: including 363 RIDT positive for influenza A, 9 RIDT-positive for influenza B, and 676 RIDT-negative. During the 2016/17 season, the overall adjusted VE was 28.8% (95% confidence interval [CI]: 6.3-46%). The adjusted VE against influenza A was 27.4% (95%CI: 4.4-45%). The VE against influenza B could not be estimated because of the very low number of influenza B patients. Twenty-nine patients were hospitalized due to influenza-associated illness-during the present study, all of whom were infected with influenza A virus. The adjusted VE, determined using a case-control study, for preventing hospitalization for influenza A infection was 72.6% (95%CI: 30.7-89.1%). In addition, the VE for preventing hospitalization of influenza patients with comorbidities was 78.2% (95%CI: 41.1-92%). Our study showed that, during the 2016/17season, IIV4 was effective for preventing both the onset of influenza and influenza-associated hospitalization.

Influenza vaccine effectiveness in adults based on the rapid influenza diagnostic test results, during the 2015/16 season.

We assessed the influenza vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine in adult patients, in our test-negative case-control design study based on the results of a rapid influenza diagnostic test. During the 2015/16 season in Japan, influenza A(H1N1)pdm09 virus and influenza B virus were epidemic. The overall adjusted VE was 44% (95% confidence interval [CI]: 13.6%-63.7%). The adjusted VE was 52.9% (95%CI: 20%-72.3%) against any influenza virus among those < 65 years of age and -5% (95%CI: 136%-53.5%) among the elderly ≧ 65 years of age. The adjusted VE against influenza A was 49.1% (95%CI: 13.9%-69.9%). Although the VE was 55.5% (95%CI: 14.8%-76.8%) among those <65 years of age, it was only 15.3% (95%CI: 120%-67.4%) among the elderly ≧ 65 years of age. The adjusted VE against influenza B was 33.8% (95%CI: 25%-64.8%) among adult patients (≧16 years of age) and 46.8% (95%CI: 13%-75%) among those < 65 years of age, the VE against influenza B could not be estimated in those ≧65 years of age because of the low number of elderly patients with that virus.

[Effectiveness of Influenza Vaccine in Adults Using A Test-negative, Case-control Design ­2013/2014 and 2014/2015 Seasons­].

The influenza vaccine forms the basis of efforts to prevent the occurrence of influenza virus infection. However, vaccine effectiveness (VE) differs every season, which complicates efforts to combat the spread of infection. To develop a robust method to analyse variations in VE, we assessed VE among adult patients with influenza using a test-negative, case-control study design that evaluated vaccination records and the corresponding results of rapid influenza diagnostic tests during the 2013/14 and 2014/15 influenza seasons. During the 2013/14season, the adjusted VEs against influenza A and B viruses were 54.9% (95% confidence interval [CI] = 24.2% - 73.2%) and 56.6% (95% CI = 19.1% - 76.7%), respectively. In contrast, during the 2014/15season, the adjusted VE against the influenza A (H3N2), virus was -2% (95% CI = -66% - 37.5%). Moreover, only a few patients were infected with the influenza B virus, thus, the VE against influenza B could not be assessed. The low VE during the 2014/15 season could be attributed to antigenic drift in the circulating influenza A (H3N2) viruses and mutations in the egg-adapted vaccine strains. Estimation of the VE against the influenza virus using this test-negative, case-control study design was simple and easy, and this study design had a precision similar to that of a randomized control trial. Therefore, this study design could be employed to predict VE through out the influenza season and may be used as the basis of influenza prophylaxis.

Time course of the incidence/multiplicity and histopathological features of murine colonic dysplasia, adenoma and adenocarcinoma induced by benzo[a]pyrene and dextran sulfate sodium.

Benzo[a]pyrene (BP) is mutagenic but noncarcinogenic in the murine colon. Recently, we reported rapid induction of colonic tumors by treatment of CD2F1 mice with BP (125 mg/kg for 5 days) followed by a colitis inducer, dextran sulfate sodium (DSS) (4% in drinking water for 1 or 2 weeks). However, there are no reports on detailed time course and histopathological features of colonic proliferative lesions in this model. Here, we show the detailed time course of colonic dysplasia, adenoma and adenocarcinoma induced by treatment with BP, DSS, and a combination of the two (BP/DSS). In the colon of mice exposed to BP/DSS, 14.6 dysplastic foci per mouse were present one week after DSS treatment (week 4). The number of dysplastic foci decreased with time to 3.1 at week 9 and thereafter remained almost constant. At week 4, 1.5 adenocarcinomas were also observed, with a marked increase in numbers with time, reaching 29.3 at week 14. In contrast, the number of dysplastic foci induced by DSS alone showed a time course similar to that following BP/DSS treatment; however, only a few tumors appeared. Neither dysplastic foci nor neoplastic lesions were induced by BP only. In mice exposed to BP/DSS, ß-catenin was demonstrated immunohistochemically in the nucleus and/or cytoplasm of the tumor cells, and this translocation from the cell membrane was evident in subsets of dysplastic foci. In dysplastic foci induced by DSS alone, ß-catenin was absent in the nucleus/cytoplasm. These finding suggest that aberrant ß-catenin accumulation in dysplastic foci is associated with tumor progression in this BP/DSS model.

Cytomegalovirus enteritis in immunocompetent subjects: a case report and review of the literature.

Cytomegalovirus (CMV) enteritis (or colitis) is generally diagnosed in immunocompromised patients in association with human immunodeficiency virus infection as well as in recipients of solid organ or hematopoietic stem cell transplant. CMV enteritis has been reported only sporadically in immunocompetent individuals. We encountered a 76-year-old woman who developed CMV enteritis without any previously identified immunocompromised states. An extensive literature review of 33 cases of CMV enteritis or colitis diagnosed in immunocompetent individuals, including the present case, revealed that the median age of the patients was 68, the accompanying symptoms were diarrhea (76%), abdominal pain (52%), and hematochezia or melena (27%), and that the outcome was generally favorable, including resolution without any treatment in 24% of the patients. CMV enteritis should be recognized more widely as a disease entity not only in immunocompromised patients but also in immunocompetent individuals, especially in elderly populations.

[Acute hepatitis C infection with prolonged intrahepatic cholestasis and remarkable progression of fibrosis mimicking fibrosing cholestatic hepatitis].

We report the case of a 71-year-old woman with acute hepatitis C infection and persistent viremia since 2 years. Her clinical course was characterized by general fatigue and prolonged jaundice with unusually high serum bilirubin levels. Liver histology showed lymphocyte infiltration, marked fibrosis, and severe cholestasis in the periportal zone, findings mimicking fibrosing cholestatic hepatitis (FCH). Fibrosing cholestatic hepatitis is a life-threatening form of recurrent hepatitis C infection that typically occurs in immunosuppressed patients. Here we report the rare case of an immunocompetent patient who developed this condition.

Impact of Circular Stapler Size on the Risk of Anastomotic Complications in Patients With Left-sided Colorectal Cancer: A Propensity Score-matched Study.

Background/Aim: The present study examined the impact of circular stapler size on anastomotic complications, including leakage and stricture in patients undergoing double-stapling technique (DST) anastomosis for left-sided colon or rectal cancer. Patients and Methods: A total of 403 patients were enrolled in this study, with circular stapler sizes  of 25, 28, and 29 mm. Results: A small circular stapler (25 mm) was used in 170 cases (42.2%), and a medium-sized circular stapler (28/29 mm) was used in 233 cases (57.8%). After propensity score matching, there was no marked difference in the incidence of anastomotic leakage/stricture between the groups (13.9% vs. 10.9%, 3.0% vs. 1.0%, respectively). Conclusion: The size of the circular stapler was not associated with the incidence of anastomotic leakage or stricture in this cohort.

Cachexia and efficiency of trifluridine/thymidine phosphorylase inhibitor + bevacizumab in metastatic colorectal cancer.

In later-line treatment of metastatic colorectal cancer (mCRC), there may be large differences in treatment efficacy depending on cancer cachexia. Recently, the cachexia index (CXI), which was calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio, was developed to evaluate cancer cachexia. We retrospectively examined the CXI of 80 patients who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) + bevacizumab (Bmab) therapy as a later-line treatment for mCRC, and assessed the impact of cancer cachexia on chemotherapeutic efficacy using CXI. Progression-free and overall survival rates were significantly worse in the low CXI group than in the high CXI group, although there were no marked differences in tumor factors, such as the number of metastatic organs or gene mutations, between the two groups. As the cross-sectional area of the iliopsoas muscle was significantly associated with that of the skeletal muscle, the accuracy of the CXI based on the psoas mass index (P-CXI), which is easier to calculate than the SMI, in predicting treatment outcomes was equivalent to that of the CXI based on the SMI (S-CXI). Cancer cachexia is an important factor related to treatment efficacy in later-line treatments, such as FTD/TPI + Bmab therapy.

Comparative sensitivity of laboratory animals used for preclinical convulsion risk assessment to drug-induced convulsion.

Drug-induced convulsion is a serious concern in drug development, such that the convulsion liability of drug candidates must be evaluated in preclinical safety studies. However, information on the differences among species regarding their sensitivity to convulsions induced by convulsant drugs in humans remains limited. Here, we selected 11 test articles from several pharmacological classes and compared the sensitivities of three types of laboratory animal to convulsion. All 11 test articles were examined in mice via intraperitoneal injection and in rats via intravenous bolus; and 6 of the 11 test articles, selected mainly based on availabilities of data on drug plasma concentrations in humans at convulsion, were examined in non-human primates (NHPs) via intravenous infusion. Plasma concentrations of the test articles shortly after convulsion onset or 5 min after administration were measured. All 11 articles tested in mice, 10 of 11 articles tested in rats, and all 6 articles tested in NHPs induced convulsion with premonitory signs. Although there was a general tendency that rats and NHPs exhibited convulsions at lower plasma drug concentrations than did mice, the plasma concentrations at convulsion onset were generally comparable, within 3-fold differences, across the animal species. We conclude that the mice, rats, and NHPs examined in the present study generally showed similar sensitivities to convulsion induced by the test articles. Thus, each of these laboratory animals can be used for the assessment of convulsion risk in the early stages of drug development, depending on throughput, cost, and test article-specific requirements.

Successful resection of a rectal gastrointestinal stromal tumor using a transperineal approach: a case report.

BACKGROUND: Rectal gastrointestinal stromal tumors (GISTs) complicate surgical approaches because of their anatomical position. We herein report a patient with rectal GIST on the anterior wall of the lower rectum, hat was successfully resected using a transperineal approach. CASE PRESENTATION: This report describes a unique case of a 73-year-old man who was diagnosed with rectal GIST on the anterior wall of the lower rectum. The tumor was located within 3 cm of the anal verge, a location that would require highly invasive surgery. A transperineal approach was planned to preserve the anal function. Under general anesthesia, the patient was placed in a lithotomy position and a Mercedes-Benz incision was made in the perineum. Excision of the tumor was performed. The post-operative course was uneventful, and the patient remained free from recurrence. CONCLUSION: This case highlights the importance of performing minimally invasive and safe surgery. With some surgical refinements, a transperineal approach may be an option for surgical procedures in patients with rectal GIST on the anterior wall of the lower rectum.

The Efficacy of Chemical Bowel Preparation Against Incisional Surgical Site Infection in Colorectal Cancer Surgery: A Propensity Score Matching Study.

BACKGROUND/AIM: In colorectal cancer surgery, the risk of surgical site infection (SSI) is relatively high. The development of SSI is related to longer and costlier hospitalization and reduced quality of life; therefore, perioperative prevention of SSI is important. Chemical bowel preparation (CBP) combined with mechanical bowel preparation (MBP) may be more effective in preventing surgical site infection (SSI) compared to MBP alone. Since May 2021, we have been administering oral kanamycin and metronidazole as CBP, in addition to MBP, as a preoperative treatment for colorectal cancer surgery on the day before surgery. In this study, we investigated the clinical value of CBP in addition to MBP in colorectal cancer surgery using propensity score matching (PSM). PATIENTS AND METHODS: From January 2017 to December 2021, 136 consecutive patients underwent radical surgery for sigmoid colon and rectal cancer at the Osaka Metropolitan University Hospital. Patients were divided into two groups: CBP and N-CBP. In the N-CBP group, we performed only preoperative MBP, whereas in the CBP group, we performed preoperative CBP in addition to MBP. We retrospectively analyzed this relationship with PSM. RESULTS: Overall, 46 patients underwent preoperative CBP and MBP, 90 patients underwent preoperative MBP only. PSM was performed between the CBP and N-CBP groups based on the following ten factors: age, sex, diabetes mellitus, preoperative therapy, Glasgow Prognostic Score (GPS), operative time, blood loss, stoma, and pathological stage. After PSM, univariate and multivariate analyses of the relationship between SSI and clinicopathological factors were performed. Univariate analysis showed that age and CBP were correlated with the rate of SSI (p=0.039 and p=0.017, respectively), whereas sex was relatively correlated with the rate of SSI (p=0.066). The multivariate analysis of significant factors identified age of 75 or more and non-CBP as an independent risk factor for incisional SSI (HR=9.5; p=0.049 and HR=5.4×e-8; p=0.020). CONCLUSION: Preoperative CBP in addition to MBP was effective in preventing incisional SSI during colorectal cancer surgery.

Epidermal distribution of tetrodotoxin-rich cells in newly hatched larvae of Takifugu spp.

Pufferfish of the genus Takifugu possess tetrodotoxin (TTX), known as "pufferfish toxin" and it is believed that pufferfish eggs and newly hatched larvae utilize TTX as a defensive substance against predators. However, the mechanism for the placement of TTX to specific cells on the larval body surface during the developmental process remains unknown. In this study, we clarify the distribution and characteristics of TTX-rich cells. We performed whole-mount immunohistochemistry (IHC) using anti-TTX monoclonal antibody on larvae of two pufferfish species, Takifugu rubripes and Takifugu alboplumbeus, just after hatching. This allowed observation of the TTX location and compared it with those of wheat germ agglutinin (WGA)-positive (periodic acid-Schiff (PAS)-positive) cells for mucous cells and IHC using anti-Na+/K+-ATPase (NKA) monoclonal antibody for ionocytes. As a result, uniformly scattered localization of TTX-rich cells was commonly observed in the epidermis of the larvae of the two Takifugu species. TTX-rich cells were WGA-negative (PAS-negative) and structurally distinct from NKA-positive cells, suggesting that TTX-rich cells are unreported small cells unique to pufferfish skin, but not mucous cells nor ionocytes.

Granulomatous nephritis consistent with malakoplakia in a cynomolgus monkey.

Malakoplakia is a rare form of chronic granulomatous inflammation in mammals, and usually affects the urinary tract in humans. In this report, we present a case of granulomatous nephritis consistent with malakoplakia in a 4-year-old male cynomolgus monkey. Gross examination showed that the kidney was markedly enlarged and adhered to the surrounding organs. Histology showed that there was diffuse interstitial infiltration of histiocytes with abundant foamy eosinophilic cytoplasm resembling von Hansemann cells, PAS-positive granular cytoplasm and occasional PAS- and iron-positive intracellular small inclusion bodies. Electron microscopy showed that these histiocytes contained abundant lysosomes and phagolysosomes but no obvious Michaelis-Gutmann bodies. Based on these findings, a diagnosis of granulomatous nephritis consistent with early malakoplakia was made. This is the first report in a monkey of a renal lesion consistent with malakoplakia.

DNA polymerase κ suppresses inflammation and inflammation-induced mutagenesis and carcinogenic potential in the colon of mice.

BACKGROUND: Chronic inflammation induces DNA damage and promotes cell proliferation, thereby increasing the risk of cancer. DNA polymerase κ (Pol κ), involved in translesion DNA synthesis, counteracts mutagenesis induced by inflammation in the colon of mice. In the present study, we examined whether Pol κ suppressed inflammation-induced colon tumorigenesis by treating inactivated Polk knock-in (Polk-/-) mice with dextran sulfate sodium (DSS), an inducer of colon inflammation. RESULTS: Male and female Polk-/- and Polk+/+ mice were administered 2% DSS in drinking water for six consecutive days, succeeded via a recovery period of 16 days, followed by 2% DSS for another two days. DSS treatment strongly induced colitis, and the severity of colitis was higher in Polk-/- mice than in Polk+/+ mice. The mice were sacrificed after 19 weeks from the initiation of the first DSS treatment and subjected to pathological examination and mutation analysis. DSS treatment induced colonic dysplasia, and the multiplicity of dysplasia was higher in Polk-/- mice than in Polk+/+mice. Some of the dysplasias in Polk-/- mice exhibited ß-catenin-stained nucleus and/or cytoplasm. Mutation frequencies in the gpt reporter gene were increased by DSS treatment in Polk-/- mice, and were higher than those in Polk+/+ mice. CONCLUSIONS: Pol κ suppresses inflammation and inflammation-induced dysplasia as well as inflammation-induced mutagenesis. The possible mechanisms by which Pol κ suppresses colitis- and colitis-induced dysplasia are discussed.

Association of CD8 + T cells expressing nivolumab-free PD-1 with clinical status in a patient with relapsed refractory classical Hodgkin lymphoma.

A 37-year-old man with refractory classical Hodgkin lymphoma (cHL) underwent PD-1 blockade therapy with nivolumab, which resulted in a partial response. However, treatment was discontinued due to immune-related adverse events (irAEs), including myasthenia gravis and myositis. Retreatment with nivolumab resulted in a complete metabolic response and hepatic irAE. Subsequently, nivolumab was administered at extended dosing intervals. Intermittent infusion of ten doses of nivolumab for a total dose of 2400 mg/body helped control the relapsed/refractory cHL over three years. During nivolumab treatment, disease progression and emergence of irAEs were associated with the proportion of CD8 + T cells expressing nivolumab-free PD-1 relative to the total number of CD8 + T cells. The findings in this nivolumab-sensitive patient highlight the clinical utility of monitoring immune cells expressing nivolumab-free PD-1 in patients with cHL who have been treated with nivolumab and have experienced irAEs.

o-Aminoazotoluene, 7,12-dimethylbenz[a]anthracene, and N-ethyl-N-nitrosourea, which are mutagenic but not carcinogenic in the colon, rapidly induce colonic tumors in mice with dextran sulfate sodium-induced colitis.

BACKGROUND: Several rodent models with chemically induced colon cancer have been developed. Among these models, dextran sulfate sodium (DSS), a colitis inducer, combined with azoxymethane as a colon mutagenic carcinogen, is commonly used. We previously reported that although benzo [a] pyrene (BP) is mutagenic but not carcinogenic in the colon, it rapidly develops colon tumors at a high incidence/multiplicity after treatment with DSS. In the present study, we examined whether other colon-mutagenic non-carcinogens (CMNCs) induced colon tumors after treatment with DSS. RESULTS: o-Aminoazotoluene, 7,12-dimethylbenz[a]anthracene, and N-ethyl-N-nitrosourea were selected as CMNCs. Male CD2F1 mice were orally administered CMNC for 5 consecutive days. After a 9-day dose-free period, mice were treated with 4% DSS in drinking water for 1 week. Three months after DSS treatment, colon samples were collected for histopathology and ß-catenin immunohistochemistry analyses. All CMNCs in combination with DSS induced colonic adenocarcinomas at a high incidence/multiplicity in the distal and middle parts of the colon, coinciding with the location of colitis. Unlike in normal cells where ß-catenin is exclusively located on the cell membrane, in adenocarcinoma cells, it was translocated to both the nucleus and cytoplasm or only to cytoplasm. The translocation of ß-catenin is closely associated with colon carcinogenesis in rodents and humans. No colonic tumors or dysplastic lesions were found after exposure to either CMNC or DSS alone. CONCLUSION: We provided further evidence clearly showing that CMNCs can rapidly induce colonic tumors in mice with DSS-induced colitis, even if they are not colonic carcinogens.