Association of consumption of sugar-sweetened beverages with elevated blood pressure among college students in Yunnan Province, China.

OBJECTIVE: Although some studies have examined the association between eating behaviour and elevated blood pressure (EBP) in adolescents, current data on the association between sugar-sweetened beverages (SSB) and EBP in adolescents in Yunnan Province, China, are lacking. SETTING: Cluster sampling was used to survey freshmen at a college in Kunming, Yunnan Province, from November to December. Data on SSB consumption were collected using an FFQ measuring height, weight and blood pressure. A logistic regression model was used to analyse the association between SSB consumption and EBP, encompassing prehypertension and hypertension with sex-specific analyses. PARTICIPANTS: The analysis included 4781 college students. RESULTS: Elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) were detected in 35·10 % (1678/4781) and 39·34 % (1881/4781) of patients, respectively. After adjusting for confounding variables, tea beverage consumption was associated with elevated SBP (OR = 1·24, 95 % CI: 1·03, 1·49, P = 0·024), and carbonated beverage (OR = 1·23, 95 % CI: 1·04, 1·45, P = 0·019) and milk beverage (OR = 0·81, 95 % CI: 0·69, 0·95, P = 0·010) consumption was associated with elevated DBP in college students. Moreover, fruit beverage (OR = 1·32, 95 % CI: 1·00, 1·75, P = 0·048) and milk beverage consumption (OR = 0·69, 95 % CI: 0·52, 0·93, P = 0·014) was associated with elevated DBP in males. CONCLUSION: Our findings indicated that fruit and milk beverage consumption was associated with elevated DBP in males, and no association was observed with EBP in females.

Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice.

Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a-mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.

RBM33 is a unique m6A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity.

Regulation of RNA substrate selectivity of m6A demethylase ALKBH5 remains elusive. Here, we identify RNA-binding motif protein 33 (RBM33) as a previously unrecognized m6A-binding protein that plays a critical role in ALKBH5-mediated mRNA m6A demethylation of a subset of mRNA transcripts by forming a complex with ALKBH5. RBM33 recruits ALKBH5 to its m6A-marked substrate and activates ALKBH5 demethylase activity through the removal of its SUMOylation. We further demonstrate that RBM33 is critical for the tumorigenesis of head-neck squamous cell carcinoma (HNSCC). RBM33 promotes autophagy by recruiting ALKBH5 to demethylate and stabilize DDIT4 mRNA, which is responsible for the oncogenic function of RBM33 in HNSCC cells. Altogether, our study uncovers the mechanism of selectively demethylate m6A methylation of a subset of transcripts during tumorigenesis that may explain demethylation selectivity in other cellular processes, and we showed its importance in the maintenance of tumorigenesis of HNSCC.

Orthostatic hypotension following posterior spinal fusion surgeries for spinal deformity correction in adolescents: prevalence and risk factors.

STUDY DESIGN: Retrospective case series. OBJECTIVES: This study aimed to determine the prevalence and risk factors for orthostatic hypotension (OH) in adolescents undergoing posterior spinal fusion for spinal deformity correction. METHODS: The data of 282 consecutive adolescents who underwent posterior spinal fusion for spinal deformity correction in our center over 12 months were retrieved. Patient characteristics, including whether laminectomy or osteotomy was performed during the surgery, the occurrence of postoperative nausea and vomiting (PONV), perioperative hemoglobin albumin changes, perioperative blood transfusion, length of bed rest, willingness to ambulate, length of postoperative exercises of the lower limbs, and length of hospital stay, were collected and compared statistically between patients who did and did not develop postoperative OH. RESULTS: Of 282 patients, 197 (69.86%) developed OH postoperatively, and all cases completely resolved 5 days after the first out-of-bed exercises. Significant differences in the incidence of PONV, the willingness to ambulate and the length of postoperative exercises of the lower limbs were observed. The mean length of hospital stay of the patients with OH was longer than that of the patients without OH. CONCLUSION: Our study suggests that temporary OH is a common manifestation following posterior spinal fusion for spinal deformity correction in adolescents. Postoperative OH may increase the length of hospital stay in these patients. Patients with PONV, who are not willing to ambulate and who perform postoperative lower limb exercises for a shorter time are more likely to have OH.

A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication.

YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We found that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem and progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides compelling evidence that shows an oncogenic role and a distinct mechanism of YTHDC1 in AML.

Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.

Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.

Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.

This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/ß-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/ß-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc-heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc-mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.

FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.

FOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells. Here we show that Foxm1 is required for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in vivo. Mechanistically, Foxm1 upregulation activates the Wnt/ß-catenin signaling pathways by directly binding to ß-catenin and stabilizing ß-catenin protein through inhibiting its degradation, thereby preserving LSC quiescence, and promoting LSC self-renewal in MLL-rearranged AML. More importantly, inhibition of FOXM1 markedly suppresses leukemogenic potential and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in vivo in xenograft mice. Thus, our study shows a critical role and mechanisms of Foxm1 in MA9-LSCs, and indicates that FOXM1 is a potential therapeutic target for selectively eliminating LSCs in MLL-rearranged AML.

miR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3.

MicroRNAs (miRNAs) are emerging as critical regulators of normal and malignant hematopoiesis. In previous studies of acute myeloid leukemia miR-9 overexpression was commonly observed. Here, we show that ectopic expression of miR-9 in vitro and in vivo significantly blocks differentiation of erythroid progenitor cells with an increase in reactive oxygen species (ROS) production. Consistent with this observation, ROS scavenging enzymes, including superoxide dismutase (Sod2), Catalase (Cat), and glutathine peroxidase (Gpx1), are down-regulated by miR-9. In addition, miR-9 suppresses expression of the erythroid transcriptional regulator FoxO3, and its down-stream targets Btg1 and Cited 2 in erythroid progenitor cells, while expression of a constitutively active form of FoxO3 (FoxO3-3A) reverses miR-9-induced suppression of erythroid differentiation, and inhibits miR-9-induced ROS production. Thus, our findings indicate that aberrant expression of miR-9 blocks erythropoiesis by deregulating FoxO3-mediated pathways, which may contribute to the ineffective erythropoiesis observed in patients with hematological malignancies.

Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation.

BACKGROUND AND PURPOSE: The poor prognosis of acute megakaryoblastic leukaemia (AMKL) means there is a need to develop novel therapeutic methods to treat this condition. It was recently shown that inducing megakaryoblasts to undergo terminal differentiation is effective as a treatment for AMKL. This encouraged us to identify a compound that induces megakaryocyte differentiation, which could then act as a potent anti-leukaemia agent. EXPERIMENTAL APPROACH: The effects of tetrandrine on the expression of CD41 and cell morphology were investigated in AMKL cells. We used CRISPR/Cas9 knockout system to knock out ATG7 and verify the role of autophagy in tetrandrine-induced megakaryocyte differentiation. shNotch1 and CA-Akt were transfected into K562 cells to examine the downstream pathways of ROS signalling and the mechanistic basis of the tetrandrine-induced megakaryocyte differentiation. The anti-leukaemia effects of tetrandrine were analysed both in vitro and in vivo. KEY RESULTS: A low dose of tetrandrine induced cell cycle arrest and megakaryocyte differentiation in AMKL cells via activation of autophagy. Molecularly, we demonstrated that this effect is mediated by activation of Notch1 and Akt and subsequent accumulation of ROS. In contrast, in normal mouse fetal liver cells, although tetrandrine induced autophagy, it did not affect cell proliferation or promote megakaryocyte differentiation, suggesting a specific effect of tetrandrine in malignant megakaryoblasts. Finally, tetrandrine also showed in vivo efficacy in an AMKL xenograft mouse model. CONCLUSIONS AND IMPLICATIONS: Modulating autophagy-mediated differentiation may be a novel strategy for treating AMKL, and tetrandrine has the potential to be developed as a differentiation-inducing agent for AMKL chemotherapy.

Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L-induced signaling and myeloproliferative neoplasms.

BACKGROUND: Myeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. Abnormal mutations in stem cells were found accompanying with the occurrence of MPN. It has been shown that MPL mutations (MPL W515L or MPL W515K) were involved in patients with MPN. Since tyrosine residues 625 and 630 mediate normal MPL signaling, whether them affect MPL W515L-induced myeloproliferative neoplasms (MPNs) is unknown. RESULTS: In this study, we further tested their functions in MPL W515L-induced myeloproliferative neoplasms (MPNs) by substituting either or both of them with phenylalanine in MPL W515L (termed as MPL515/625, MPL515/630 and MPL515/625/630, respectively). In vitro, MPL515/630 but not MPL515/625 or MPL515/625/630 retained the ability to induce TPO-independent proliferation and increase colony-forming unit megakaryocytes (CFU-Mk). Accordingly, differential activation of the downstream signaling by four mutants was observed and constitutively active STAT5 or AKT instead of STAT3 partially compensated MPL515/625/630 function. Further support this, STAT5-deficiency impaired MPL W515L-induced CFU-Mk expansion. In vivo, MPL515/630 but not MPL515/625 or MPL515/625/630 induced typical features of MPNs with high WBC and platelet counts, splenomegaly, hepatomegaly and hypercellularity in the bone marrow. Surprisingly, MPL515/625 also caused hypercellularity of bone marrow and splenomegaly without any other significant features. We also observed differential effects of the four mutants on progenitors, myeloid cells and megakaryocytes. CONCLUSIONS: Our studies have revealed distinct features of tyrosine sites 625 and 630 in mediating MPL W515L-induced megakaryocyte hyperproliferation and MPNs. Our study also suggests that MPL cytosolic phosphorylated Y625 and flanking amino acids could become targets for pharmacologic inhibition in MPNs.

Baicalein antagonizes acute megakaryoblastic leukemia in vitro and in vivo by inducing cell cycle arrest.

BACKGROUND: The prognosis of acute megakaryoblastic leukemia (AMKL) is really dismal, which urges for development of novel treatment. Baicalein is one type of flavonoids extracted from Scutellaria baicalensis Georgi (Huang Qin). It inhibited cell proliferation and subcutaneous tumor formation of many tumor cell lines. However, whether baicalein possesses anti-AMKL activities has not been tested. RESULTS: We found that baicalein potently inhibited proliferation of multiple AMKL cells including CMK, CMY, Y10, 6133, and 6133 MPL/W515L due to apoptosis and cell cycle arrest at G1 phase. Unexpectedly, caspase inhibitor z-VAD-fmk did not restore cell proliferation. In contrast, ectopic expression of Cyclin D1 efficiently antagonized the inhibitory effect of baicalein. In addition, baicalein induced differentiation of 6133 MPL/W515L cells. Finally, baicalein promoted mice survival and reduced disease burden in a mouse model of AMKL. CONCLUSIONS: Baicalein possesses potent anti-AMKL activity in vitro and in vivo. Baicalein may be a potent reagent for AMKL therapy.

ZNF300 knockdown inhibits forced megakaryocytic differentiation by phorbol and erythrocytic differentiation by arabinofuranosyl cytidine in K562 cells.

Previously, we reported that ZNF300 might play a role in leukemogenesis. In this study, we further investigated the function of ZNF300 in K562 cells undergoing differentiation. We found that ZNF300 upregulation in K562 cells coincided with megakaryocytic differentiation induced by phorbol-12-myristate-13-acetate (PMA) or erythrocytic differentiation induced by cytosine arabinoside (Ara-C), respectively. To further test whether ZNF300 upregulation promoted differentiation, we knocked down ZNF300 and found that ZNF300 knockdown effectively abolished PMA-induced megakaryocytic differentiation, evidenced by decreased CD61 expression. Furthermore, Ara-C-induced erythrocytic differentiation was also suppressed in ZNF300 knockdown cells with decreased γ-globin expression and CD235a expression. These observations suggest that ZNF300 may be a critical factor controlling distinct aspects of K562 cells. Indeed, ZNF300 knockdown led to increased cell proliferation. Consistently, ZNF300 knockdown cells exhibited an increased percentage of cells at S phase accompanied by decreased percentage of cells at G0/G1 and G2/M phase. Increased cell proliferation was further supported by the increased expression of cell proliferation marker PCNA and the decreased expression of cell cycle regulator p15 and p27. In addition, MAPK/ERK signaling was significantly suppressed by ZNF300 knockdown. These findings suggest a potential mechanism by which ZNF300 knockdown may impair megakaryocytic and erythrocytic differentiation.

A retrospective evaluation of benign prostatic hyperplasia treatment by transurethral vaporization using a 1470 nm laser.

OBJECTIVE: This article aims to evaluate the safety and efficacy of a new diode laser at a wavelength of 1470 nm, in the surgical treatment of benign prostatic hyperplasia (BPH). BACKGROUND DATA: BPH is very common. Laser surgeries, such as photoselective vaporization of the prostate (PVP), have gained interest over the past decade because of their satisfying clinical results and reduced morbidity. METHODS: A total of 24 patients who underwent transurethral vaporization of the prostate with a new diode laser prototype at a wavelength of 1470 nm were included in this retrospective study. The baseline characteristics of patients and treatment outcomes were evaluated at 4 weeks after the operation with the International Prostate Symptoms Score (IPSS), duration of catheterization, and maximum urinary flow rate (Qmax). RESULTS: The mean age of patients was 69 ± 8.6 years. The mean time of operation and hospitalization were 97 ± 39 min and 5.3 ± 5.2 days, respectively. The mean duration of catheterization after surgery was 3.1 ± 2.7 days. No recatheterizations or secondary surgeries were required. IPSS and Qmax at 4 weeks postoperatively were significantly changed compared with the baseline (p<0.001). CONCLUSIONS: Transurethral vaporization of the prostate using a 1470 nm laser is effective to treat benign prostatic hyperplasia.

Factors influencing HIV infection in men who have sex with men in China.

To identify risk factors for HIV infection among men who have sex with men (MSM) and to provide a theoretical basis for prevention interventions. Between December 2011 and August 2012, a case-control study was conducted among MSM who underwent voluntary counselling and testing for HIV. Confirmed HIV-positive MSM were included in the case group, and HIV-negative MSM were included in the control group. Information on possible risk factors was collected by a survey questionnaire and a qualitative interview. The results of a conditional logistic regression showed that the following were influencing factors for HIV infection: average monthly income between 2001 and 3000 Yuan (odds ratio (OR)=6.341, 95% CI: 1.714-12.544), only sometimes using condoms when having anal sex with men in the last 6 months (OR=7.601, 95% CI: 1.359-23.083), having HIV-positive sex partners (OR=5.273, 95% CI: 1.572-17.691), rectal trauma with bleeding in the last 6 months (OR=2.947, 95% CI: 1.308-6.638), not using condoms at last sexual encounter (OR=1.278, 95% CI: 1.012-5.595), engaging in commercial sex (OR=5.925, 95% CI: 1.923-13.890) and having more than 16 sex partners in the last 6 months (OR=1.175, 95% CI: 1.021-1.353). These seven factors were the risk factors of HIV infection (OR>1). However, having anal sex less than 10 times in the previous 1 month (OR=0.002, 95% CI: 0.000-0.287) was a protective factor against HIV infection among MSM (OR<1), and insertive (OR=0.116, 95% CI: 0.000-0.236) (OR<1) anal intercourse influenced HIV infection. Interventions should be targeted at MSM whose average monthly income is between 2001 and 3000 Yuan, and who engage in commercial sex. In addition, the importance of using condoms at every sexual encounter should be emphasised in health education, as should the treatment of rectal trauma with bleeding. Finally, MSM should decrease the number of sex partners and frequency of anal sex to decrease the rate of HIV infection.

Complete genome sequence of the bacterium Ketogulonicigenium vulgare Y25.

Ketogulonicigenium vulgare is characterized by the efficient production of 2KGA from L-sorbose. Ketogulonicigenium vulgare Y25 is known as a 2-keto-L-gulonic acid-producing strain in the vitamin C industry. Here we report the finished, annotated genome sequence of Ketogulonicigenium vulgare Y25.