Normalization of Red Cell Enolase Level Following Allogeneic Bone Marrow Transplantation in a Child with Diamond-Blackfan Anemia

We describe a girl with Diamond-Blackfan anemia with accompanying red cell enolase deficiency. At the age of 9 yr old, the patient received allogeneic bone marrow transplantation from her HLA-identical sister who had normal red cell enolase activity. While the post transplant DNA analysis with short tandem repeat has continuously demonstrated a stable mixed chimerism on follow-up, the patient remains transfusion independent and continues to show a steady increase in red cell enolase activity for over two and a half years following bone marrow transplantation

Huge Intrathoracic Malignant Peripheral Nerve Sheath Tumor in an Adolescent with Neurofibromatosis Type 1

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue malignancy usually found in patients with neurofibromatosis type 1 (NF1) with a poor outcome. Although MPNST can be found in any part of the body including head and neck or extremities, intrathoracic MPNST with or without NF1 is uncommon, especially in children or adolescents. Reported herein is a case of huge intrathoracic MPNST in a 16-year-old girl with NF1, and a brief review of the literature

Second malignant neoplasms after childhood cancer: A nationwide population-based study in Korea.

BACKGROUND:Second malignant neoplasm is one of the most devastating late effects of childhood cancers. This study aimed to evaluate the incidence and survival outcomes of patients developing second malignant neoplasms (SMNs) after surviving childhood cancer in Korea. METHODS:Medical data of childhood cancer patients diagnosed between 1993 and 2012 were obtained from the Korea Central Cancer Registry. The risk of developing SMNs was calculated using standardized incidence ratio (SIR), excess absolute risk (EAR), and cumulative risk. Kaplan-Meier survival curves were estimated, stratified by SMN status. RESULTS:A total of 28,405 childhood cancer patients were diagnosed in the study period, and 337 (1.2%) developed SMN. The total follow-up period was 197,359 person-years at risk (PYR), with a median follow-up duration of 5.6 years. Overall SIR was 20.0, which was 23.2 in women, and 17.6 in men. The overall EAR was 16.4 per 10,000 PYR. The most common types of SMNs, in order of incidence, were other malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. The cumulative incidence of developing SMNs was 0.7% at 5 years, 1.2% at 10 years, and 2% at 15 years. After primary cancer diagnosis, the 10-year overall survival rate of patients with SMNs was 65.1%, which was lower than the 73.4% in patients without SMN. After SMN diagnosis, the 10-year overall survival rate was 55.8%. CONCLUSION:Through this registry-based study of 5.6 years of follow up, childhood cancer survivors were found to be at 20-fold higher risk of developing a malignant neoplasm compared to the general population. The majority of malignant neoplasms are malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. Continued surveillance for assessing long-term risks, and guidance for appropriate long-term follow up of childhood cancer survivors, are needed

Common Variable Immunodeficiency (CVI) 1례

Common variable immunodeficiency is a heterogeneous group of disorders characterized by hypogammaglobulinemia, impaired antibody response and recurrent bacterial infections. Although it is represented by an acquired defect of humoral immunity, cellular defect is occasionally found. Though variable, it usually manifests in the second or third decade of life. This report deals with a case of common variable immunodeficiency in a 6-year-old boy who presented with recurrent infections since 3 7/12 years of age, associated with aortic aneurysm and involvement of the liver, testis and polyserosa, which were believed to be autoimmune in nature

HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress

The plasma membrane microdomains, lipid rafts, are involved in regulation of cellular functions such as cell survival and adhesion. Cholesterol is a critical component of lipid rafts in terms of their integrity and functions and rafts disruption by cholesterol depletion can induce detachment-induced cell death. Hypoxia inducible factor-1 (HIF-1) alpha is stabilized in hypoxia and transactivates numerous genes required for cellular adaptation to hypoxia. It is also induced by non-hypoxic stimuli and contributes to cell survival. Because hypoxia inhibits cholesterol synthesis and HIF-1 alpha plays a role in this process, we here explored a possible connection between lipid rafts and HIF-1 alpha. We investigated whether HIF-1 alpha is regulated during cholesterol depletion/rafts disruption in A431 cells in normoxic conditions. Methyl-beta cyclodextrin (M beta CD), which induces cholesterol depletion, upregulated HIF-1 alpha even under normoxic conditions and this upregulation required epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1 and 2 activation, but not Akt activation. M beta CD treatment induced HIF-1 alpha upregulation at both the transcriptional and translational levels but not at the posttranslational levels. In addition, M beta CD robustly induced vascular endothelial growth factor production and stimulated an hypoxia response element-driven luciferase reporter activity under normoxic conditions, indicating that M beta CD-induced HIF-1 alpha is functionally activated. Both EGFR activity and HIF-1 alpha expression were higher in the attached cells than in the detached cells after M beta CD treatment. Furthermore, inhibition of HIF-1 alpha by RNA interference accelerated cell detachment, thus increasing cell death, indicating that HIF-1 alpha expression attenuates M beta CD-induced anoikis-like cell death. These data suggest that, depending on cholesterol levels, lipid rafts or membrane fluidity are probably to regulate HIF-1 alpha expression in normoxia by modulating rafts protein activities such as EGFR, and this connection between lipid rafts and HIF-1 alpha regulation may provide cell survival under membrane-disturbing stress.Park EK, 2009, J PATHOL, V218, P337, DOI 10.1002/path.2531Bellot G, 2009, MOL CELL BIOL, V29, P2570, DOI 10.1128/MCB.00166-09Gauthaman K, 2009, J CELL BIOCHEM, V106, P975, DOI 10.1002/jcb.22092Chiche J, 2009, CANCER RES, V69, P358, DOI 10.1158/0008-5472.CAN-08-2470Rohwer N, 2008, CANCER RES, V68, P10113, DOI 10.1158/0008-5472.CAN-08-1839Pedersen M, 2008, BIOCHEM BIOPH RES CO, V377, P98, DOI 10.1016/j.bbrc.2008.09.102Magura L, 2008, CANCER CAUSE CONTROL, V19, P1259, DOI 10.1007/s10552-008-9197-7Diebold I, 2008, THROMB HAEMOSTASIS, V100, P1021, DOI 10.1160/TH08-07-0473Song G, 2008, CANCER SCI, V99, P1901, DOI 10.1111/j.1349-7006.2008.00911.xLaura B, 2008, J CELL BIOCHEM, V105, P503, DOI 10.1002/jcb.21850Semenza GL, 2008, IUBMB LIFE, V60, P591, DOI 10.1002/iub.93Fedida-Metula S, 2008, CARCINOGENESIS, V29, P1546, DOI 10.1093/carcin/bgn146Niu GL, 2008, MOL CANCER RES, V6, P1099, DOI 10.1158/1541-7786.MCR-07-2177Patra SK, 2008, BBA-REV CANCER, V1785, P182, DOI 10.1016/j.bbcan.2007.11.002Nishimoto-Hazuku A, 2008, J CARDIOVASC PHARM, V51, P267Shin DH, 2008, ONCOGENE, V27, P1939, DOI 10.1038/sj.onc.1210826Indovina P, 2008, ANTICANCER RES, V28, P1013Nguyen AD, 2007, J BIOL CHEM, V282, P27436, DOI 10.1074/jbc.M704976200Maynard MA, 2007, CELL MOL LIFE SCI, V64, P2170, DOI 10.1007/s00018-007-7082-2Kilic M, 2007, ONCOGENE, V26, P2027, DOI 10.1038/sj.onc.1210008Freeman MR, 2007, STEROIDS, V72, P210, DOI 10.1016/j.steroids.2006.11.012Jacobson K, 2007, NAT CELL BIOL, V9, P7, DOI 10.1038/ncb0107-7Mitra SK, 2006, CURR OPIN CELL BIOL, V18, P516, DOI 10.1016/j.ceb.2006.08.011Peng XH, 2006, J BIOL CHEM, V281, P25903, DOI 10.1074/jbc.M603414200Summons RE, 2006, PHILOS T R SOC B, V361, P951, DOI 10.1098/rstb.2006.1837Hancock JF, 2006, NAT REV MOL CELL BIO, V7, P456, DOI 10.1038/nrm1925Li YC, 2006, AM J PATHOL, V168, P1107, DOI 10.2353/ajpath.2006.050959Hwang JI, 2005, P NATL ACAD SCI USA, V102, P9493, DOI 10.1073/pnas.0503503102Zhuang LY, 2005, J CLIN INVEST, V115, P959Dery MAC, 2005, INT J BIOCHEM CELL B, V37, P535, DOI 10.1016/j.biocel.2004.08.012Chen SD, 2005, ANN NY ACAD SCI, V1042, P357, DOI 10.1196/annals.1338.033Koike T, 2004, P NATL ACAD SCI USA, V101, P8132Chen X, 2002, J BIOL CHEM, V277, P49631, DOI 10.1074/jbc.M208327200Kim YN, 2000, J BIOL CHEM, V275, P7481Zhong H, 2000, CANCER RES, V60, P1541

DataSheet_1_ICSBP-induced PD-L1 enhances osteosarcoma cell growth.docx

BackgroundInterferon (IFN) consensus sequence binding protein (ICSBP) is a transcription factor induced by IFN-γ. We previously reported that ICSBP expression promotes osteosarcoma progression by enhancing transforming growth factor-β signaling. In cancer cells, programmed death-ligand 1 (PD-L1) contributes to immune escape and may also be involved in tumor progression. Because IFN-γ induces the expression of both ICSBP and PD-L1, we explored the association between ICSBP and PD-L1 expression in terms of osteosarcoma progression.MethodsThree osteosarcoma cell lines (Saos2, U2OS, and 143B) were employed. Gene expression was measured by qRT-PCR, and protein levels were assessed by immunoblotting. PD-L1 expression was evaluated in cells overexpressing ICSBP and in ICSBP knockdown cells. The effects of PD-L1 expression on cell growth were examined by MTS assays, Incucyte analysis, soft agar assays, and three-dimensional (3D) culture. Cell cycle and apoptosis were evaluated by FACS analysis of cells stained with propidium iodide (PI) and annexin V/PI, respectively. The antitumor effects of PD-L1 knockdown without or with doxorubicin treatment were evaluated in vivo in nude mice bearing ICSBP-overexpressing 143B cell xenograft. The clinical relevance of PD-L1 and ICSBP expression was evaluated immunohistochemically using a human osteosarcoma microarray and through analysis of publicly available data using Gene Expression Profiling Interactive Analysis2.ResultsICSBP overexpression upregulated PD-L1 expression in all three cell lines, whereas ICSBP knockdown decreased the PD-L1 expression. PD-L1 knockdown attenuated the cell growth and reduced colony-forming capacity in both soft agar assays and 3D culture. PD-L1 knockdown increased apoptosis and induced G2/M arrest, which was associated with decreased expression of survivin, cyclin-dependent kinase 4 (CDK4), cyclin E, and cyclin D1 expression and increased the expression of p27, phosphorylated Cdc2, and phosphorylated Wee1. PD-L1 knockdown decreased the growth of tumor xenografts and increased the doxorubicin sensitivity of ICSBP-overexpressing 143B cells both in vitro and in vivo. PD-L1 was expressed in human osteosarcoma tissues, and its expression was moderately correlated with that of ICSBP in osteosarcoma patients.ConclusionICSBP regulates PD-L1 expression in osteosarcoma cells, and PD-L1 knockdown combined with doxorubicin treatment could represent a strategy for controlling osteosarcoma expressing ICSBP.</p

DataSheet_2_ICSBP-induced PD-L1 enhances osteosarcoma cell growth.zip

BackgroundInterferon (IFN) consensus sequence binding protein (ICSBP) is a transcription factor induced by IFN-γ. We previously reported that ICSBP expression promotes osteosarcoma progression by enhancing transforming growth factor-β signaling. In cancer cells, programmed death-ligand 1 (PD-L1) contributes to immune escape and may also be involved in tumor progression. Because IFN-γ induces the expression of both ICSBP and PD-L1, we explored the association between ICSBP and PD-L1 expression in terms of osteosarcoma progression.MethodsThree osteosarcoma cell lines (Saos2, U2OS, and 143B) were employed. Gene expression was measured by qRT-PCR, and protein levels were assessed by immunoblotting. PD-L1 expression was evaluated in cells overexpressing ICSBP and in ICSBP knockdown cells. The effects of PD-L1 expression on cell growth were examined by MTS assays, Incucyte analysis, soft agar assays, and three-dimensional (3D) culture. Cell cycle and apoptosis were evaluated by FACS analysis of cells stained with propidium iodide (PI) and annexin V/PI, respectively. The antitumor effects of PD-L1 knockdown without or with doxorubicin treatment were evaluated in vivo in nude mice bearing ICSBP-overexpressing 143B cell xenograft. The clinical relevance of PD-L1 and ICSBP expression was evaluated immunohistochemically using a human osteosarcoma microarray and through analysis of publicly available data using Gene Expression Profiling Interactive Analysis2.ResultsICSBP overexpression upregulated PD-L1 expression in all three cell lines, whereas ICSBP knockdown decreased the PD-L1 expression. PD-L1 knockdown attenuated the cell growth and reduced colony-forming capacity in both soft agar assays and 3D culture. PD-L1 knockdown increased apoptosis and induced G2/M arrest, which was associated with decreased expression of survivin, cyclin-dependent kinase 4 (CDK4), cyclin E, and cyclin D1 expression and increased the expression of p27, phosphorylated Cdc2, and phosphorylated Wee1. PD-L1 knockdown decreased the growth of tumor xenografts and increased the doxorubicin sensitivity of ICSBP-overexpressing 143B cells both in vitro and in vivo. PD-L1 was expressed in human osteosarcoma tissues, and its expression was moderately correlated with that of ICSBP in osteosarcoma patients.ConclusionICSBP regulates PD-L1 expression in osteosarcoma cells, and PD-L1 knockdown combined with doxorubicin treatment could represent a strategy for controlling osteosarcoma expressing ICSBP.</p

Five-year RSRs for Korean AYAs according to the time period of cancer diagnosis<b>.</b>

<p>*<i>P</i>-values <0.05 for trend.</p>†<p>Change (%) in the 5-year RSR from 1993–1995 to 2006–2010.</p>‡<p>Thyroid carcinoma was excluded from the calculation of the incidence rate of all cancers combined because of its unusually high incidence rate.</p><p>N/S: not shown because <20 cases were reported in each period.</p><p>AYAs, adolescents and young adults (aged 15–29 years); CNS, central nervous system; PNET, primitive neuroectodermal tumor; NOS, not otherwise specified.</p

Trends in age-standardized incidence rates among Korean AYAs and estimated annual percent changes (APCs).

<p>*<i>P</i>-values <0.05.</p>†<p>Thyroid carcinoma was excluded from the calculation of the incidence rate of all cancers combined because of its unusually high incidence rate.</p><p>AYAs, adolescents and young adults (aged 15–29 years); CNS, central nervous system; PNET, primitive neuroectodermal tumor; NOS, not otherwise specified.</p