MTHFR-C677T Gene Polymorphism and Susceptibility to Acute Lymphoblastic Leukemia in Children: A Meta-Analysis.

BACKGROUND: The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) and childhood acute lymphoblastic leukemia (ALL) is inconsistent. OBJECTIVE: To explore the relationship between MTHFR-C677T polymorphism and susceptibility to childhood ALL. METHODS: PubMed, EMBASE, Web of Science, CNKI, Wanfang, VIP, and other databases were searched from the establishment of the database to November 2019, and all the case-control studies that met the inclusion criteria were collected. Stata 15.0 was used for meta-analysis, with calculation of the odds ratio (OR) of the relationship between MTHFR-C677T polymorphism and childhood ALL susceptibility. Ethnicity was analyzed by subgroup analysis. RESULTS: A total of 26 studies were included in this meta-analysis, including 4,682 children with ALL and 7144 controls. The results showed that there was no significant difference in the comparison of population of allele model, dominant gene model, recessive gene model, homozygous gene model, heterozygous gene model, and the comparison of Caucasian children. The results of the Asian child analysis suggested that the combined OR of the dominant gene model (CC + CT versus TT), homozygous model (CC versus TT) and heterozygous model (CT versus TT) was 1.32 (95% confidence interval [CI]: 1.03-1.70), 1.37 (95% CI: 1.02-1.84), and 1.27 (95% CI: 1.01-1.59), respectively, with statistically significant differences. However, there was no significant difference between the allele model and recessive gene model among Asian children. CONCLUSION: The MTHFR C677T polymorphism is related to ALL in children, especially in Asian children. CC + CT, CC, and CT genotypes can increase the risk of ALL, but no association has been found in Caucasian children.

Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study.

Intravenous arsenic trioxide (ATO) has been adopted as the first-line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As4 S4 , has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML-RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all-trans-retinoic acid and low intensity chemotherapy. End points included event-free survival (EFS), adverse events and hospital days. After a median 3-year follow-up, the estimated 5-year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.

Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China.

BACKGROUND: Mandibuloacral dysplasia type A (MADA) is a rare autosomal recessive disorder, characterized by growth retardation, skeletal abnormality with progressive osteolysis of the distal phalanges and clavicles, craniofacial anomalies with mandibular hypoplasia, lipodystrophy and mottled cutaneous pigmentation. Some patients may show progeroid features. MADA with partial lipodystrophy, more marked acral, can be caused by homozygous or compound heterozygous mutation in the gene encoding lamin A and lamin C (LMNA). MADA and Hutchinson-Gilford progeria syndrome are caused by the same gene and may represent a single disorder with varying degrees of severity. MAD patients characterized by generalized lipodystrophy (type B) affecting the face as well as extremities and severe progressive glomerulopathy present heterozygous compound mutations in the ZMPSTE24 gene. CASES PRESENTATIONS: We described a rare pedigree from Southern China, among them all three children presented with phenotypes of MADA associated progeria. The two elder sisters had developed severe mandibular hypoplasia associated progeria since the age of 1 year. The eldest sister showed a progressive osteolysis. The youngest son of 10 months showed severer lesions than those of his sisters at the same age, and presented possible muscle damage, and his symptoms progressed gradually. Three genes mutations including LMNA, ZMPSTE24 and BANF1 were tested in the family. LMNA gene sequencing revealed a homozygous missense mutation, c.1579C > T, p.R527C for all three siblings, and heterozygous mutations for their parents, whereas no mutations of ZMPSTE24 and BANF1 genes was detected among them. CONCLUSIONS: The same homozygous mutation of c.1579C > T of LMNA gene led to MADA associated progeria for the present family. The course of osteolysis for MADA is progressive.

Intensive chemotherapy with dual induction and ALL-like consolidation for childhood acute myeloid leukemia: a respective report from multiple centers in China.

Background: Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. Objectives: To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Design: Retrospective, single-arm study. Methods: From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. Results: A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 109/L, 11 of whom ⩾100 × 109/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 109/L (n = 59) and ⩾100 × 109/L (n = 11) were 76.4% ± 5.7% and 45.5% ± 15% (p = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%). Conclusion: This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 109/L was the only independent risk factor in this cohort. Trial registration: It is a retrospective study, and no registration on ClinicalTrials.gov.

Five Chinese pediatric patients with leukemias possibly arising from immature natural killer cells: clinical features and courses.

Leukemias arising from immature nature killer (NK) cells have been proposed as distinct entities and are rare. Treatment and prognosis of these diseases are controversial, and data on children are limited. According to the literature, one of these distinct leukemias may be myeloid/NK cell precursor acute leukemia (MNKPL), with the blasts being cytochemically myeloperoxidase negative (MPO(-)) and phenotypically CD56(+)CD3(-)CD7(+)CD34(+) and myeloid antigens(+). The other may be myeloid/NK cell acute leukemia (MNKL), in which the blasts were cytochemically MPO(dim) and phenotypically CD56(+)CD16(-)CD3(-)CD33(+)HLA-DR(-). Between 2005 and 2008, 4 MNKPL and 1 MNKL children aged 1.3 to 12.5 years were encountered in the First Affiliated Hospital of Sun Yat-Sen University. In those with MNKPL, remarkable extramedullary involvement usually occurring in adults was not observed; however, myelofibrosis was found in 2 children. The child with MNKL abandoned treatment. Those with MNKPL were treated with a protocol designed for childhood high-risk acute lymphoblastic leukemia (ALL) containing cytarabine, mitoxantrone, etoposide, l-asparaginase, and methotrexate according to the myeloid and lymphoid characteristics of MNKPL. They responded slowly to chemotherapy and were in complete remission (CR) for 26 to 63 months, except 1 who died in CR from pneumonia. They had longer survival and seemed to have a better outcome than those reported previously. In conclusion, childhood leukemias with immature NK cell markers may have different characteristics from their adult counterparts. A protocol including agents used for acute myeloid leukemia combined with those for ALL is seemingly effective for treatment of MNKPL. However, a modified treatment strategy designed more specifically for MNKPL and longer observations are needed.

[microRNA expression in childhood acute granulocytic leukemia and its subtypes].

OBJECTIVE: Recent studies have suggested that there is a close relation between microRNA and acute leukemia (AL). The aim of this study was to investigate and better understand the classification and diagnosis of AL as well as pathogenesis and prognosis of this disease. METHODS: A total of 93 children with AL and and 12 cases of idiopathic thrombocytopenic purpura (as control group) were enrolled in this study. Microarray chip analysis of their bone marrow samples was conducted to evaluate the microRNA profiles. Quantitative real-time PCR was performed for validating the abnormal expression of microRNA. RESULTS: The microRNA expression profiles were different between acute granulocytic leukemia and acute lymphoblastic leukemia and also between the three subtypes (M1, M2 and M3) of acute granulocytic leukemia according to FAB classification based on leukemic cell differentiation. These three subtypes of leukemia could be identified by unsupervised hierarchical cluster analysis of microRNA expression and had specific up-regulation of miR-335, miR-126 and miR-125b, respectively. However, in the M2 and M3 subtypes with positive AML1-ETO and PML-RARα, respectively, which have a better prognosis, the expressions of miR-126 and miR-125b were significantly higher than those with negative AML1-ETO and PML-RARα. Further more, miR-335 and miR-146 were up-regulated in acute granulocytic leukemia observed in this study, which are different from those reported for adult patients. CONCLUSIONS: microRNA cascade may serve as new biomarkers for the classification and diagnosis of pediatric AL. It is also suggested that there might be different pathogenesis and prognosis between AL types related to specific expression and regulation of microRNA.

Arsenic trioxide induces autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD acute myeloid leukemia cells.

The prognosis of acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations is poor. Some studies, including our previous study, have indicated that arsenic trioxide (ATO) exhibited significant anti-carcinogenic activity in FLT3-ITD AML cells and explored the possibility of targeting the FLT3-ITD protein for degradation as a therapy. Autophagy is a critical mechanism of the anti-leukemic effects of ATO. In this study, we explored the therapeutic efficacy of ATO treatment in a mouse model bearing FLT3-ITD AML and found that ATO significantly reduced the leukemic burden in bone marrow and spleen. We also found that autophagy was responsible for, at least in part, the degradation of the FLT3-ITD protein by ATO. After ATO treatment, MV4-11 cells showed complete autophagic flux. The autophagy inhibitor bafilomycin A or down-regulation of the key autophagy genes Atg5 and Atg7 reversed the FLT3 degradation induced by ATO. We also found that p62/SQSTM1 delivered FLT3-ITD proteins to the lysosome, where they were subsequently degraded. These results indicate that ATO can induce autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD AML.

High-risk childhood acute lymphoblastic leukemia in China: factors influencing the treatment and outcome.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) with high-risk features has an inferior outcome. Factors influencing the treatment and outcome of pediatric ALL with high-risk features in developing countries have not been well studied. METHODS: High-risk features were defined as: age <1 year or >10 years, white blood cell (WBC) > 50 x 10(9)/L, CNS or testicular involvement at diagnosis, T-ALL, BCR-ABL/MLL-AF4, poor prednisone response, slow early response to induction chemotherapy which was defined as M3 status (>25% blasts) on day 15 bone marrow with age >6 years or presenting WBC > 20 x 10(9)/L at diagnosis and/or non-remission (NR) after 33 days of induction therapy. RESULTS: Ninety-one children were analyzed. The total rate of treatment abandonment was 24.2% and treatment-related mortality was 3.3% (3/91). The event-free survival (EFS) was 52.3% (95% CI, 41.5-63.1%) at 4 years and 49.9% (95% CI, 38.9-60.9%) at 8 years, respectively. When the cases who abandoned treatment were excluded, the EFS of the remainder was 68.3% (95% CI, 56.5-80.1%) at 4 years and 65.2% (95% CI, 52.5-77.9%) at 8 years, respectively. NR on day 33 or BCR-ABL remained as an independent unfavorable prognostic factor in the Cox model even if more intense chemotherapy was administrated. CONCLUSION: A decreased treatment-related death frequency was associated with an improved outcome of leukemia. This emphasizes the importance of improving supportive care in developing countries for children with high-risk ALL who receive very intensive chemotherapy. Treatment abandonment remains a prominent reason for treatment failure in China.

Improved outcome for Chinese children with acute promyelocytic leukemia: a comparison of two protocols.

OBJECTIVE: Acute promyelocytic leukemia (APL) is now highly curable, except in many developing countries. Introduction of current treatment strategies may improve the outcome for children with APL in these countries. METHODS: The diagnosis was based on the FAB classification and detection of PML-RAR alpha rearrangement. From December 1999 to September 2004, 16 eligible children were treated with an intensive in-house protocol including high-dose AraC and anthracycline. Subsequently, 14 cases were treated with a less intensive protocol modified from the PETHEMA LPA99. RESULTS: The 3.5 years event-free survival (EFS) was 37.5% (95% CI, 13.8-61.2%) for patients treated on initial protocol. The treatment failures were: six patients abandoned treatment (37.5%), two who died of intracranial hemorrhage at diagnosis (6.3%) and sepsis in remission (6.3%) respectively, and two who relapsed (12.5%). Those treated on modified PETHEMA had a 3.5 years EFS of 79.6% (95% CI, 52.9-106.3%). Treatment failures included: one who died of intracranial hemorrhage at diagnosis (7.1%) and one who relapsed (7.1%). The patients on modified PETHEMA had a significantly higher EFS (P = 0.012), lower frequency of sepsis during treatment (7.7% vs. 77.8%; P = 0.0015), and lower hospitalization cost (median US$ 4,700 vs. US$ 20,000; P < 0.0001) than those on in-house protocol. CONCLUSION: Treatment with the less intensive protocol based on the PETHEMA LPA99 study of childhood APL successfully reduced chemotherapy toxicity and lowered hospitalization costs without increasing relapses. This led to decreases in treatment-related morbidity and the treatment abandonment rate, thus improving overall outcome.

Current status of diagnosis and prognosis of infant acute leukemia in China.

OBJECTIVE: Treatment and outcome of infant acute leukemia (IAL) in developed countries have been well documented. However, reports summarizing diagnosis and outcome of IAL in developing countries are limited. METHODS: Five hundred ninety seven pediatric patients were diagnosed with acute leukemia in our hospital between January 1997 and June 2008, of which 19 were younger than 12 months. Data from our 19 cases and the Chinese literature were analyzed. RESULTS: Of the 19 cases, 14 had acute lymphoblastic leukemia (ALL) and 5 had acute myeloid leukemia (AML) based on FAB classification. Immunophenotyping and molecular genetic analysis were performed in only 6 cases. Only 16% (3/19) of the infants received treatment. Two infants with immunophenotypic AML who abandoned treatment achieved spontaneous remission without chemotherapy within 2 and 4 months respectively. Combining our data with those from Chinese literature, less than one third of the infants had immunophenotypic and genetic verification of leukemia and 29% (18/63) of them received treatment. CONCLUSION: Family financial difficulties and physicians' lack of confidence in treatment outcome in IAL contributed to a high treatment abandonment rate and poor outcome. Public health insurance as well as physician education on current IAL treatment strategies may decrease treatment abandonment in China.

Melatonin inhibits MLL-rearranged leukemia via RBFOX3/hTERT and NF-κB/COX-2 signaling pathways.

MLL-rearranged leukemia is an aggressive malignancy associated with poor outcome, which is refractory to conventional treatment. Melatonin has been proven to exert anti-tumor activity, but the effect of melatonin on MLL-r leukemia and the underlying mechanism remain poorly understood. In this study, melatonin inhibited cell proliferation and induced apoptosis by activating the caspase-dependent apoptotic pathway in MLL-r leukemia cells. Mechanistic investigations revealed that melatonin suppressed the expression of hTERT by abrogating the binding activity of RBFOX3 to the hTERT promoter. Melatonin also blocked NF-κB nuclear translocation and suppressed NF-κB binding to the COX-2 promoter, thereby suppressing the expression of COX-2. In addition, clinical samples revealed that melatonin exerts anti-leukemic activity in primary MLL-r leukemia blasts ex vivo. In vivo, the mice treated with melatonin experienced a larger reduction in leukemic burden than the control group in a MLL-r leukemia xenograft mouse model. Collectively, these results suggest that melatonin inhibits MLL-rearranged leukemia through suppressing the RBFOX3/hTERT and NF-κB/COX-2 signaling pathways. Our findings provide new insights into the role of melatonin for MLL-r leukemia treatment.

The comparison of outcome and cost of three protocols for childhood non-high risk acute lymphoblastic leukemia in China.

OBJECTIVE: To compare the outcome and treatment cost of three protocols for childhood non-high risk acute lymphoblastic leukemia (ALL), and evaluate the feasibility of less intensive treatment protocol for low income families. METHODS: Two hundred forty-three children were newly diagnosed ALL in a university hospital from May 1999 to August 2006. Three protocols were offered to the patients: China-98 protocol, or modified ALLIC BFM2002 protocol, or an in-house Reduced Intensity Protocol (or also known as Economic Protocol). RESULTS: Among 243 patients, 19 abandoned treatment, 3 transferred to other hospitals, 48 were high-risk and were treated with the high risk protocol, and 4 had mature B-ALL. A total of 169 cases were enrolled on non-high risk protocols: 46 treated on China-98 protocol, 73 on modified ALLIC BFM2002 and 50 from low income families on Economic Protocol. The event-free survival (EFS) at 4 years was 80.4% (95%CI, 68.8-92.2%), 83.5% (95%CI, 73.5-93.5%), and 72.8% (95%CI, 59.3-86.3%) for China-98 protocol, modified ALLIC BFM2002, and Economic Protocol respectively. The hospitalization costs (range and median) were significantly different between protocols: US$ 8,700-25,500 (12,500), US$ 6,900-16,400 (9,900), US$ 3,100-6,800 (4,300) for China-98 protocol, modified ALLIC BFM2002, and Economic Protocol respectively. CONCLUSION: This report from China has systematically reviewed the outcome and costs of protocols for ALL having different dose intensity. The reduced intensity protocol appears to achieve reasonable EFS (72.8% at 4 years) for non-high risk ALL at a much lower cost. This is especially important for low income families in developing countries.

High-dose chemotherapy without stem cell transplantation for refractory childhood systemic lupus erythematosus.

BACKGROUND: Intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is effective for refractory systemic lupus erythematosus (SLE). When intensive chemotherapy is immunoablative but nonmyeloablative, ASCT for hematopoietic reconstitution, with the risk of reinfusing autoreactive lymphocytes, is unnecessary. METHODS: Four children aged 12-16 years were enrolled, 3 with WHO class IV nephritis, 2 with hemolytic anemia and 1 with thrombocytopenia. Median disease duration prior to the study was 4 years (range 1-6). Previous therapy, including intravenous bolus cyclophosphamide (Cy) with a median accumulated dose of 6.5 g/m(2) and high-dose methylprednisolone with a median accumulated dose of 370 mg/kg, had failed. The protocol included: Cy 1.2 g/m(2) daily for 4 days, fludarabine 30 mg/m(2) daily for 4 days, porcine antilymphocyte globulin 25 mg/kg daily for 3 days. RESULTS: Themedian duration of absolute neutrophil count <0.5 x 10(9)/l was 5.5 days after treatment. The median SLE Disease Activity Index and urine protein decreased from 8.5 and 3.4 to 1.0 and 0.1 g/day at the date of last follow-up (median 20 months), respectively. Two cases with hemolytic anemia and 1 with thrombocytopenia before treatment recovered to normal or near normal hemogram, respectively. All patients achieved complete or partial remission within 10-28 months of follow-up. CONCLUSION: Intensive chemotherapy leads to rapid hematopoietic reconstitution without ASCT and appears beneficial in refractory childhood SLE. Further study is needed.

MiR-124 contributes to glucocorticoid resistance in acute lymphoblastic leukemia by promoting proliferation, inhibiting apoptosis and targeting the glucocorticoid receptor.

Acute lymphoblastic leukemia (ALL) is characterized by the accumulation of abnormal lymphoblasts in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, some children with ALL still relapsed. Glucocorticoid (GC) resistance is an important clinical problem for ALL treatment failure. Therefore, further understanding of the mechanism of GC resistance and exploring novel therapeutic strategies are crucial for improving treatment outcome. The reported involvement of microRNAs (miRNAs) in drug resistance implied that deregulated miRNA expression might contribute to GC treatment response of ALL. However, individual miRNAs and their functional mechanisms potentially involved in the GC response are still largely unknown. In the present study, we found that miR-124 was up-regulated in prednisone insensitive human ALL cell line and prednisone-poor response ALL patients. Furthermore, it was found that miR-124 might contribute to GC resistance by promoting proliferation and inhibiting apoptosis of ALL cells. Importantly, we validated that miR-124, targeted and decreased the expression of glucocorticoid receptor (NR3C1), prevented the inhibitory effect of GC in ALL. These findings strongly suggest that miR-124 is critical in poor GC response and may serve as a potential therapeutic target in ALL with poor GC resistance.

Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways.

FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.

Butein inhibits cell proliferation and induces cell cycle arrest in acute lymphoblastic leukemia via FOXO3a/p27kip1 pathway.

Acute lymphoblastic leukemia (ALL) is a common hematological malignancy characterized by the uncontrolled proliferation of leukemia cells in children. Discovering and developing effective chemotherapeutic drugs are needed for ALL. In this study, we investigated the anti-leukemic activity of butein and its action mechanisms in ALL. Butein was found to significantly suppress the cellular proliferation of ALL cell lines and primary ALL blasts in a dose-dependent manner. It also induced cell cycle arrest by decreasing the expression of cyclin E and CDK2. We also found that butein promoted nuclear Forkhead Class box O3a (FOXO3a) localization, enhanced the binding of FOXO3a on the p27kip1 gene promoter and then increased the expression of p27kip1. Moreover, we showed that FOXO3a knockdown significantly decreased the proliferation inhibition by butein, whereas overexpression of FOXO3a enhanced the butein-mediated proliferation inhibition. However, overexpression of FOXO3a mutation (C-terminally truncated FOXO3a DNA-binding domain) decreased the proliferation inhibition by butein through decreasing the expression of p27kip1. Our results therefore demonstrate the therapeutic potential of butein for ALL via FOXO3a/p27kip1 pathway.

Effect of early nutrition on intestine development of intrauterine growth retardation in rats and its correlation to leptin.

AIM: To investigate the intestine and body development of intrauterine growth retardation (IUGR) rats under early different protein diet and to analyze the correlation between leptin and intestine and body development. METHODS: An IUGR rat model was established by food restriction of pregnant female rats. Fifty-six neonatal IUGR rats and 24 neonatal normal rats were randomly divided into normal control group (C group), IUGR model group (SC group), low protein diet IUGR group (SL group), and high protein diet IUGR group (SH group). Eight rats were killed per group at wk 0, 4, and 12. Serum leptin, body weight (BW), body length (BL), intestinal weight (IW), intestinal length (IL), and intestinal disaccharidase (including lactase, maltase, and saccharase) were detected. RESULTS: BW (4.50+/-0.41 g), BL (5.96+/-0.40 cm), IW (0.05+/-0.01 g), and IL (15.9+/-2.8 cm) in neonatal IUGR rats were much lower than those in C group (6.01+/-0.55 g, 6.26+/-0.44 cm, 0.10+/-0.02 g, 21.8+/-2.7 cm, P<0.05), while intestinal lactase and maltase activities were higher than those in C group. SH group showed the fastest catch up growth and their BW, BL, IW, and IL reached the C group level at wk 4. SC group showed relatively slower catch up growth than SH group, and their BW, BL, IW did not reach the C group level at wk 4. SL group did not show intestine and body catch up growth. Intestinal maltase (344+/-33 micromol/(min.g)) and saccharase activities (138+/-32 micromol/(min.g)) in SL group were both markedly lower than those in C group (751+/-102, 258+/-27 micromol/(min.g), P<0.05). There were no significant differences in lactase activities at wk 4 and disaccharidase activities at wk 12 among all groups (P>0.05). The leptin level in SL group (0.58+/-0.12 ng/mL) was the highest in all groups, and much lower in SH group (0.21+/-0.03 ng/mL) than that in any other IUGR groups at wk 4 (P<0.05). Leptin was negatively related to BW (r = -0.556, P = 0.001), IW (r = -0.692, P = 0.001) and IL (r = -0.738, P = 0.000) at wk 4, while no correlation was found at wk 12. CONCLUSION: High protein diet is a reasonable early nutritional mode to IUGR rats in promoting intestine and body catch up growth.

[Adenovirus-mediated CDglyTK fusion gene system driven by KDR promoter selectively kills colorectal cancer cells].

OBJECTIVE: To observe the selective killing effect of adenovirus (Ad)-mediated double suicide gene driven by kinase domain-containing receptor(KDR) promoter on human colorectal cancer LoVo cells and human umbilical vein endothelial ECV304 cells. METHODS: The plasmid pAdEasy-KDR-CDglyTK was transfected into 293 packaging cells for amplification of the infectious Ad and used to infect the KDR-producing cells (ECV304 and LoVo) and the KDR-nonproducing cells (LS174T) respectively. The three cells were treated with the prodrugs 5-flurocytosine (5-FC) and ganciclovir (GCV) at different concentrations after infection. The killing effects of the fusion gene system on the cells were evaluated. The distribution of cell cycle was detected by flow cytometry. RESULTS: The infection rates of the recombinant Ad were similar among the 3 cells, gradually increasing with the increment of multiplicity of infection (MOI) and reaching 100% with the MOI of 200. The LoVo cells and ECV304 cells infected with Ad-KDR-CDglyTK were highly sensitive to both of the prodrugs (P>0.1), whereas the infected LS174T cells failed to exhibit similar sensitivity (P<0.001). The killing effect of CD/TK fusion gene on the target cells was much stronger than that of either suicide gene (P<0.001). The cell cycle of LoVo cells was arrested at G1 phase. CONCLUSION: The CD/TK fusion gene system driven by KDR promoter can selectively kill KDR-expressing human colorectal cancer LoVo cells and endothelial cells.

Flavokawain B inhibits the growth of acute lymphoblastic leukemia cells via p53 and caspase-dependent mechanisms.

The development of novel chemotherapeutic drugs is needed for the treatment of patients with acute lymphoblastic leukemia (ALL). In this study, the anti-leukemic effect and the potential molecular mechanisms of action of flavokawain B on ALL were investigated. Flavokawain B was found to significantly inhibit the cellular proliferation of B-ALL and T-ALL cell lines in a dose-dependent manner. It also induced cellular apoptosis by increasing the expression of p53, Bax and Puma, and activating the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP). Furthermore, the enhancement of p53-dependent apoptosis by flavokawain B could be rescued by pifithrin-α, a pharmacological inhibitor of p53 transcriptional activity. Moreover, the proliferation of leukemia blast cells from 16 patients with ALL was inhibited by flavokawain B, and tumor growth in xenograft mice was also suppressed by this drug. In conclusion, our results demonstrate the therapeutic potential of flavokawain B for the treatment of ALL.

Effects of early nutrition intervention on IGF1, IGFBP3, intestinal development, and catch-up growth of intrauterine growth retardation rats.

OBJECTIVE: To investigate the effects of early nutritional intervention on the serum insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), intestinal development, and catch-up growth of intrauterine growth retardation (IUGR) rats by giving the IUGR new born rats different protein level diet. METHODS: IUGR rat model was built by starvation of pregnant female rats. Twenty-four IUGR pups and 8 normal pups were divided randomly into 4 groups: normal control group (C group); IUGR control group (S group), IUGR low-protein diet group (SL group), and IUGR high-protein diet group (SH group). Detected the serum IGF1, IGFBP3, body weight, body length, intestinal weight length, intestinal villi height (VH), crypt depth (CD), villi absorbing area (VSA), mucous thickness (MT), and disaccharidase at the 4th week. RESULTS: (1) The SH group showed the fastest catch-up growth, serum IGF1, IGFBP3, VH, and VSA were significantly higher than those of normal control group and IUGR control group. The intestinal weight and length, and the activities of lactase and saccharase of the SH group also reached the normal control group level. (2) The SL group kept on small size, the serum IGF1, IGFBP3, and most of intestinal histological indexes were all significantly lower than other groups. (3) IGF1, IGFBP3 were positively correlated to intestinal VH, VSA, saccharase, body weight and length. CONCLUSIONS: The serum IGF1 was a sensitive index to the catch-up growth. The early nutritional intervention of high-protein diet after birth is helpful for the catch-up growth of IUGR through promoting the intestinal development and the absorption of nutrition.