Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.

Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Alveolar RMS (ARMS) is characterized by FOXO1-related chromosomal translocations that result in a poorer clinical outcome compared with embryonal RMS (ERMS). Because the chromosomal features of RMS have not been comprehensively defined, we analyzed the clinical and laboratory data of childhood RMS patients and determined the clinical significance of chromosomal abnormalities in the bone marrow. METHODS: Fifty-one Korean patients with RMS < 18 years of age treated between 2001 and 2015 were enrolled in this study. Clinical factors, bone marrow and cytogenetic results, and overall survival (OS) were analyzed. RESULTS: In total, 36 patients (70.6%) had ERMS and 15 (29.4%) had ARMS; 80% of the ARMS patients had stage IV disease. The incidences of bone and bone marrow metastases were 21.6% and 19.6%, respectively, and these results were higher than previously reported results. Of the 40 patients who underwent bone marrow cytogenetic investigation, five patients had chromosomal abnormalities associated with the 13q14 rearrangement. Patients with a chromosomal abnormality (15 vs 61 months, P=0.037) and bone marrow involvement (17 vs 61 months, P=0.033) had a significantly shorter median OS than those without such characteristics. Two novel rearrangements associated with the 13q14 locus were detected. One patient with concomitant MYCN amplification and PAX3/FOXO1 fusion showed an aggressive clinical course. CONCLUSIONS: A comprehensive approach involving conventional cytogenetics and FOXO1 FISH of the bone marrow is needed to assess high-risk ARMS patients and identify novel cytogenetic findings.
Arm ; Bone Marrow* ; Child* ; Chromosome Aberrations ; Cytogenetics* ; Humans ; Incidence ; Neoplasm Metastasis ; Rhabdomyosarcoma* ; Sarcoma ; Translocation, Genetic

This article was published with a misspelled the date of acceptance. The date of acceptance should be corrected as “March 7, 2013”.
Breast Neoplasms* ; Breast* ; Humans ; Recurrence*

Precursor B-cell acute lymphoblastic leukemia (ALL), which is the most common subtype of pediatric acute leukemia, generally has a good prognosis. However, the prognosis also depends on the genetic abnormalities of the leukemic blast. Concurrent MYC and IGH/BCL2 translocations have recently been reported as a “double hit” in adult patients, but non-immunoglobulin (non-IG)/MYC translocation has rarely been reported. In this paper, we report a case of pediatric precursor B-cell ALL associated with translocations (14;18)(q32;q21) and (8;9)(q24;p13). The patient was a previously healthy 13-year-old boy. Complete remission was not achieved after first-line four-drug induction chemotherapy; thus, intensive salvage regimen, including high-dose cytarabine and L-asparaginase, were administered, which resulted in morphologic remission. However, his disease relapsed during the second cycle of salvage regimen, and he died of sepsis-induced multiorgan failure.
Adolescent ; Adult ; Cytarabine ; Humans ; Induction Chemotherapy ; Leukemia ; Male ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cells, B-Lymphoid ; Prognosis

BACKGROUND: Flow cytometric analysis is the standard method for enumerating CD34+ stem cells in hematopoietic stem cell transplantation. However, it has some limitations such as expensive instrumentation, high reagent costs, and discrepancies between technicians and laboratories. We compared counts of total nucleated cells (TNCs) and CD34+ cells counts obtained from a flow cytometer with a newly-developed image-based microscopic cell counter (ADAM II) to evaluate the possibility of clinical application of the ADAM II.METHODS: We used 18 samples of circulating peripheral blood (PB) and waste tube fractions of peripheral blood stem cells (PBSCs) harvested by apheresis after G-CSF mobilization from adult volunteer donors. We assessed the reproducibility and linearity of the new procedure and compared the numbers of TNCs and viable CD34+ cells determined with the ADAM II and two different flow cytometers (FACSCalibur, FACSCanto II).RESULTS: Numbers of viable CD34+ cells determined with the ADAM II were accurate over the expected range; the intra-assay coefficient of variation was ≤19.8%. Linearity was also satisfactory (R²=0.99). TNC counts obtained with the ADAM II were highly correlated with those obtained with the FACSCalibur (R²>0.9841, P<0.0001) and FACSCanto II (R²>0.9620, P<0.0001), as were the numbers of viable CD34+ cells obtained with the ADAM II and the FACSCalibur and FACSCanto II (R²>0.9911, P<0.0001 and R²>0.9791, P<0.0001), respectively.CONCLUSION: The newly developed image-based microscopic cell counter (ADAM II) appears to be suitable for enumerating TNCs and viable CD34+ cells.
Adult ; Blood Component Removal ; Cell Count ; Granulocyte Colony-Stimulating Factor ; Hematopoietic Stem Cell Transplantation ; Humans ; Methods ; Stem Cells ; Tissue Donors ; Volunteers

Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.
Acetyl Coenzyme A ; Decarboxylation ; Diabetes Mellitus, Type 2 ; Glucose ; Homeostasis ; Humans ; Isoenzymes ; Mammals ; Metabolic Diseases ; Metabolism ; Obesity ; Oxidoreductases* ; Phosphoric Monoester Hydrolases ; Phosphorylation ; Phosphotransferases* ; Pyruvate Dehydrogenase Complex ; Pyruvic Acid* ; Risk Factors ; Up-Regulation

Preventive and therapeutic effects of egg yolk antibody, immunoglobulin Y (IgY), against canine parvovirus (CPV) was evaluated in 25 pups orally challenged with CPV-2a. Oral administration of IgY using powder, paste and coated paste delivery systems was compared. Each type of IgY was administered orally for 17 days from 3 days before challenge. The group of pups administered coated IgY showed mild symptoms such as a moderate decrease in total white blood cell count, no depression, vomiting and diarrhea when compared with other groups. The overall clinical score of the group of pups administered coated IgY was significantly lower than that of the challenge control group. However, mortality did not differ among groups because not all pups received symptomatic treatment. These results implied that oral treatment of coated IgY could improve therapeutic effects against CPV challenge if pups received symptomatic treatment.
Administration, Oral ; Chickens* ; Depression ; Diarrhea ; Egg Yolk* ; Enteritis* ; Immunoglobulins ; Immunotherapy ; Leukocyte Count ; Mortality ; Parvovirus, Canine ; Vomiting

BACKGROUND: The prognostic impact of the presence of differentiating neuroblasts in bone marrow (BM) remains unclear in BM metastatic neuroblastoma (NB). We aimed to identify the prognostic impact of differentiating neuroblasts in BM at diagnosis and after chemotherapy. METHODS: A total of 51 patients diagnosed with BM metastatic NB at Asan Medical Center between January 1990 and July 2005 were enrolled. BM histology and laboratory data along with overall survival (OS) were compared with regard to the differentiation status of neuroblasts in BM at diagnosis and after chemotherapy. RESULTS: Among the 51 patients, 13 (25.5%) exhibited differentiating neuroblasts in BM at diagnosis and 17/51 (33.3%) exhibited them after chemotherapy. The only significant difference among patient groups was the improved OS in patients with differentiated neuroblasts in BM at diagnosis (P=0.021). In contrast, the differentiation status of neuroblasts in BM after chemotherapy did not affect OS (P=0.852). CONCLUSIONS: Our study is the first report describing the presence of differentiating neuroblasts in BM. The presence of differentiating neuroblasts in BM at diagnosis may be a favorable prognostic factor for patients with BM metastatic NB; however, the same phenomenon after chemotherapy is irrelevant to prognosis.
Adolescent ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bone Marrow/*pathology ; Bone Marrow Cells/*cytology ; Bone Marrow Neoplasms/*diagnosis/secondary ; Cell Differentiation ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Karyotyping ; Male ; Neoplasm Grading ; Neuroblastoma/*diagnosis/drug therapy/pathology ; Prognosis ; Survival Analysis ; Young Adult

PURPOSE: IBTR! 2.0 is a web-based nomogram that predicts the 10-year ipsilateral breast tumor recurrence (IBTR) rate after breast-conserving therapy. We validated this nomogram in Korean patients. METHODS: The nomogram was tested for 520 Korean patients, who underwent breast-conserving surgery followed by radiation therapy. Predicted and observed 10-year outcomes were compared for the entire cohort and for each group, predefined by nomogram-predicted risks: group 1, <3%; group 2, 3% to 5%; group 3, 5% to 10%; group 4, >10%. RESULTS: In overall patients, the overall 10 year predicted and observed estimates of IBTR were 5.22% and 5.70% (p=0.68). In group 1, (n=124), the predicted and observed estimates were 2.25% and 1.80% (p=0.73), in group 2 (n=177), 3.95% and 3.90% (p=0.97), in group 3 (n=181), 7.14% and 8.80% (p=0.42), and in group 4 (n=38), 11.66% and 14.90% (p=0.73), respectively. CONCLUSION: In a previous validation of this nomogram based on American patients, nomogram-predicted IBTR rates were overestimated in the high-risk subgroup. However, our results based on Korean patients showed that the observed IBTR was higher than the predicted estimates in groups 3 and 4. This difference may arise from ethnic differences, as well as from the methods used to detect IBTR and the healthcare environment. IBTR! 2.0 may be considered as an acceptable nomogram in Korean patients with low- to moderate-risk of in-breast recurrence. Before widespread use of this nomogram, the IBTR! 2.0 needs a larger validation study and continuous modification.
Breast ; Breast Neoplasms ; Cohort Studies ; Delivery of Health Care ; Humans ; Mastectomy, Segmental ; Nomograms ; Recurrence