Mutagenic metabolites in urine and feces of rats fed with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a carcinogenic mutagen present in cooked meat

To study the in vivo fate of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a carcinogenic mutagen present in cooked meat, rats were fed MeIQx in the diet and their urine and feces were analyzed for the metabolites. The isolation procedure included specific adsorption of MeIQx derivatives to blue cotton and subsequent fractionations by thin layer chromatography on silica gel and by high pressure liquid chromatography. Attention was focused on mutagenically active metabolites. Three metabolites were isolated from the urine, and their structures were elucidated on the basis of 1H nuclear magnetic resonance, ultraviolet, and mass spectra. The first metabolite characterized was 2-amino-8-hydroxymethyl-3-methylimidazo[4,5-f]quinoxaline (Compound I), the second was 2-acetylamino-3,8-dimethylimidazo[4,5-f]quinoxaline (Compound II), and the third was 2-amino-8-methylimidazo[4,5-f]quinoxaline (Compound III). Compound I was isolated also from the feces. Compounds I-III were mutagenic to Salmonella typhimurium TA98 with metabolic activation. The mutagenic potency of Compounds I and II was as high as that of MeIQx, and that of Compound III was much lower than that of MeIQx.     

Expression of p33 ING1 in Hepatocellular Carcinoma: Relationships to Tumour Differentiation and Cyclin E Kinase Activity

Background: Inhibitor of growth-1 (ING1) is a new candidate for the tumour suppressor gene that encodes a 33k Da protein (p33 ING1 ). While reduction of p33 ING1 is an important event in some human cancers, the expression of p33 ING1 in human hepatocellular carcinoma (HCC) remains to be examined. We evaluated p33 ING1 expression in various liver diseases including HCC. Methods: Expression of p33 ING1 was evaluated immunohistochemically not only in the normal liver ( n = 5), but also in specimens of chronic hepatitis ( n = 39) and HCC ( n = 86). We also analysed the relationship between p33 ING1 expression and cyclin E kinase activity detected by autoradiography in 29 HCCs. Results: Expression of p33 ING1 was reduced in HCC, especially in moderately and poorly differentiated HCCs, and those at advanced stages. Furthermore, expression of p33 ING1 correlated inversely with cyclin E kinase activity. Conclusions: These data suggest that reduction of p33 ING1 may contribute to the process of malignant transformation, progression and dedifferentiation of HCC via an increase of cyclin E kinase activity.     

Left atrial thrombus resolution in non-valvular atrial fibrillation or flutter: biomarker substudy results from a prospective study with rivaroxaban (X-TRA)

Abstract

Background: Non-vitamin K antagonist oral anticoagulants including rivaroxaban are widely used for stroke prevention in patients with atrial fibrillation (AF). We investigated the relationship between plasma biomarkers (indicative of thrombogenesis, fibrinolysis and inflammation) and left atrial thrombus resolution after rivaroxaban treatment.

Methods: This was an ancillary analysis of the X-TRA study, which was a prospective interventional study evaluating the use of rivaroxaban for left atrial/left atrial appendage (LA/LAA) thrombus resolution in AF patients. We assessed various biomarkers of thrombogenesis/fibrinolysis [D-dimer, plasminogen activator inhibitor-1 (PAI-1), prothrombin fragment 1?+?2 (F1,2), thrombin–antithrombin (TAT) complexes, von Willebrand factor (vWF)] and inflammation [high-sensitivity interleukin-6 (hsIL-6), and high-sensitivity C-reactive protein (hsCRP)], measured at baseline and after 6 weeks’ of rivaroxaban treatment.

Results: There was a significant decrease in the mean levels of hsCRP, D-dimer, vWF, and TAT from baseline to end of treatment with rivaroxaban. Although none of the thrombogenesis/fibrinolysis biomarkers showed a significant relationship with thrombus resolution, high inflammatory biomarkers at baseline were significantly associated with an increased chance of the thrombus being completely resolved (hsIL-6) or reduced/resolved (hsCRP).

Conclusions: Biomarkers of inflammation are significantly associated with LA/LAA thrombus outcomes in AF patients prospectively treated with rivaroxaban.     

Screening of a heptamer-type sgRNA library for potential therapeutic agents against hematological malignancies

tRNase-Z^L-utilizing efficacious (TRUE) gene silencing is an RNA-mediated gene expression control technology that has therapeutic potential. This technology is based on the property of tRNase Z^L that it can cleave any target RNA at any desired site under the direction of an appropriate artificial small guide RNA (sgRNA). To search for novel potential therapeutic sgRNAs for hematological malignancies, we screened a library composed of 156 sgRNAs, and found that 20 sgRNAs can efficiently induce apoptosis in leukemia and/or myeloma cells. Furthermore, we demonstrated that 4 of the 20 sgRNAs can reduce growth rates of HL60 cells in mouse xenograft models.     

Phase II clinical study of alternate-day oral therapy with S-1 as first-line chemotherapy for locally advanced and metastatic pancreatic cancer

Purpose

Based on the results of first-line chemotherapy for advanced pancreatic cancer, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration followed by 2 weeks of drug withdrawal frequently causes adverse effects. On the other hand, we experienced in clinical practice that alternate-day administration of S-1 reduced adverse effects and were tolerable for advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multicenter cooperative prospective study to compare daily with alternate-day administration of S-1 for advanced pancreatic cancer.

Methods

Patients with advanced pancreatic cancer were eligible for enrollment in this trial. S-1 was administered at a dose of 40–60 mg twice daily, calculated according to body surface area, on Monday, Wednesday, Friday, and Sunday. Each treatment cycle was 42 days. The primary end point was overall survival (OS). Secondary end points were safety, response rate (RR), progression-free survival (PFS), and time to treatment failure (TTF).

Results

Forty-eight patients were evaluable for response. OS as the primary end point was 8.4 months (95 % CI 5.4–10.8), and the 1-year survival rate was 29.2 %. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4 %, and the disease control rate was 79.2 %. Grade 3/4 hematological and non-hematological toxicities were minor. All of these adverse reactions were tolerable and reversible.

Conclusions

The current data demonstrate the mitigation of adverse effects with alternate-day administration of S-1, and this appears to be a more sustainable option for advanced pancreatic cancer.     

Convexity En Plaque Meningioma Manifesting as Subcutaneous Mass: Case Report

A 67-year-old woman sensed a slowly growing, painless hard mass in the left parietal region. Cranial computed tomography showed focal bony erosion and homogeneous sclerotic change at the affected site. Magnetic resonance (MR) imaging revealed an enhanced subcutaneous mass and irregularly thickened dura mater. Intraoperatively, the subcutaneous tumor was found to be strongly adhered to the temporalis muscle. The outer table was eroded adjacent to the subcutaneous tumor, whereas the bony structures of the inner table were intact. The dura mater underneath had irregular-shaped, yellowish convolutions both on the outer and inner surfaces. The patient underwent total tumor resection with sufficient normal margins. The histological diagnosis was World Health Organization (WHO) grade I meningioma, with finger-like outward extensions through the dura mater and overlying skull, and infiltration among into the temporalis muscle fibers. Meningiomas may form a subcutaneous mass without intracranial growth.     

Pitfalls and promises of bile duct alternatives: A narrative review

Biliodigestive anastomosis between the extrahepatic bile duct and the intestine for bile duct disease is a gastrointestinal reconstruction that abolishes duodenal papilla function and frequently causes retrograde cholangitis. This chronic inflammation can cause liver dysfunction, liver abscess, and even bile duct cancer. Although research has been conducted for over 100 years to directly repair bile duct defects with alternatives, no bile duct substitute (BDS) has been developed. This narrative review confirms our understanding of why bile duct alternatives have not been developed and explains the clinical applicability of BDSs in the near future. We searched the PubMed electronic database to identify studies conducted to develop BDSs until December 2021 and identified studies in English. Two independent reviewers reviewed studies on large animals with 8 or more cases. Four types of BDSs prevail: Autologous tissue, non-bioabsorbable material, bioabsorbable material, and others (decellularized tissue, 3D-printed structures, etc.). In most studies, BDSs failed due to obstruction of the lumen or stenosis of the anastomosis with the native bile duct. BDS has not been developed primarily because control of bile duct wound healing and regeneration has not been elucidated. A BDS expected to be clinically applied in the near future incorporates a bioabsorbable material that allows for regeneration of the bile duct outside the BDS.