SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8⁺ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8⁺ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8⁺ T cells. In vitro treatment of CD8⁺ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8⁺ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8⁺ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8⁺ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8⁺ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1–ACAT1 axis is regulating effector functions of CD8⁺ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.     

Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma

In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287-7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.     

Hypercalcemia Associated with the Ectopic Expression of 25-hydroxyvitamin D3-1α-hydroxylase in Diffuse Large B-cell Lymphoma

An 82-year-old man was transferred to our hospital due to impaired consciousness. His albumin-corrected calcium level was 14.2 mg/dL, intact parathyroid hormone (PTH) and PTH-related protein levels were reduced, and his 1,25-dihydroxyvitamin D [1,25(OH)₂VitD] level was elevated at 71.5 pg/mL. Computed tomography revealed masses on the bilateral ribs. The mass on the rib was biopsied and diagnosed as diffuse large B-cell lymphoma (DLBCL). Immunostaining of the biopsy sample with the anti-CYP27B1 antibody revealed the ectopic expression of 1α-hydroxylase in the lesion. We herein report a rare case of hypercalcemia induced by the overproduction of 1,25(OH)₂VitD in DLBCL ectopically expressing 1α-hydroxylase.     

The Impact of Antiviral Therapy for Hepatitis C Virus on the Survival of Patients after Hepatocellular Carcinoma Treatment

Objective Owing to advances in direct-acting antiviral (DAA) therapy, a considerable number of patients with hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) are now able to achieve a sustained viral response (SVR) after curative treatment of HCC. However, the beneficial effect of a DAA-SVR on the survival remains unclear. Methods A total of 205 patients with HCC who were HCV-positive with Child-Pugh A at the onset from 2008 to 2018 were categorized into 2 groups: 140 patients untreated for HCV throughout the entire course after HCC development (untreated group) and 65 patients treated for HCV with DAAs following HCC treatment who achieved an SVR (SVR group). After propensity score matching, 63 patients from each group were selected. Using these patients, the survival and maintenance of Child-Pugh A after HCC treatment were compared between the untreated group and SVR group. Results There was a significant difference in the overall survival (p<0.001) and the rate of maintaining Child-Pugh A (p<0.001) between the groups. The 5-year survival rates were 96% (SVR group) and 60% (untreated group), and the proportions of patients with Child-Pugh A at 5 years after HCC treatment were 96% (SVR group) and 38% (untreated group). Conclusion In patients with HCV-positive HCC, achieving a DAA-SVR after HCC treatment significantly improved the overall survival rate compared with HCV-untreated patients. The contribution of DAA-SVR during the course of HCC treatment to a longer survival is mainly due to the prevention of the progression of Child-Pugh A to B/C. Further research is needed to determine whether aggressive antiviral therapy is also effective for HCC patients with Child-Pugh B/C.     

Abdominal aortic calcification is associated with Fibrosis‐4 index and low body mass index in type 2 diabetes patients: A retrospective cross‐sectional study

Aims/IntroductionThis study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus.Materials and MethodsThis retrospective cross‐sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models.ResultsThe AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis‐4 (Fib‐4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography‐diagnosed fatty liver. There was a significant interaction between BMI and Fib‐4 index; lower BMI and Fib‐4 index >2.67 showed a synergistic association with high AAC grade.ConclusionsAAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib‐4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.     

Clinical characteristics and treatment outcomes of patients with small cell carcinoma of the urinary bladder

BackgroundSmall cell carcinoma of the urinary bladder (SCUB) is rare. The optimal treatment for SCUB remains unclear. To address the problem of appropriate treatment for each case, we assessed single-modality and surgery-based multimodality treatments in patients with SCUB.Materials and methodsWe retrospectively reviewed the medical records of 12 patients with SCUB between 1990 and 2013. All patients underwent transurethral resection of the bladder tumor and were diagnosed with SCUB. Their clinicopathological characteristics were assessed, and the outcomes were compared according to the treatment modality.ResultsThe median (range) age at diagnosis was 66 years (range, 53–85 years). T1–4N0M0 was observed in 8 patients (66%), N1–3M0 in 2 (17%), and NanyM1 in 2 (17%). After transurethral resection of the bladder tumor, 6 patients (50%) underwent cystectomy alone, and 4 (33%) underwent cystectomy and presurgical or adjuvant chemotherapy with etoposide and cisplatin. During the median follow-up period of 20.7 months, 6 patients (50%) died of cancer, and 2 patients (17%) died of other causes. The median overall survival period was 1.9 years. The 5-year overall survival rate in patients who underwent cystectomy and chemotherapy was 75%, whereas that in those who underwent cystectomy alone and transurethral resection alone were 22% and 0%, respectively (p = 0.012). Recurrence-free survival was significantly correlated with cause-specific survival (r = 0.95; 95% confidence interval, 0.81–0.99; p < 0.001).ConclusionsRadical cystectomy with chemotherapy using the etoposide and cisplatin regimen improved the prognosis of patients with SCUB and TxNxM0. The time from initial progression to death due to cancer was very short, indicating that the initial treatment strategy is crucial.     

Association of ALDH2 Genotypes and Alcohol Intake with Dietary Patterns: The Bunkyo Health Study

Dietary habits are associated with various diseases and assessed by dietary patterns (DPs). Since the ALDH2 genotype is correlated with alcohol and several food preferences, this genotype is probably associated with DPs. In this cross-sectional study of 1612 elderly adults, we investigated the effects of the ALDH2 genotype on DPs and the mediating role of alcohol intake. We identified the ALDH2 genotype and conducted a dietary history survey, then used principal component analysis to determine DPs for each gender. We performed multiple regression analysis to determine the independent contribution of the ALDH2 genotype and alcohol intake to DP scores. We identified three DPs: the “Japanese side dish type” (DP1), the “Japanese dish with alcohol type” (DP2), and the “Western dish with alcohol type” (DP3). In men, the single nucleotide polymorphism ALDH2 rs671 was significantly associated with all DP scores. When alcohol intake was added as a covariate, ALDH2 rs671 was still significantly correlated with the DP2 score but not with the DP1 or DP3 score, and alcohol intake was significantly correlated with all DP scores. In women, ALDH2 rs671 was significantly associated with the DP2 and DP3 scores; however, after adding alcohol intake as a covariate, these associations disappeared, and alcohol intake significantly correlated with all DP scores. In conclusion, the ALDH2 genotype was associated with several DPs in elderly adults, but most associations were mediated by alcohol intake.