Bone marrow mononuclear cell therapy limits myocardial infarct size through vascular endothelial growth factor

Abstract. No prior study has examined the effect of intravenous injection of bone marrow mononuclear cells (MNCs) on myocardial infarction size (IS). We tested the hypothesis that transplantation of MNCs decreases IS through the release of vascular endothelial growth factor (VEGF). Immediately after ligation of the left coronary artery of immunodeficient mice, PBS or MNCs were intravenously administered. Myocardial IS was significantly less in MNCs-treated mice than in PBS-treated mice. Trace experiments showed accumulation of exogenously administered MNCs into the vicinity of infarcted myocardium. Injection of MNCs did not affect capillary density after infarction, but did reduced myocardial cell apoptosis. Blockade of VEGF by a neutralizing antibody or by gene transfer of a soluble form of Flt-1 VEGF receptor diminished the IS-limiting effects of MNCs. In conclusion, injection of MNCs can reduce myocardial IS through the release of VEGF. The MNC therapy for acute myocardial infarction might improve prognosis of patients with myocardial infarction.     

Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma,unspecified: comparison with AILD,ALCL, lymphoblastic lymphoma,and ATLL

A new World Health Organization classification was recently proposed. However, classification of peripheral T-cell lymphomas remains to be clarified. Particularly, unspecified type was considered as a heterogeneous category. Here we studied the expressions of chemokine receptors, Th1-associated CXCR3 and CCR5 and Th2-associated marker ST2(L), and activated T-cell receptor OX40/CD134 in 185 patients with nodal T-cell lymphoma, and evaluated the relationship to prognosis. Their expression patterns correlated with the specific subtype of nodal T-cell lymphoma, such as angioimmunoblastic T-cell lymphoma (AILD), anaplastic large cell lymphoma (ALCL), and in peripheral T-cell lymphoma (PTCL), unspecified. In AILD, almost all cases were immunoreactive for OX40/CD134 (96%) and for CXCR3 (89%). In ALCL, all cases were immunonegative for OX40/CD134, and only a few cases (24%) were immunoreactive for CXCR3, whereas almost all cases (94%) were positive for ST2(L). Cases of PTCL, unspecified, were divided into 2 groups; group 1 (cases positive for either ST2(L), CCR5, or CXCR3) tended to show favorable prognosis compared with group 2 (cases negative for ST2(L), CCR5, and CXCR3). Our results indicate that further subtyping of PTCL, unspecified, into groups 1 and 2 could be significant for evaluating prognosis and understanding the functional role of these tumors.     

Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer

Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.     

Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese

Plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins. Since CETP regulates the plasma levels of HDL cholesterol and the size of HDL particles, CETP is considered to be a key protein in reverse cholesterol transport (RCT), a protective system against atherosclerosis. The importance of plasma CETP in lipoprotein metabolism was demonstrated by the discovery of CETP-deficient subjects with marked hyperalphalipoproteinemia (HALP). Genetic CETP deficiency is the most important and common cause of HALP in the Japanese. Ten mutations of the CETP gene have been demonstrated as causes of HALP, including two common mutations: an intron 14 splicing defect (Int14 + 1 G --> A) and an exon 15 missense mutation (D442G). The subjects with CETP deficiency show a variety of abnormalities in the concentration, composition, and function of both HDL and low density lipoprotein (LDL). CETP deficiency is considered a physiological state of impaired RCT, which may possibly lead to the development of atherosclerosis despite high HDL cholesterol levels. However, the pathophysiological significance of CETP in terms of atherosclerosis has been controversial. Epidemiological studies in Japanese-Americans living in Hawaii and Japanese in the Omagari area, where HALP subjects with an intron 14 splicing defect of the CETP gene are markedly frequent, have shown a relatively increased incidence of coronary atherosclerosis in CETP deficiency. On the other hand, the TaqIB polymorphism-B2 allele with low CETP mass and increased HDL cholesterol has been related to a decreased risk for coronary heart disease (CHD) in many studies, including the Framingham Offspring Study. The current review focused on the characterization of the Japanese subjects with CETP deficiency, including our recent findings.     

GPR43 Suppresses Intestinal Tumor Growth by Modification of the Mammalian Target of Rapamycin Complex 1 Activity in ApcMin/+ Mice

ObjectiveG protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using Apc^Min/+, a murine model of intestinal tumors.Materials and MethodsUsing GPR43^−/− Apc^Min/+ and GPR43^+/− Apc^Min/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways.ResultsOur results revealed that GPR43 deficiency resulted in increased tumor numbers in Apc^Min/+ mice. Ki67 was highly expressed in GPR43^−/− mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088).ConclusionCollectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway.     

Practical Application of Urinary Zearalenone Monitoring System for Feed Hygiene Management of a Japanese Black Cattle Breeding Herd—The Relationship between Monthly Anti-Müllerian Hormone and Serum Amyloid A Concentrations

This study addresses an advantageous application of a urinary zearalenone (ZEN) monitoring system not only for surveillance of ZEN exposure at the production site of breeding cows but also for follow-up monitoring after improvement of feeds provided to the herd. As biomarkers of effect, serum levels of the anti-Müllerian hormone (AMH) and serum amyloid A (SAA) concentrations were used. Based on the results of urinary ZEN measurement, two cows from one herd had urinary ZEN concentrations which were two orders of magnitude higher (ZEN: 1.34 mg/kg, sterigmatocystin (STC): 0.08 mg/kg in roughages) than the levels of all cows from three other herds (ZEN: not detected, STC: not detected in roughages). For the follow-up monitoring of the herd with positive ZEN and STC exposure, urine, blood, and roughage samples were collected from five cows monthly for one year. A monitoring series in the breeding cattle herd indicated that feed concentrations were not necessarily reflected in urinary concentrations; urinary monitoring assay by ELISA may be a simple and accurate method that reflects the exposure/absorption of ZEN. Additionally, although the ZEN exposure level appeared not to be critical compared with the Japanese ZEN limitation in dietary feeds, a negative regression trend between the ZEN and AMH concentrations was observed, indicating that only at extremely universal mycotoxin exposure levels, ZEN exposure may affect the number of antral follicles in cattle. A negative regression trend between the ZEN and SAA concentrations could also be demonstrated, possibly indicating the innate immune suppression caused by low-level chronic ZEN exposure. Finally, significant differences (p = 0.0487) in calving intervals between pre-ZEN monitoring (mean ± SEM: 439.0 ± 41.2) and post-ZEN monitoring (349.9 ± 6.9) periods were observed in the monitored five cows. These preliminary results indicate that the urinary ZEN monitoring system may be a useful practical tool not only for detecting contaminated herds under field conditions but also provides an initial look at the effects of long-term chronic ZEN/STC (or other co-existing mycotoxins) exposure on herd productivity and fertility.     

Associations between Chest CT Abnormalities and Clinical Features in Patients with the Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care.     

Metastatic intradural extramedullary spinal cord tumor from ovarian cancer: A case report with a literature review

Context: Metastatic intradural extramedullary spinal cord tumors are extremely rare.Findings: A 76-year-old woman presented with intractable neck pain. Three years earlier, she had been treated for ovarian cancer with bilateral salpingo-oophorectomy. A year later, she underwent resection of a brain metastasis. Magnetic resonance imaging (MRI) showed an encapsulated intradural extramedullary mass at C4–C5. C4–C5 hemilaminectomy, tumor resection, and biopsy were performed. Histological examination of the resection revealed an adenocarcinoma. After surgery, her intolerable neck-shoulder pain was fully resolved, and she had no difficulties with daily living activities. However, two months later, she underwent gamma knife radiosurgery for the recurrent metastatic brain tumor, and four months later, she died from cachexia.Conclusion: Although cases of metastatic intradural extramedullary spinal tumors from ovarian cancer are extremely rare, their possibility should be considered in the differential diagnosis. A history of brain metastases and enhancement on T1-weighted MRI were helpful for making an accurate diagnosis.