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P P Liu

Publications and source records attributed to P P Liu.

At least 19 recordsLinked to original sources
PubMed2004

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia.

Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.

Acute Disease↗
PubMed2001

Molecular cloning, genetic mapping, and expression analysis of four zebrafish c/ebp genes.

The CCAAT/enhancer binding protein family (C/EBP) are transcription factors that play integral roles in the development and function of many organ systems, including hematopoietic cells, adipose tissues, and liver. We have identified and characterized putative zebrafish orthologs of mammalian C/EBP alpha, beta, gamma, and delta using low-stringency hybridization screening and computer searches of the GenBank EST database. c/ebpa and g were mapped within 1 cM of each other on linkage group (LG) 7, syntenic with human CEBPA and G genes on chromosome 19. c/ebpb was mapped to LG8, and c/ebpd was mapped to LG24, on the same LG as a recently identified unique c/ebp in zebrafish, c/ebp1. The mapping of these genes established new syntenic relationships between LG8 and human chromosome 20, extended existing synteny between LG7 and human chromosome 19, and confirmed the synteny between LG24 and human chromosome 8. In addition, these syntenies between zebrafish and human chromosomes are also conserved in the mouse genome. To characterize the expression of these genes, RNA in situ hybridization in embryos of wild type and a hematopoietic mutant, cloche, was performed. The results showed that zebrafish c/ebpa, b, g, and d were expressed in many embryonic tissues. c/ebpa and b were expressed in a subset of hematopoietic cells in a region consistent with myeloid expression. In addition, there was expression of c/ebpa and b in the liver and c/ebpa, b, and d in regions of the gastrointestinal tract. The expression of the c/ebps may serve as important markers for analysis of myelopoiesis, hepatic development, and other developmental processes in the future.

Amino Acid Sequence↗
PubMed2001

A novel myeloid-restricted zebrafish CCAAT/enhancer-binding protein with a potent transcriptional activation domain.

The CCAAT/enhancer-binding protein (C/EBP) family consists of transcription factors essential for hematopoiesis. The defining feature of the C/EBPs is a highly conserved carboxy-terminal bZIP domain that is necessary and sufficient for dimerization and DNA binding, whereas their amino-terminal domains are unique. This study reports a novel c/ebp gene (c/ebp1) from zebrafish that encodes a protein homologous to mammalian C/EBPs within the bZIP domain, but with an amino terminus lacking homology to any C/EBP or to any known sequence. In zebrafish embryos, c/ebp1 expression was initially observed in cells within the yolk sac circulation valley at approximately the 16-to 18-somite stage, and at 24 hours postfertilization (hpf), also in circulating cells. Most c/ebp1(+) cells also expressed a known early macrophage marker, leukocyte-specific plastin (l-plastin). Expression of both markers was lost in cloche, a mutant affecting hematopoiesis at the level of the hemangioblast. Expression of both markers was retained in m683 and spadetail, mutants affecting erythropoiesis, but not myelopoiesis. Further, c/ebp1 expression was lost in a mutant with defective myelopoiesis, but intact erythropoiesis. These data suggest that c/ebp1 is expressed exclusively in myeloid cells. In electrophoretic mobility shift assays, c/ebp1 was able to bind a C/EBP consensus DNA site. Further, a chimeric protein containing the amino-terminal domain of c/ebp1 fused to the DNA-binding domain of GAL4 induced a GAL4 reporter 4000-fold in NIH3T3 cells. These results suggest that c/ebp1 is a novel member of the C/EBP family that may function as a potent transcriptional activator in myeloid cells.

Amino Acid Sequence↗
PubMed2001

Core-binding factor beta (CBFbeta), but not CBFbeta-smooth muscle myosin heavy chain, rescues definitive hematopoiesis in CBFbeta-deficient embryonic stem cells.

Core-binding factor beta (CBFbeta) is the non-DNA-binding subunit of the heterodimeric CBFs. Genes encoding CBFbeta (CBFB), and one of the DNA-binding CBFalpha subunits, Runx1 (also known as CBFalpha2, AML1, and PEBP2alphaB), are required for normal hematopoiesis and are also frequent targets of chromosomal translocations in acute leukemias in humans. Homozygous disruption of either the Runx1 or Cbfb gene in mice results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system, and severely impairs fetal liver hematopoiesis. Results of this study show that Cbfb-deficient mouse embryonic stem (ES) cells can differentiate into primitive erythroid colonies in vitro, but are impaired in their ability to produce definitive erythroid and myeloid colonies, mimicking the in vivo defect. Definitive hematopoiesis is restored by ectopic expression of full-length Cbfb transgenes, as well as by a transgene encoding only the heterodimerization domain of CBFbeta. In contrast, the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein generated by the inv(16) associated with acute myeloid leukemias (M4Eo) cannot rescue definitive hematopoiesis by Cbfb-deficient ES cells. Sequences responsible for the inability of CBFbeta-SMMHC to rescue definitive hematopoiesis reside in the SMMHC portion of the fusion protein. Results also show that the CBFbeta-SMMHC fusion protein transdominantly inhibits definitive hematopoiesis, but not to the same extent as homozygous loss of Runx1 or Cbfb. CBFbeta-SMMHC preferentially inhibits the differentiation of myeloid lineage cells, while increasing the number of blastlike cells in culture.

Animals↗
PubMed2001

Blood pressure cuff compression injury of the radial nerve.

We describe a 19-year-old man who underwent emergency laparotomy for perforated peptic ulcer. He was otherwise healthy before this admission with no history of diabetes mellitus or neuropathy. A standard-size adult blood pressure cuff connected to a Dinamap monitor, set to cycle automatically every 3 minutes was affixed to his left upper extremity during surgery. One day after the operation he complained of numbness over the dorsum of the left hand and wrist drop. Physical examination revealed 0/5 muscle power of the left wrist and finger extensor muscles with reduced sensation on the radial aspect of the dorsum of the same hand. A diagnosis of acute radial nerve injury was made and rehabilitation was started. The wrist numbness and sensation improved with physical therapy, and he was discharged 9 days after the operation with an active wrist splint. He continued with rehabilitation on an out-patient basis. The muscle power of the wrist extensors gradually improved after three months of physical therapy and reverted to completely normal one month later. Locating the cuff higher on the arm, away from the elbow joint, to avoid the most superficial portion of radial nerve, may prevent this type of compression injury especially in asthenic patients.

Adult↗
PubMed2001

Function of the inv(16) fusion gene CBFB-MYH11.

Inv(16)(p13q22) is associated with acute myeloid leukemia subtype M4Eo, which is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This chromosomal rearrangement results in the fusion of CBFB and MYH11 genes. Mouse models indicate that the fusion gene, Cbfb-MYH11, inhibits differentiation of hematopoietic cells. Although expression of Cbfb-MYH11 is not sufficient for leukemogenesis, a combination of Cbfb-MYH11 and additional mutations can lead specifically to the development of myeloid leukemia. Normally, CBFbeta interacts with CBFalpha to form a transcriptionally active nuclear complex. In vitro studies indicate that expression of CBFB-MYH11 leads to sequestration of CBFalpha2 in the cytoplasm. It also has been shown to inhibit CBF-mediated transactivation, slow cell cycle progression, delay the apoptotic response to DNA damaging agents, and protect CBFalpha2 from degradation. The importance of these functions in vivo remains to be determined.

Animals↗
PubMed2001

Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.

STUDY OBJECTIVES: To determine the effects of hyperoxia on left ventricular (LV) function in humans with and without congestive heart failure (CHF). DESIGN: An acute physiologic study of the effect of hyperoxia on right-heart hemodynamics, LV contractility (peak positive rate of rise of LV pressure [+dP/dt]), time constant of isovolumic left ventricular relaxation (tau), and LV filling pressures. SETTING: Bayer Cardiovascular Clinical Research Laboratory at the Mount Sinai Hospital, Toronto, Ontario. PATIENTS: Sixteen patients with stable CHF and 12 subjects with normal LV function received the hyperoxia intervention. INTERVENTIONS: Patients received 21% O(2) by a nonrebreather mask, followed by 100% O(2) for 20 min, and 21% O(2) for a 10-min recovery period. RESULTS: In response to hyperoxia, there was a 22 +/- 6% increase in LV end-diastolic pressure (LVEDP) in the CHF group and a similar 29 +/- 14% increase in LVEDP in the normal LV function group (p < 0.05 for both; mean +/- SEM). Hyperoxia was also associated with a prolongation in tau of 10 +/- 2% in the CHF group (p < 0.05) and 8 +/- 2% in the normal LV function group (p < 0.05). No changes in +dP/dt were observed in either group. CONCLUSIONS: Hyperoxia was associated with impairment of cardiac relaxation and increased LV filling pressures in patients with and without CHF. These observations indicate that caution should be used in the administration of high inspired O(2) fractions to normoxic patients, especially in the setting of CHF.

Cardiac Catheterization↗
PubMed2001

The role of continuous positive airway pressure in the treatment of congestive heart failure.

Congestive heart failure (CHF) is a serious medical condition frequently associated with sleep-related breathing disorders, which remain underdiagnosed and undertreated. Recent studies have provided important insight into the pathophysiology of sleep apnea syndrome in patients with CHF, with potential therapeutic implications. In addition to abolition of sleep apnea, continuous positive airway pressure (CPAP) treatment can improve cardiac function and relieve symptoms of CHF. Postulated mechanisms include beneficial hemodynamic effects on ventricular remodeling, unloading of fatigued respiratory muscles, and neurohormonal modulation. Although medium-term studies using CPAP to treat sleep-related breathing disorders associated with CHF have been encouraging, more definitive data from ongoing large clinical trials are necessary to clarify its therapeutic role.

Heart Failure↗
PubMed2001

Left ventricular performance during prolonged exercise: absence of systolic dysfunction.

We assessed left ventricular systolic and diastolic performance during and after prolonged exercise under controlled conditions in a group of healthy, trained men. Previous studies have examined the effects of prolonged effort on left ventricular function, yet it remains unclear whether or not left ventricular dysfunction (e.g. cardiac fatigue) can be produced under such conditions. We studied 15 healthy men, aged 27+/-1 years (mean+/-S.E.M.). Subjects exercised on bicycles at a constant work rate (60% of maximum oxygen uptake per min) for 150 min. Measurements of gas exchange, blood pressure and haematocrit were obtained, concurrent with the assessment of left ventricular function using equilibrium radionuclide angiography, at rest, during exercise (every 30 min) and after 30 min of recovery. Fluid replacement was provided and monitored during the exercise period. The baseline resting and exercise ejection fractions were 66+/-2% and 78+/-2% respectively. During exercise, subjects consumed 1816+/-136 ml of fluid, and the haematocrit had increased at 120 min of exercise (from 47.2%+/-0.6 to 49.9+/-0.8%; P<0.05). There was no change in either systolic or diastolic blood pressure throughout the exercise period, but heart rate drifted upwards from 141+/-2 beats/min after 30 min to 154+/-3 beats/min after 150 min (P<0.05). There was a small decline (8%; P<0.05) in end-diastolic volume at 150 min. No changes were observed in left ventricular ejection fraction, the pressure/volume ratio or end-systolic volume. After 30 min of sitting in recovery, heart rate was still higher than the pre-exercise value (84+/-3 compared with 69+/-2 beats/min; P<0.05), as were measures of peak filling rate and time to peak filling (P<0.05). The ejection fraction in the post-exercise recovery period was similar to the pre-exercise value. The results indicate that prolonged exercise of moderate duration may not induce abnormal left ventricular systolic function or cardiac fatigue during exercise.

Adult↗
PubMed2000

Zebrafish homolog of the leukemia gene CBFB: its expression during embryogenesis and its relationship to scl and gata-1 in hematopoiesis.

Mammalian CBFB encodes a transcription factor (CBF beta) that in combination with CBF alpha 2 binds to specific DNA sequences and regulates expression of a number of hematopoietic genes. CBFB is associated with human leukemias through a chromosome 16 inversion and is essential for definitive hematopoiesis during mouse embryo development. We have isolated a zebrafish cbfb complementary DNA (cDNA) clone from a zebrafish kidney cDNA library. This cbfb is highly homologous to human and mouse CBFB/Cbfb genes at both the DNA and protein level. In biochemical analyses, cbfbeta binds to human CBF alpha 2 and enhances its DNA binding. During zebrafish development, cbfb is expressed in the lateral plate mesoderm at tail bud stage and in the intermediate cell mass (ICM, the location of embryonic hematopoiesis) between the 21- to 26-somite stages. The cbfb is also expressed in Rohon-Beard cells, cranial nerve ganglia, hindbrain, retina, branchial arches, jaw, and fin buds. Expression of cbfb is decreased or absent in the ICM and Rohon-Beard cells in some hematopoietic mutants and is unaffected in others. We have also analyzed the expression of scl and gata-1 in the same hematopoietic mutants to ascertain the relative order of these transcription factors to cbfb in zebrafish hematopoiesis. Our results indicate that cbfb is expressed in early hematopoietic progenitors and that its expression pattern in the hematopoietic mutants is similar to that of scl. (Blood. 2000;96:4178-4184)

Amino Acid Sequence↗
PubMed2000

Effects of estrogen replacement on infarct size, cardiac remodeling, and the endothelin system after myocardial infarction in ovariectomized rats.

BACKGROUND: Estrogen may increase the long-term survival of women who have suffered from a myocardial infarction (MI). We examined the acute and chronic influence of estrogen on MI in the rat left coronary artery ligation model. METHODS AND RESULTS: Female Sprague-Dawley rats (10 to 12 weeks, n=93), divided into 3 groups (rats with intact ovaries, ovariectomized rats administered 17beta-estradiol [17beta-E(2)] replacement, and ovariectomized rats administered placebo 2 weeks before MI), were randomized to left coronary artery ligation (n=66) or sham-operated (n=27) groups. Ten to 11 weeks after MI, rats were randomly assigned to either (1) assessment of left ventricular (LV) function and morphometric analysis or (2) measurement of cardiopulmonary mRNA expression of preproendothelin-1 and endothelin A and B receptors. Acutely, estrogen was associated with a trend toward increased mortality. Infarct size was increased in the 17beta-E(2) group compared with the placebo group (42+/-2% versus 26+/-3%, respectively; P:=0.01). Chronically, wall tension was normalized through a reduction in LV cavity size with estrogen treatment (419+/-41 mm Hg/mm for 17beta-E(2) versus 946+/-300 mm Hg/mm for placebo, P:=0.039). In the LV, there was a 2.5-fold increase in endothelin B mRNA expression after MI in placebo-treated rats (P:=0.004 versus sham-operated rats) that was prevented in the 17beta-E(2) group (P:=NS versus sham-operated rats). CONCLUSIONS: These results suggest that estrogen is detrimental at the time of MI or early post-MI period, resulting in an increased size of infarct or infarct expansion, but chronically, it can normalize wall tension and inhibit LV dilatation, which may in turn lead to increased long-term survival. Regulation of the endothelin system, particularly the expression of the endothelin B receptor, may contribute to these estrogenic effects.

Animals↗
PubMed2000

Pulmonary valve replacement in adults late after repair of tetralogy of fallot: are we operating too late?

OBJECTIVES: The purpose of this study is to evaluate right ventricular (RV) volume and function after pulmonary valve replacement (PVR) and to address the issue of optimal surgical timing in these patients. BACKGROUND: Chronic pulmonary regurgitation (PR) following repair of tetralogy of Fallot (TOF) leads to RV dilation and an increased incidence of sudden cardiac death in adult patients. METHODS: We studied 25 consecutive adult patients who underwent PVR for significant PR late after repair of TOF. Radionuclide angiography was performed in all at a mean of 8.2 months (+/- 8 months) before PVR and repeated at a mean of 28.0 months (+/- 22.8 months) after the operation. Right ventricular (RV) end-systolic volume (RVESV), RV end-diastolic volume (RVEDV) and RV ejection fraction (RVEF) were measured. RESULTS: Mean RVEDV, RVESV and RVEF remained unchanged after PVR (227.1 ml versus 214.9 ml, p = 0.74; 157.4 ml versus 155.4 ml, p = 0.94; 35.6% versus 34.7%, p = 0.78, respectively). Of the 10 patients with RVEF > or = 0.40 before PVR, 5 patients (50%) maintained a RVEF > or = 0.40 following PVR, whereas only 2 out of 15 patients (13%) with pre-operative values <0.40 reached an RVEF > or = 0.40 postoperatively (p < 0.001). CONCLUSIONS: Right ventricular recovery following PVR for chronic significant pulmonary regurgitation after repair of TOF may be compromised in the adult population. In order to maintain adequate RV contractility, pulmonary valve implant in these patients should be considered before RV function deteriorates.

Adolescent↗
PubMed2000

Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration.

BACKGROUND: Continuous positive airway pressure (CPAP) improves cardiac function in patients with congestive heart failure (CHF) who also have Cheyne-Stokes respiration and central sleep apnea (CSR-CSA). However, the effects of CPAP in CHF patients without CSR-CSA have not been tested, and the long-term effects of this treatment on clinical cardiovascular outcomes are unknown. METHODS AND RESULTS: We conducted a randomized, controlled trial in which 66 patients with CHF (29 with and 37 without CSR-CSA) were randomized to either a group that received CPAP nightly or to a control group. Change in left ventricular ejection fraction (LVEF) from baseline to 3 months and the combined mortality-cardiac transplantation rate over the median 2.2-year follow-up period were compared between the CPAP-treated and control groups. For the entire group of patients, CPAP had no significant effect on LVEF, but it was associated with a 60% relative risk reduction (95% confidence interval, 2% to 64%) in mortality-cardiac transplantation rate in patients who complied with CPAP therapy. Stratified analysis of patients with and without CSR-CSA revealed that those with CSR-CSA experienced both a significant improvement in LVEF at 3 months and a relative risk reduction of 81% (95% confidence interval, 26% to 95%) in the mortality-cardiac transplantation rate of those who used CPAP. CPAP had no significant effect on either of these outcomes in patients without CSR-CSA. CONCLUSIONS: CPAP improves cardiac function in CHF patients with CSR-CSA but not in those without it. Although not definitive, our findings also suggest that CPAP can reduce the combined mortality-cardiac transplantation rate in those CHF patients with CSR-CSA who comply with therapy.

Aged↗
PubMed2000

The coxsackie-adenovirus receptor (CAR) is used by reference strains and clinical isolates representing all six serotypes of coxsackievirus group B and by swine vesicular disease virus.

Group B coxsackieviruses are etiologically linked to many human diseases, and cell surface receptors are postulated to play an important role in mediating their pathogenesis. The coxsackievirus adenovirus receptor (CAR) has been shown to function as a receptor for selected strains of coxsackievirus group B (CVB) serotypes 3, 4, and 5 and is postulated to serve as a receptor for all six serotypes. In this study, we demonstrate that CAR can serve as a receptor for laboratory reference strains and clinical isolates of all six CVB serotypes. Infection of CHO cells expressing human CAR results in a 1000-fold increase in CVB progeny virus titer compared to mock transfected cells. CAR was shown to be a functional receptor for swine vesicular disease virus (SVDV), as CHO-CAR cells but not CHO mock transfected controls were susceptible to SVDV infection, produced progeny SVDV, and developed cytopathic effects. Moreover, SVDV infection could be specifically blocked by monoclonal antibody to CAR (RmcB). SVDV infection of HeLa cells was also inhibited by an anti-CD55 MAb, suggesting that this virus, like some CVB, may interact with CD55 (decay accelerating factor) in addition to CAR. Finally, pretreatment of CVB or SVDV with soluble CAR effectively blocks virus infection of HeLa cell monolayers.

Animals↗
PubMed2000

Function of CBFbeta/Bro proteins.

Mammalian core binding factor beta (CBFbeta) and Drosophila Brother (Bro) and Big-brother (Bgb) proteins are transcription factors that dimerize with mammalian Runx and Drosophila Runt and Lozenge proteins and augment their DNA binding affinity and transcriptional potency. CBFbeta is essential for development and sustenance of definitive hematopoiesis during mouse embryogenesis. Bro and Bgb are required for Runt/Lozenge functions in Drosophila development. CBFbeta contributes to leukemogenesis since the CBFB gene is specifically and consistently mutated by a chromosome 16 inversion found in patients with acute myeloid leukemia subtype M4Eo. The ubiquitous expression pattern of the CBFB gene suggests that it may play important roles in many other organ systems.

Amino Acid Sequence↗