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Several reports indicate that apelin is often over-expressed in tumors, and therefore it has been suggested that the apelin-apelin receptor (APJ) system may induce tumor progression. In contrast, our previous research revealed high expression of the apelin-APJ system in tumor blood vessels, suggesting its involvement in the regulation of tumor vessel formation and normalization, resulting in the suppression of tumor growth by promoting the infiltration of T cells. Thus, the effect of the apelin-APJ system on tumors remains controversial. In this report, to clarify the effect of apelin in tumor cells, we analyzed the function of APJ in tumor cells using APJ knock out (KO) mice. In APJ-KO mice, Apelin overexpression in B16/BL6 (B16) melanoma cells induced greater tumor growth than controls. In an APJ-KO melanoma inoculation model, although angiogenesis is suppressed compared to wild type, no difference is evident in tumor growth. We found that APJ deficiency promoted vascular mimicry in tumors. In vitro , cultured APJ-KO B16 cells demonstrated a spindle-like shape. This phenotypic change was thought to be induced by epithelial-mesenchymal transition (EMT) based on evidence that APJ-KO B16 cells show persistently high levels of the mesenchymal maker, Zeb1; however, we found that EMT did not correlate with the transforming growth factor-β/smad signaling pathway in our model. We propose that apelin-APJ system in cancer cells induces tumor growth but negatively regulates EMT and tumor malignancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Inukai, Kise, Hayashi, Jia, Muramatsu, Okamoto, Konishi, Akuta, Kidoya and Takakura.)

Background: Thrombin belongs to the most potent platelet agonists and activates human platelets through GPIbα and two protease activated receptors (PARs), PAR1 and PAR4. However, the details of thrombin receptor system, especially the role of PAR4 on human platelet activation is still not clear., Objectives: We found a significant difference in PAR4-activating peptide (PAR4-AP)-induced, but not PAR1-AP, platelet aggregation between healthy Japanese subjects. Sequencing analysis revealed a single nucleotide change in PAR4 gene F2RL3 (SNP rs773902) leading to Ala120Thr variant. To elucidate the role of PAR4 in human platelet activation, we examined if platelet activation induced by PAR4-AP may be associated with PAR4 genotype., Methods: Platelets from 202 healthy Japanese volunteers were genetically analyzed and determined the genotype frequency of rs773902. Agonist induced platelet aggregation, integrin αIIbβ3 activation, granule release, Ca 2+ mobilization, and activation of ERK and MLC were evaluated. The specificity of effects observed in platelets was confirmed in 293T cells transfected PAR4-Thr120 or Ala120., Results: The frequencies of PAR4 variant Thr/Thr120, Ala/Thr120, and Ala/Ala 120 were 5.9, 37.1, and 57.0%, respectively. Platelets with Thr/Thr120 showed significantly higher reactivity in PAR4-AP-induced platelet aggregation, αIIbβ3 activation and granule release compared to platelets with Ala/Ala120. PAR4-AP induced higher Ca 2+ mobilization and ERK activation in platelets with Thr/Thr120 than Ala/Ala120. Ca 2+ mobilization and ERK activation were also increased in 293T cells transfected with PAR4-Thr120 compared to Ala120., Conclusion: Our data suggested that PAR4-AP-induced platelet reactivity between PAR4 rs773902 was associated with altered intensity of Ca 2+ mobilization and ERK activation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The rare central nervous system (CNS) infiltration of Waldenström macroglobulinemia (WM) is known as Bing-Neel syndrome (BNS). Furthermore, the transformation of WM into diffuse large B-cell lymphoma (DLBCL) is also unusual. Herein, we report a 69-year-old male with DLBCL transformed from BNS. In November 2008, the patient visited a prior hospital because of anemia and was diagnosed with WM. After receiving chemotherapy (R-CHOP), his serum immunoglobulin M (IgM) level decreased and then remained at approximately 2000 mg/dl for 3 years. In November 2011, he complained of visual impairment and photophobia in his left eye. Magnetic resonance imaging showed enlargement of the left optic nerve and cerebrospinal fluid examination indicated CNS infiltration of WM cells. Consequently, he was diagnosed with BNS. He thus received CNS targeted chemotherapy (R-MPV) and achieved a partial response. In May 2014, IgM was elevated and swelling of systemic lymph nodes was detected. Inguinal lymph node biopsy yielded a pathological diagnosis of DLBCL and the clonality of tumor cells between WM and DLBCL was confirmed by the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR).