Remission Factors for Ustekinumab Treatment of Ulcerative Colitis: A Multicenter Retrospective Study of Real-World Data in Japan.

Ustekinumab (UST) is an anti-IL-12/23p40 monoclonal antibody used to treat inflammatory bowel disease. The aim of this retrospective, multicenter study was to investigate the effectiveness of UST administration in achieving remission in patients with ulcerative colitis (UC) and to determine patient characteristics that influence its effectiveness. Of 88 UC patients who received UST from March 2020 to August 2023, 47 with traceable data and for whom 56 weeks had elapsed since the start of treatment received UST to induce remission. The remission rates at 8 weeks were 66% overall, 73.7% for Bio Naïve (never used biologics/JAK inhibitors), and 60.7% for Bio Failure (used biologics/JAK inhibitors) groups. Remission rates at 56 weeks were 70.2% overall, 73.7% for Bio Naïve, and 67.9% for Bio Failure groups. Ustekinumab showed good mid-to-long-term results in the induction of remission of UC in both Bio Naïve and Bio Failure groups. The group showing remission at 8 weeks had a significantly higher non-relapse or continuation rate (proportion of patients with no worsened symptoms necessitating surgery/drug change) at 56 weeks. Predictive factors for achieving remission after UST in UC were female gender, low body mass index, and low lymphocyte-to-monocyte ratio. Thus, UST is effective for moderate-to-severe UC.

Enterolith Treated with a Combination of Double-Balloon Endoscopy and Cola Dissolution Therapy.

A 71-year-old woman with rheumatoid arthritis who had been taking NSAIDs for many years consulted our hospital for abdominal pain. She was diagnosed with a small bowel obstruction due to an enterolith according to an abdominal CT scan that showed dilation from the enterolith in the small intestine on the oral side. It was considered that the intestinal stone was formed due to stagnation of intestinal contents and had gradually increased in size, resulting in an intestinal obstruction. We performed antegrade double-balloon endoscopy (DBE) to observe and remove the enterolith. We used forceps and a snare to fracture the enterolith. During this attempt, we found a seed in the center of the enterolith. Since the intestinal stone was very hard, cola dissolution therapy was administered from an ileus tube for 1 week. The following week, DBE was performed again, and it was found that the stone had further softened, making attempts at fracture easier. Finally, the enterolith was almost completely fractured. Intestinal stenosis, probably due to ulcers caused by NSAIDs, was found. Small bowel obstruction with an enterolith is rare. In this case, it was considered that the seed could not pass through the stenotic region of the small intestine and the intestinal contents had gradually built up around it. It has been suggested that DBE may be a therapeutic option in cases of an enterolith. Further, cola dissolution therapy has been shown to be useful in treating an enterolith, with the possible explanation that cola undergoes an acid-base reaction with the enterolith. In summary, we report, for the first time, treatment of an enterolith with a combination of DBE and cola dissolution therapy, thereby avoiding surgery and its risks.

Hypertension and diabetes mellitus are associated with high FIB-4 index in a health checkup examination cohort without known liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is usually asymptomatic and lacks a specific biomarker; therefore, many individuals might remain undiagnosed even with advanced liver fibrosis. The aim of this study was to clarify the prevalence and clinical features of subjects with a high risk of advanced liver fibrosis in the general population, using the Fibrosis-4 (FIB-4) index. METHODS: We retrospectively investigated 6,087 subjects without known liver disease who had participated in an annual health checkup examination. We analyzed the factors associated with high FIB-4 index (≥ 2.67) using a logistic regression analysis. RESULTS: Among the 6,087 subjects, 76 (1.2%) had high FIB-4 index. Multivariate analysis identified hypertension (odds ratio [OR]; 9.040; 95% confidence interval [CI], 4.081-20.024; P < 0.001) and diabetes mellitus (OR = 4.251; 95% CI, 1.773-10.193; P = 0.001) as important risk factors for high FIB-4 index. The rates of hypertension and diabetes mellitus in subjects with high FIB-4 index were 78.9% and 23.7%, respectively. No significant association was observed between obesity or large waist circumference and high FIB-4 index. A history of cardiovascular disease was significantly more common in subjects with high FIB-4 index. These results were also observed in subjects with normal liver function test. CONCLUSIONS: The present study revealed that approximately 1% of the general Japanese population has a high risk of advanced liver fibrosis. Many of these patients had hypertension and/or diabetes mellitus. Our findings suggest that there are many undiagnosed patients NAFLD with risk of advanced liver fibrosis in the general population.

Catalytic Enantioselective Reaction of Allenylnitriles with Imines Using Chiral Bis(imidazoline)s Palladium(II) Pincer Complexes.

The first highly enantioselective reaction of allenylnitriles with imines has been developed. Excellent yields and enantioselectivities were observed for the reaction with various imines using chiral Phebim-PdII complexes. This process offers a simple and efficient synthetic route for various functionalized α-vinylidene-ß-aminonitriles and their derivatives.

GABP, HCF-1 and YY1 are involved in Rb gene expression during myogenesis.

Muscle cell differentiation, or myogenesis, is a well-characterized process and involves the expression of specific sets of genes in an orderly manner. A prerequisite for myogenesis is the exit from the cell cycle, which is associated with the up-regulation of the tumor suppressor Rb. In this study, we set to investigate the regulatory mechanism of the Rb promoter that allows adequate up-regulation in differentiating myoblasts. We report that Rb expression is regulated by the transcription factors GABP, HCF-1 and YY1. Before induction of differentiation, Rb is expressed at a low level and GABP and YY1 are both present on the promoter. YY1, which exerts an inhibitory effect on Rb expression, is removed from the promoter as cells advance through myogenesis and translocates from the nucleus to the cytoplasm. On the other hand, upon induction of differentiation, the GABP cofactor HCF-1 is recruited to and coactivates the promoter with GABP. RNAi-mediated knock-down of HCF-1 results in inhibition of Rb up-regulation as well as myotube formation. These results indicate that the Rb promoter is subject to regulation by positive and negative factors and that this intricate activation mechanism is critical to allow the accurate Rb gene up-regulation observed during myogenesis.

Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex.

The multisubunit transcription elongation factor NELF (for negative elongation factor) acts together with DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) sensitivity-inducing factor (DSIF)/human Spt4-Spt5 to cause transcriptional pausing of RNA polymerase II (RNAPII). NELF activity is associated with five polypeptides, A to E. NELF-A has sequence similarity to hepatitis delta antigen (HDAg), the viral protein that binds to and activates RNAPII, whereas NELF-E is an RNA-binding protein whose RNA-binding activity is critical for NELF function. To understand the interactions of DSIF, NELF, and RNAPII at a molecular level, we identified the B, C, and D proteins of human NELF. NELF-B is identical to COBRA1, recently reported to associate with the product of breast cancer susceptibility gene BRCA1. NELF-C and NELF-D are highly related or identical to the protein called TH1, of unknown function. NELF-B and NELF-C or NELF-D are integral subunits that bring NELF-A and NELF-E together, and coexpression of these four proteins in insect cells resulted in the reconstitution of functionally active NELF. Detailed analyses using mutated recombinant complexes indicated that the small region of NELF-A with similarity to HDAg is critical for RNAPII binding and for transcriptional pausing. This study defines several important protein-protein interactions and opens the way for understanding the mechanism of DSIF- and NELF-induced transcriptional pausing.