Shingo Imanishi

Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice

Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6-16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD.

SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice

Silent information regulator 2 (SIR2) is a highly conserved protein, the mammalian orthologue of which, SIRT1, exhibits histone deacetylase activity. SIRT1 is involved not in only longevity due to caloric restriction but in a variety of diseases such as diabetes, cardiovascular dysfunction and neurodegeneration. However, accumulating evidence shows that SIRT1 is overexpressed in various types of malignant cells, and its inhibitors suppress the growth of tumor cells. The relationship between SIRT1 and metastasis remains to be clarified. Here, we examined the effect of SRT1720, a SIRT1 activator, on lung metastasis of breast cancer cells. 4T1 breast cancer cells were subcutaneously implanted into syngeneic BALB/c mice and SRT1720 was administered alone or with an antitumor agent, cisplatin. As expected, cisplatin decreased the lung metastasis score, whereas SRT1720 increased metastasis irrespective of cisplatin. In the primary tumors, cisplatin suppressed the mRNA level of angiopoietin-like protein 4 (angptl4), a lung metastasis-promoting gene product of breast cancer, but SRT1720 reduced the effectiveness of cisplatin. The results obtained with animal experiments were in accordance with those in human cancer cells; SRT1720 significantly increased the amount of VEGF secreted from MDA-MB-231 cells. Moreover, a transendothelial cell migration assay showed that SRT1720 promotes the migration of MDA-MB-231 cells across an endothelial cell layer despite the presence of cisplatin. These findings imply that SRT1720 promotes the pulmonary metastasis of breast cancer cells and SIRT1 may be an important target for suppressing metastasis to the lung.

Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma.

Background and objective:  In asthma, reduced histone deacetylase activity and enhanced histone acetyltransferase activity in the lungs have been reported. However, the precise function of Sirtuin 1 (Sirt1), a class III histone deacetylase, and the effect of the Sirt1 activator SRT1720 on allergic inflammation have not been fully elucidated.

Visceral adipose tissue level, as estimated by the bioimpedance analysis method, is associated with impaired lung function

Aims/Introduction:  It has been reported that metabolic syndrome is associated with impaired lung function, and abdominal obesity is regarded as the most important determinant of this association. We evaluated the association between a component of metabolic syndrome, indices of body composition, including the total adipose tissue content, lean bodyweight and visceral adipose tissue content, as assessed by bioimpedance analysis, and lung function.

Outcome and prognostic factors in patients with small cell lung cancer who receive third-line chemotherapy.

Aims and Background It is reported that about 20% of patients with small cell lung cancer (SCLC) receive third-line chemotherapy. We conducted a retrospective study to investigate the outcome and prognostic factors of patients with SCLC who receive third-line chemotherapy. Methods and Study Design The medical records of patients with SCLC who received third-line chemotherapy at our institution were reviewed. Overall survival (OS) from the initiation of third-line chemotherapy was evaluated, and the association between OS and patient characteristics was assessed by the log-rank test. Results A total of 73 patients with SCLC were treated with cytotoxic drugs between 2004 and 2012, and 19 patients received third-line chemotherapy. Median OS from initiation of third-line chemotherapy was 8.5 months. Patients with higher body mass index (BMI) (P = 0.0071), lower levels of lactate dehydrogenase (LDH) (P = 0.0036), higher levels of hemoglobin (P = 0.048), longer time to progression (TTP) from the initiation of second-line treatment (P = 0.0036), and better response to second-line treatment (P = 0.029) had longer duration of OS. Conclusions It is suggested that TTP and tumor response in second-line chemotherapy, serum levels of LDH and hemoglobin, and BMI at initiation of third-line chemotherapy could be possible prognostic factors.

Miliary brain metastasis presenting with calcification in a patient with lung cancer: a case report

IntroductionMiliary brain metastasis is an extremely rare form of brain metastasis which can present with atypical imaging findings. We report the case of a patient with miliary brain metastasis of lung cancer showing calcification in metastatic lesions.Case presentationA 68-year-old Japanese woman was diagnosed with lung adenocarcinoma. Brain computed tomography revealed multiple small calcified lesions in both cerebral hemispheres. Mutation of the epidermal growth factor receptor gene (exon 21, L858R) in lung cancer cells was detected, and treatment with gefitinib was initiated. A partial response was observed; however, the patient was readmitted to our hospital because of regrowth of the primary lesion and complaints of nausea, headache, and difficulty walking. Brain magnetic resonance imaging revealed scattered tiny nodules enhanced by gadolinium. A diagnosis of leptomeningeal carcinomatosis was made on the basis of cerebrospinal fluid cytology. The patient’s general status worsened, and she died 356 days after the day of first medical examination. Upon autopsy, the brain was found to be edematous and swollen. Lung carcinoma cells were diffusely disseminated on the meningeal surface. Metastatic foci of small nodular form, accompanied by calcifications, were also found in the brain parenchyma. We diagnosed miliary metastasis of lung carcinoma.ConclusionsTo the best of our knowledge, this is the third report of calcified miliary brain metastasis confirmed by autopsy. We describe calcified lesions that increased in size during the clinical course of nine months. Brain computed tomography findings that reveal multiple small calcified lesions in patients with malignancy should raise suspicion of miliary brain metastasis.

Clinical Parameters for Predicting the Survival in Patients with Squamous and Non-squamous-cell NSCLC Receiving PD-1 Inhibitor Therapy

We explored the associations between progression-free survival (PFS) after the initiation of PD-1 inhibitor therapy and the clinical parameters in patients with NSCLC. We reviewed the clinical data of patients with NSCLC treated with PD-1 inhibitor. Data of a total of 36 patients, including 16 patients with squamous cell NSCLC and 20 patients with non-squamous cell NSCLC were reviewed. Multivariate analyses identified EGFR status, C-reactive protein (CRP), and PFS following previous therapy as being significantly associated with the PFS after initiation of PD-1 inhibitor therapy in patients with NSCLC. In patients with squamous cell NSCLC, the blood neutrophil/lymphocyte ratio (NLR), serum lactate dehydrogenase (LDH), serum C-reactive protein (CRP), and PFS following previous therapy were identified as being significantly associated with the PFS after initiation of PD-1 inhibitor therapy. However, none of these associations, except for PFS following previous therapy, were found in patients with non-squamous cell NSCLC. NLR, LDH and CRP were associated with the PFS after initiation of PD-1 inhibitor therapy in patients with squamous cell NSCLC, and PFS following previous therapy was the common parameter associated with the PFS after initiation of PD-1 inhibitor therapy in both squamous-cell NSCLC and non-squamous-cell NSCLC patients.

Clinical Course After Initiation of Nivolumab Therapy in Patients with EGFR-Mutated Non-Small Cell Lung Cancer With or Without Pd-L1 Expression

IntroductionNivolumab has been reported to be more effective in the subset of non-squamous non-small cell lung cancer (NSCLC) patients with tumors harboring wild-type epidermal growth factor receptor (EGFR) and/or expressing programmed death ligand-1 (PD-L1). However, it is unclear whether PD-L1 expression influences the efficacy of nivolumab in patients with EGFR-mutated NSCLC. Therefore, tumor PD-L1 expression was evaluated in five patients with EGFR-mutated NSCLC who had been treated with nivolumab.MethodsWe have identified patients with NSCLC harboring EGFR gene mutation retrospectively out of a group of 23 consecutive patients treated with nivolumab at our hospital between January 2016 and March 2017. The tumors of patients with EGFR-mutated NSCLC who had received nivolumab treatment based on clinical judgment were analyzed retrospectively. Tumor PD-L1 expression was evaluated by measurement of the tumor proportion score (TPS) using a rabbit antihuman PD-L1 antibody (clone 22C3).ResultsThree patients received the treatment with nivolumab as second line treatment, and two patients received the treatment as third line treatment. One out of five patients had a response with treatment with nivolumab and that was the only patient with a positive PD-L1 expression (TPS of 80–90%).ConclusionThe results of the present study suggest that evaluation of tumor PD-L1 expression might be useful for predicting the efficacy of nivolumab, even in patients with EGFR-mutated NSCLC.