Contribution of hematopoietic stem cells in blood vessel formation

Vascular development consists of vasculogenesis and angiogenesis. The system of TIE2-Angiopoietin (Ang) is involved in angiogenesis. TIE2 regulates adhesion and dissociation between endothelial cells and mural cells, and survival, apoptosis, and chemotaxis of endothelial cells. Ang-2, which is produced by endothelial cells under tissue hypoxia, has been suggested to be a key regulator for the initiation of endothelial cell sprouting from pre-existing vessels. Although Ang-2 binds to TIE2, it does not promote activation of TIE2 on endothelial cells. Ang-2 produced from endothelial cells under hypoxia inhibits the binding of Ang-1 to TIE2. On the other hand, Ang-1 promotes activation of TIE2 and adhesion between endothelial cells and mural cells. Therefore, endothelial cells dissociated from mural cells by Ang-2 are free to move to avascular area where oxygen or nutrient is needed. We recently found that hematopoietic stem cells produce Ang-1 and promote chemotaxis and network formation of TIE2-positive endothelial cells. Moreover, hematopoietic stem cells change their fate into mural cell and stabilize the vessel structure. This novel function may be applied clinically to promote neovascularization by transplanting the hematopoietic stem cells at the desired site.Biomedical Reviews 2003; 14: 1-8

The role of glucocorticoid receptors in the induction and prevention of hippocampal abnormalities in an animal model of posttraumatic stress disorder

Rationale: Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Numerous clinical studies have led to the hypothesis that elevated glucocorticoid levels in response to extreme stress might trigger a pathophysiological cascade which consequently leads to functional and morphological changes in the hippocampus. Objectives: To elucidate the pathophysiology of PTSD, we examined the alteration of hippocampal gene expression through the glucocorticoid receptor (GR) in the single prolonged stress (SPS) paradigm, a rat model of PTSD. Methods: We measured nuclear GRs by western blot, and the binding of GR to the promoter of Bcl-2 and Bax genes by chromatin immunoprecipitation-qPCR as well as the expression of these 2 genes by RT-PCR in the hippocampus of SPS rats. In addition, we examined the preventive effects of a GR antagonist on SPS-induced molecular, morphological, and behavioral alterations (hippocampal gene expression of Bcl-2 and Bax, hippocampal apoptosis using TUNEL staining, impaired fear memory extinction (FME) using the contextual fear conditioning paradigm). Results: Exposure to SPS increased nuclear GR expression and GR binding to Bcl-2 gene, and decreased Bcl-2 mRNA expression. Administration of GR antagonist immediately after SPS prevented activation of the glucocorticoid cascade, hippocampal apoptosis, and impairment FME in SPS rats. Conclusion: The activation of GRs in response to severe stress may trigger the pathophysiological cascade leading to impaired FME and hippocampal apoptosis. In contrast, administration of GR antagonist could be useful for preventing the development of PTSD.This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (a grant-in aid for Scientific Research, C) Grant Number JP18K07562, and Takeda Science Foundation

Morphology and Anatomy of Holocene Raised Coral Reef Terraces in Kodakara Island, Tokara Islands, northwestern Pacific, Japan

Well-developed Holocene raised coral reef terraces are formed in Kodakara Island (29°13'N 129°19'E), Tokara Islands, northwestern Pacific, Japan. Detailed morphology and sedimentary structure of the raised reef terraces are observed by field survey through the terraces surface and core drillings. The Holocene raised reef in Kodakara Island are divided into three terraces (TI to III). The surface geo-biological facies and paleo-morphology such as spur and groove system or reef mounds are well preserved on these terraces. The raised coral reefs in Kodakara Island consist of reef flats and reef slopes. No lagoon formed in these terraces. On the raised reef surface, we observed five distinct reefal facies (S-f1-5). The platy and encrusting Acropora facies is the major constituent of the terrace surfaces. We obtained seven drilling cores (B1 to 7) from Terraces I and II along a transect in the southern part of the island. The thickness of the Holocene reef is more than 14m which is approximately equivalent to the Holocene reefs in the middle and southern Ryukyu Islands. Sedimentary structure consists of seven facies (C-f1-7: five reefal and two non-reefal facies). The drilling cores indicating the shallowing sequence at the upward of the cores which characterized by platy-encrusting Acropora facies overlying massive Porites, favid and/or encrusting-foliaceous coral facies. It may indicate the environmental change such as wave-energy gradients and turbidity during the reef development

Cancer apelin receptor suppresses vascular mimicry in malignant melanoma

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

Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study

AbstractObjectiveDisease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy.Patients and methodsThis was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed.ResultsOverall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax.ConclusionsSuccess rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs

Surgical resection combined with perioperative chemotherapy for a patient with locally recurrent, previously stage IV thymic small-cell carcinoma : A case report

An 83-year-old Japanese man visited our hospital with dyspnea and general fatigue. Computed tomography (CT) revealed a tumor in the anterior mediastinum, bilateral pleural effusion, pericardial fluid, and multiple liver nodules. We performed a CT-guided tumor biopsy, and the patient was diagnosed with thymic small-cell carcinoma, Masaoka–Koga stage classification IVb. The patient received four cycles of carboplatin and etoposide, and all lesions disappeared on CT. However, after 6 months, CT revealed a recurrent tumor in the anterior mediastinum. After one cycle of rechallenge chemotherapy, we performed extended total thymectomy followed by another three cycles of chemotherapy. More than 2.5 years after the last chemotherapy session, the patient’s carcinoma did not recur. Thus, this case suggests that salvage surgery may be a treatment option for local recurrence of thymic carcinoma after complete remission with chemotherapy, even in patients with stage IV cancer

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase Ill KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFRIALK alterations and a PD-L1 tumor proportion score of 50% or greater

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738