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This paper presents an unusual complex suicide case that died of nicotine addiction. The deceased was a 40-year-old male who was found lying dead on the floor in his room. In external findings, many incision wounds on his forearms and skin discoloration with epidermolysis on his cervical region could be seen. In the room, a blood-stained scissors and electric cord hanged on the exercise bike were found. Moreover, nine cigarette residues which were only the filter part and empty bottle of coffee were found on his side. At autopsy, we found that those injuries were not serious enough to lead him to the death. Toxicologically, caffeine, nicotine, cotinine, mirtazapine, and olanzapine could be detected, and the concentrations of nicotine were 3.740, 2.140, 3.100, and 451.100 μg/ml in cardiac blood, peripheral blood, urine, and stomach contents, respectively. These concentrations were evaluated as the fatal levels, and the cause of his death was diagnosed as acute nicotine intoxication. [ABSTRACT FROM AUTHOR]

Programmed cell death ligand 1 (PD‐L1) on tumor cells suppresses anti‐tumor immunity and has an unfavorable prognostic impact in ovarian cancer patients. We herein report the pathophysiological and therapeutic impacts of PD‐L1 disruption in ovarian cancer. PD‐L1 was genetically disrupted in the murine ovarian cancer cell line ID8 using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9‐mediated genome editing. PD‐L1 knockout (KO) and control ovarian cancer cells were intraperitoneally inoculated into syngeneic mice, and survival and tumor dissemination were evaluated. Survival times were significantly longer in the PD‐L1‐KO ID8‐inoculated groups than in their control groups, and its therapeutic benefit was enhanced in combination with the cisplatin treatment. Tumor weights and ascites volumes were significantly lower in the PD‐L1‐KO ID8 groups than in their control groups. Immunohistochemical and immunofluorescence analyses showed that intratumoral CD4+ T cells, CD8+ T cells, NK cells and CD11c+ M1 macrophages were significantly increased, whereas regulatory T cells were significantly decreased in the PD‐L1‐KO ID8 groups compared with those in their control groups. The intratumoral mRNA expression of interferon‐γ, tumor‐necrosis factor‐α, interleukin (IL)‐2, IL‐12a, CXCL9 and CXCL10 was significantly stronger, while that of IL‐10, vascular endothelial growth factor, CXCL1 and CXCL2 was significantly weaker in the PD‐L1‐KO ID8 groups. These results indicate that CRISPR/Cas9‐mediated PD‐L1 disruption on tumor cells promotes anti‐tumor immunity by increasing tumor‐infiltrating lymphocytes and modulating cytokine/chemokine profiles within the tumor microenvironment, thereby suppressing ovarian cancer progression. These results suggest that PD‐L1‐targeted therapy by genome editing may be a novel therapeutic strategy for ovarian cancer. We established a programmed cell death ligand 1 (PD‐L1) knockout ovarian cancer cell line using the clustered regularly interspaced short palindromic repeats/Cas9 system. We demonstrated that the complete disruption of PD‐L1 on tumor cells promoted anti‐tumor immunity by increasing tumor‐infiltrating lymphocytes and modulating cytokine/chemokine production within the tumor microenvironment, thereby suppressing ovarian cancer progression. [ABSTRACT FROM AUTHOR]

Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl2 application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3−/− mice and Ccr5−/− but not Ccr1−/− mice exhibit exaggerated CaCl2-inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl2-treated Ccl3−/− mice. On the contrary, CCL3 treatment attenuates CaCl2-induced AAA in both wild-type and Ccl3−/− mice. Consistently, we find that the CCL3–CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl2-induced AAA by suppressing MMP-9 expression. Inflammatory cytokines and chemokines are involved in the development of abdominal aortic aneurysm (AAA). Here the authors show that CCL3 prevents the development of CaCl2-induced AAA by suppressing MMP-9 expression. [ABSTRACT FROM AUTHOR]

Introduction: Mechanical stress-induced chronic hypertension can initiate the development of cardiac hypertrophy and, ultimately, congestive heart failure. It is widely accepted that various chemokines are expressed in the heart in response to pressure overload. These chemokines might be involved in the cardiac remodeling and pathogenesis of heart failure. In this study, we investigated the roles of CCR5 in pressure overload-induced cardiac hypertrophy and heart failure in mice. Methods: Male C57BL/6J (WT) and CCR5-deficient (CCR5-KO) mice were subjected to transverse aortic constriction (TAC). Aortic constriction was achieved by tying around the transverse thoracic aorta against a 27-gauge needle using a 7–0 silk suture, and then removing the needle. Cardiac hypertrophy, fibrosis, cardiac function by echocardiography and expression of hypertrophy related molecules were examined. Results and discussion: Three weeks after TAC, CCR-5-KO mice exhibited more significant loss of cardiac function with cardiac hypertrophy, compared with WT mice, indicating that CCR5 plays a protective role in TAC-induced cardiac hypertrophy and heart failure. In WT mice, intracardiac Ccr5 expression was increased at 3 day and 1 week TAC, and CCR5 protein was expressed in the cardiac fibroblasts. Mechanical stress-induced inflammation is known to be indispensable for compensatory hypertrophy, however, which was significantly attenuated in CCR5-KO mice, compared with WT mice. Consistently, CCR5-KO mice lacked the initial compensatory hypertrophy. The lack of initial compensatory cardiac hypertrophy might lead CCR5-KO mice to pathological cardiac hypertrophy. Enhanced CCR5 expression in intracardiac fibroblasts might be crucially involved in the compensatory hypertrophy-induced by mechanical stress. [ABSTRACT FROM AUTHOR]