Curcumin analog,GO‐Y078, overcomes resistance to tumor angiogenesis inhibitors

Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO‐Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO‐Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC‐R). GO‐Y078 inhibited the growth and mobility of HUVEC‐R at 0.75 μmol/L concentration. Expression analyses by microarray and RT‐PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO‐Y078. In a knockdown experiment using Si‐oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO‐Y078. Knockdown of FN1 resulted in the suppression of HUVEC‐R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO‐Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO‐Y078.     

Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non–Small-cell Lung Cancer: A Mini-review

Immune checkpoint inhibitors against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) are a standard pharmacologic therapy for patients with non–small-cell lung cancer (NSCLC). Substantial data have accumulated in recent years showing that radiotherapy combined with immunotherapy is more effective than monotherapy alone. Preclinical studies have shown that PD-L1 expression is upregulated on tumor cells after radiotherapy, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. In the clinical setting, patients receiving radiotherapy before anti-PD-1 treatment have had a significantly better prognosis than those who have not undergone radiotherapy. In the present report, we reviewed previous studies of the combination of radiotherapy and anti-PD-1/PD-L1 treatment for NSCLC. In addition, we report our case of a patient whose PD-L1 expression gradually increased in brain metastases from NSCLC after repeated radiotherapy. In the perspectives portion, we focused on the questions of how to integrate radiotherapy into anti-PD-1/PD-L1 agent regimens and described several ongoing clinical trials.     

Analysis of Early Death in Japanese Patients With Advanced Non–small-cell Lung Cancer Treated With Nivolumab

Background

The increased risk for early death owing to anti-programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting.

Epithelial Paradox: Clinical Significance of Coexpression of E-cadherin and Vimentin With Regard to Invasion and Metastasis of Breast Cancer

Background

E-cadherin and vimentin are regarded as major conventional canonical markers of the epithelial–mesenchymal transition. It is commonly assumed that E-cadherin is uniformly lost during the process of epithelial–mesenchymal transition. Breast tumor cells typically invade as a cohesive multicellular unit in a process called collective invasion. The aim of this study was to reveal the clinical importance of the expression pattern of E-cadherin and vimentin in breast cancer.

<Superscript>18</Superscript>F-FPYBF-2, a new F-18-labelled amyloid imaging PET tracer: first experience in 61 volunteers and 55 patients with dementia

Objective

Recently, we developed a benzofuran derivative for the imaging of β-amyloid plaques, 5-(5-(2-(2-(2-¹⁸F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N-methylpyridin-2-amine (¹⁸F-FPYBF-2) (Ono et al., J Med Chem 54:2971–9, 2011). The aim of this study was to assess the feasibility of ¹⁸F-FPYBF-2 as an amyloid imaging PET tracer in a first clinical study with healthy volunteers and patients with various dementia and in comparative dual tracer study using ¹¹C-Pittsburgh Compound B (¹¹C-PiB).

Methods

61 healthy volunteers (age: 53.7?±?13.1 years old; 19 male and 42 female; age range 24–79) and 55 patients with suspected dementia [Alzheimer’s Disease (AD); early AD: n?=?19 and moderate stage AD: n?=?8, other dementia: n?=?9, mild cognitive impairment (MCI): n?=?16, cognitively normal: n?=?3] for first clinical study underwent static head PET/CT scan using ¹⁸ F ^? FPYBF-2 at 50–70 min after injection. 13 volunteers and 14 patients also underwent dynamic PET scan at 0–50 min at the same instant. 16 subjects (volunteers: n?=?5, patients with dementia: n?=?11) (age: 66.3?±?14.2 years old; 10 males and 6 females) were evaluated for comparative study (50–70 min after injection) using ¹⁸F-FPYBF-2 and ¹¹C-PiB on separate days, respectively. Quantitative analysis of mean cortical uptake was calculated using Mean Cortical Index of SUVR (standardized uptake value ratio) based on the established method for ¹¹C-PiB analysis using cerebellar cortex as control.

Results

Studies with healthy volunteers showed that ¹⁸F-FPYBF-2 uptake was mainly observed in cerebral white matter and that average Mean Cortical Index at 50–70 min was low and stable (1.066?±?0.069) basically independent from age or gender. In patients with AD, ¹⁸F-FPYBF-2 uptake was observed both in cerebral white and gray matter, and Mean Cortical Index was significantly higher (early AD: 1.288?±?0.134, moderate AD: 1.342?±?0.191) than those of volunteers and other dementia (1.018?±?0.057). In comparative study, the results of ¹⁸F-FPYBF-2 PET/CT were comparable with those of ¹¹C-PiB, and the Mean Cortical Index (¹⁸F-FPYBF-2: 1.173?±?0.215; ¹¹C-PiB: 1.435?±?0.474) showed direct proportional relationship with each other (p?<?0.0001).

Conclusions

Our first clinical study suggest that ¹⁸F-FPYBF-2 is a useful PET tracer for the evaluation of β-amyloid deposition and that quantitative analysis of Mean Cortical Index of SUVR is a reliable diagnostic tool for the diagnosis of AD.

     

Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: A comprehensive analysis of systemic inflammatory markers

Objectives

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.

The involvement of a novel mechanism distinct from the thrombin receptor in the vasocontraction induced by trypsin

1. The vasocontracting effect of a serine protease trypsin and its mechanisms were investigated by monitoring the isometric tension in endothelium-denuded rings of rabbit thoracic aortae and its effects on intracellular free Ca²⁺ concentrations ([Ca²⁺]_i) in dispersed rabbit vascular smooth muscle cells with a Ca²⁺ indicator fura-2. The actions of trypsin were compared with those of thrombin.
2. Both thrombin and trypsin reversibly contracted aortic rings without endothelium in a concentration-dependent manner. The vasocontraction induced by trypsin was well correlated with the protease activity of trypsin actually added to the tissue baths containing the aortic rings and was completely blocked by soybean trypsin inhibitor and phenylmethylsulphonyl fluoride (PMSF), a serine protease inhibitor.
3. The trypsin-induced contractions of the aortic rings were not the result of irreversible damage to vascular smooth muscle cells, since the contractile responses induced by noradrenaline or 30 mM KCl were unaffected by pretreatment with trypsin.
4. The contractions induced by either thrombin or trypsin were reduced to about 30% of control responses after removal of extracellular Ca²⁺, indicating that most of the contraction is dependent on extracellular Ca²⁺. By contrast, the contractions induced by either of the proteases were reduced by an antagonist of L-type voltage-operated Ca²⁺ channels, nifedipine, to about 70% of control responses, indicating that both nifedipine-sensitive and -resistant Ca²⁺ channels are involved in these contractions.
5. In the aortic rings precontracted by a maximally effective concentration of thrombin, the second application of thrombin virtually failed to induce contractions but trypsin could still induce contractions amounting to 10% of control values by it''s protease activity.
6. After the first application of a maximal concentration of thrombin, the second application of thrombin could not induce an increase in [Ca²⁺]_i, but an application of trypsin could still induce an increase in [Ca²⁺]_i in dispersed rabbit vascular smooth muscle cells.
7. These data suggest that in addition to activation of a thrombin receptor, trypsin can contract rabbit aortae by a proteinase-activated receptor 2 or a novel mechanism.

     

Asunaprevir and daclatasvir for recurrent hepatitis C after liver transplantation: A Japanese multicenter experience

The safety and efficacy of an IFN‐free regimen using asunaprevir (ASV) and daclatasvir (DCV) for recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) have not been evaluated in Japan. A multicenter study of LT recipients (n = 74) with recurrent HCV genotype 1b infection treated with ASV‐DCV for 24 weeks was performed. Medical history was positive for pegylated interferon and ribavirin (Peg‐IFN/RBV) in 40 (54.1%) patients, and for simeprevir (SMV) with Peg‐IFN/RBV in 12 (16.2%) patients. Resistance‐associated variants (RAVs) were positive at D168 (n = 1) in the NS3, and at L31 (n = 4), Y93 (n = 4), and L31/Y93 (n = 1) in the NS5A region of the HCV genome. Sixty‐one (82.4%) patients completed the 24‐week treatment protocol. Although sustained viral response (SVR) was achieved in 49 (80.3%) patients, it was achieved in only two (16.7%) patients among those with histories of receiving SMV (n = 12). Univariate analysis showed that a history of SMV (P < .01) and the presence of mutations in NS5A (P = .02) were the significant factors for no‐SVR. By excluding the patients with either a history of SMV‐based treatment or RAVs in NS3/NS5A, the SVR rate was 96.4%. By excluding the patients with a history of SMV and those with RAVs in NS3/NS5A, viral clearance of ASV‐DCV was favorable, with a high SVR rate.