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Biomedical subjects

Anthony Chan

Publications and source records attributed to Anthony Chan.

17 recordsLinked to original sources
PubMed2026

Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia.

N7-methylguanosine (m7G), a prevalent modification in transfer RNAs (tRNAs), is primarily catalyzed by the methyltransferase METTL1. Although growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby promoting leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as hematopoietic cell kinase (HCK). Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterized a small-molecule METTL1 inhibitor (M1i; NSC137443), through high-throughput screening. Pharmacological inhibition of METTL1 demonstrated potent antitumor efficacy by reducing tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Together, our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for antileukemia therapy.

Humans↗
PubMed2006

Monitoring Unfractionated Heparin (UFH) therapy: which Anti-Factor Xa assay is appropriate?

INTRODUCTION: Anti-Factor Xa (Anti-Xa) assays specifically determine the anticoagulant activity of UFH by measuring the ability of heparin-bound Antithrombin (AT) to inhibit a single enzyme, Factor Xa (FXa). Recent improvements in the automation, cost-effectiveness and accessibility of the assay to clinicians, have resulted in the Anti-Xa assay becoming a part of daily clinical practice in many institutions. OBJECTIVES: We hypothesized that different Anti-Xa assays have different applicability for use in clinical settings, depending on the amount of UFH administered. This was investigated in a tertiary paediatric institution. MATERIALS AND METHODS: Samples were collected from children receiving Low-dose of UFH of at least 10 IU/kg/h, with or without a previous bolus of up to 25 IU/kg/h, within the previous 6 h in the PICU and HDU. High-dose UFH population consisted of children undergoing Cardiac Catheterization (CC), who received a bolus of UFH of 100 IU/kg body weight, 30 min prior to sampling. RESULTS AND CONCLUSIONS: The Anti-Xa activity for a given dose of UFH was found to vary significantly based on the Anti-Xa assay and the population being monitored. Our study suggests that the MODIFIED COMATIC Anti-Xa assay provides the best physiological measure of the UFH effect in children, as it does not introduce sources of error, such as exogenous AT, which may increase the measured ant Factor Xa activity, nor Dextran Sulphate which can displace plasma protein bound heparin and once again leading to falsely elevated assay results. Further studies that include assessment of clinical outcomes are required to confirm the applicability of use of this particular assay in monitoring UFH therapy.

Anticoagulants↗
PubMed2006

Race and sex: predictors of the severity of hyperparathyroidism in peritoneal dialysis patients.

BACKGROUND: Uraemic hyperparathyroidism remains a common clinical problem. Conversely, oversuppression of parathyroid hormone (PTH), particularly in diabetic patients on peritoneal dialysis, has been implicated in low bone turnover disease. Race may also be an important factor determining susceptibility to hyperparathyroidism and the different forms of renal osteodystrophy. These compounding factors that might influence the severity of hyperparathyroidism have been studied in US dialysis and predialysis populations. Dialysis-dependant Africans and Afro-Caribbeans (AC) are known to have higher circulating PTH concentrations than comparable Caucasians (C) but Indo-Asians (IA) living in temperate climates have not been studied. METHODS: We performed a cross-sectional study of all patients undergoing peritoneal dialysis at St Bartholomew's and The Royal London Hospital on 1 May 2000. The highest historical recorded PTH was recorded with concurrent biochemical and demographic details. Regression models were used for the analysis of covariance and separate manova was performed incorporating the factors that were shown on univariate analysis to be significant. RESULTS: The current study confirmed that in 50 AC patients on peritoneal dialysis, the mean (+/- SEM) peak PTH concentration (93.9 +/- 9.3 pmol/L) was higher than in 148 C (56.7 +/- 4.3 pmol/L) and 67 IA (60.2 +/- 5.7 pmol/L), P < 0.0001 and P < 0.002, respectively. This is despite there being no significant difference in serum calcium concentrations and AC having a lower serum phosphate concentration at the time of peak hyperparathyroidism. There was no significant difference in mean peak PTH concentration between C and IA. Females were also found to have higher peak PTH concentrations, but the presence of diabetes did not influence the peak PTH concentration in this study. CONCLUSION: Although we have demonstrated that patients of African (but not Asian) descent undergoing peritoneal dialysis have more severe hyperparathyroidism than Caucasians, other studies suggest that Afro-Americans develop low bone turnover at higher PTH. This would suggest that PTH values should be interpreted with care and that bone biopsies to determine histology remain important. It may emerge that there are different optimal PTH concentrations according to race.

Cross-Sectional Studies↗
PubMed2006

Developmental haemostasis. Impact for clinical haemostasis laboratories.

Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980's. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whether a current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to age-related changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.

Adolescent↗
PubMed2006

Craniocervical arterial dissection in children: clinical and radiographic presentation and outcome.

Craniocervical arterial dissection is a recognized cause of arterial ischemic stroke in children. Whether children with craniocervical arterial dissection have dissection characteristics different from those of adults is unclear. A retrospective review of children, 1 month to 18 years of age, with dissection from two Canadian pediatric ischemic stroke registry centers was conducted. From 213 patients with arterial ischemic stroke, 16 (7.5%) were identified with dissection, 37.5% had warning symptoms, and 50% had a history of head or neck trauma. The clinical presentation included headache (44%), altered consciousness (25%), seizures (12.5%), and focal deficits (87.5%). Dissection involved extracranial vessels in 75% and anterior circulation in 56%. Follow-up included complete recovery in 43%, mild to moderate deficits in 44%, and severe deficits in 13%. Fourteen (87.5%) children received antithrombotic treatment. Follow-up angiography showed resolution of abnormalities in 60% of vessels. Total occlusion had the worst outcome for recanalization. In conclusion, the etiology of arterial dissection in the majority of children appears to be either trauma or idiopathic. Long-term angiography shows variable outcomes, depending on the initial findings. The relationship of angiographic outcomes with recurrent strokes requires further study in pediatric dissection. (J Child Neurol 2006;21:8-16).

Adolescent↗
PubMed2006

Prediction of the effect of acute normovolemic hemodilution on the hematological constituents of sequestered autologous whole blood.

During acute normovolemic hemodilution (ANH), autologous whole blood is collected in a series of collection bags containing anticoagulant. The effect of hemodilution on the actual hematological constituents of this sequestered whole blood product has never been examined. We developed a mathematical model that predicts how whole blood bag constituents change during ANH to elucidate the theoretical basis for ANH efficacy. Formulas were derived to calculate the effect of ANH on [X], the blood constituent of interest. An exponential envelope was defined so that the projected impact of ANH on each constituent could be computed while initial blood volume and whole blood bag volume (WB(ANH)) were manipulated. Equivalency of autologous whole blood hemoglobin, platelets, and fibrinogen were determined by comparison with standard allogeneic blood products. We determined that the concentration of blood constituent X in a particular unit of collected blood ([X](n)) is provided as a fraction of the initial concentration ([X](0)). As WB(ANH) increases relative to estimated blood volume, the decrement in [X](n) increases in successive blood collection bags. Irrespective of initial blood volume, the equivalence of a 450-mL autologous whole blood bag to 1 U of packed red cells and 1 U of whole blood-derived platelet concentrate is 13.3 g/dL and 123 x 10(3)/microL, respectively. The impact of ANH on autologous whole blood constituents may be accurately predicted using this model. Conversion of WB(ANH) into equivalent allogeneic blood products could provide a useful method of comparing outcome in various ANH studies. The exponential envelope may be used to assess the actual ANH technique performed by the anesthesiologist, which in turn may impact quality assurance standards.

Blood Preservation↗
PubMed2005

Age-related differences in heparin response.

INTRODUCTION: Major physiological differences in the coagulation system throughout childhood, compared to adults, are well documented. However, the impact of this on anticoagulant drugs is unknown. This study aimed to determine whether heparin therapeutic range determination is affected by the age of plasma donors and whether age-specific therapeutic ranges for heparin therapy may need to be considered in the clinical setting. MATERIALS AND METHODS: Plasma samples were obtained from healthy children and adults, and pooled into age-specific pools. These were spiked with different concentrations of heparin and APTT; Anti-Factor Xa and Anti-Factor IIa were measured using standard techniques. The experiments were repeated using three separate plasma pools, and results expressed as means with standard deviations. RESULTS AND CONCLUSIONS: The results show clear age-related differences in APTT for the same Anti-Factor Xa heparin concentration. The differences were more pronounced in younger children, with higher APTT for same Anti-Factor Xa. The Anti-Factor IIa activity of heparin for a given Anti-Factor Xa activity also differed between age-specific plasma pools. This study suggests that when using heparin in children, basic assumptions about the drug mechanism of action and implications for therapeutic ranges need to be considered.

Adolescent↗
PubMed2005

Volutrauma activates the clotting cascade in the newborn but not adult rat.

Coagulopathy and alveolar fibrin deposition are common in sick neonates and attributed to the primary disease, as opposed to their ventilatory support. Hypothesizing that high tidal volume ventilation activates the extrinsic coagulation pathway, we air ventilated newborn and adult rats at low (10 ml/kg) or high (30 ml/kg) tidal volume and compared them with age-matched nonventilated controls. Blood was collected at the end of the experiment for measurement of clot time, tissue factor, and other coagulation factor content. Similar measurements were obtained from lung lavage material. The newborn clot time (44+/-1) was lower and plasma tissue factor content higher (103.4+/-0.4) than adults (88+/-4 s and 26.6+/-1.4 units; P<0.01). High, but not low, tidal volume ventilation of newborns for as little as 15 min significantly reduced clot time and increased plasma tissue factor content (P<0.01). High volume ventilation increased plasma factor Xa (0.1+/-0.1 to 1.6+/-0.4 nM; P<0.01) and thrombin (1.3+/-0.2 to 2.2+/-0.4 nM; P<0.05) and decreased antithrombin (0.12+/-0.01 to 0.05+/-0.01; P<0.01) in the newborn. Lung lavage material of high volume-ventilated newborns showed increased (P<0.01) factor Xa and thrombin. No changes in these parameters were observed in adult rats that were high volume ventilated for up to 90 min. Compared with adults, newborn rats have a greater propensity for volutrauma-activated intravascular coagulation. These data suggest that mechanical ventilation promotes neonatal thrombosis via lung tissue factor release.

Aging↗
PubMed2005

Osmotic tolerance and membrane permeability characteristics of rhesus monkey (Macaca mulatta) spermatozoa.

Biophysical characteristics of the plasma membrane, such as osmotic sensitivity and water and cryoprotectant permeability are important determinants of the function of spermatozoa after cryopreservation. A series of experiments was conducted with rhesus macaque spermatozoa at 23 degrees C to determine their: (1) cell volume and osmotically inactive fraction of the cell volume; (2) permeability coefficients for water and the cryoprotectants dimethyl sulfoxide, glycerol, propylene glycol, and ethylene glycol; (3) tolerance to anisosmotic conditions; and (4) motility after a one step addition and removal of the four cryoprotectants. An electronic particle counter and computer aided semen analysis were used to determine the cell volume and permeability coefficients, and motility, respectively. Rhesus spermatozoa isosmotic cell volume was 27.7+/-3.0 microm3 (mean+/-SEM) with an osmotically inactive cell fraction of 51%. Hydraulic conductivity in the presence of dimethyl sulfoxide, glycerol, propylene glycol, and ethylene glycol was 1.09+/-0.30, 0.912+/-0.27, 1.53+/-0.53, and 1.94+/-0.47 microm/min/atm, respectively. Cryoprotectant permeability was 1.39+/-0.31, 2.21+/-0.32, 3.38+/-0.63, and 6.07+/-1.1 (x10(-3)cm/min), respectively. Rhesus sperm tolerated all hyposmotic exposures. However, greater than 70% motility loss was observed after exposure to solutions of 600 mOsm and higher. A one step addition and removal of all four cryoprotectants did not cause significant motility loss. These data suggest that rhesus sperm are tolerant to hyposmotic conditions, and ethylene glycol may be the most appropriate cryoprotectant for rhesus sperm cryopreservation, as it has the highest permeability coefficient of the tested cryoprotectants.

Animals↗
PubMed2004

Effect of age and disease on taste perception.

Abnormalities in taste function may contribute to poor dietary intake in the elderly, and in patients with renal failure or cancer. This study examined the effect of age on taste thresholds, and taste thresholds adjusted for age, in patients with renal failure with and without dialysis, and patients with cancer receiving chemotherapy and/or radiotherapy. Three groups of healthy volunteers aged 21-34 (n=26), 36-61 (n=13), and 69-94 (n=24), were recruited for the study on the effect of age. Nineteen patients with chronic renal failure on chronic ambulatory peritoneal dialysis (CAPD) and 11 age-matched chronic renal failure patients not yet requiring dialysis were recruited to examine the effect of chronic renal failure on taste function. Twenty-four inpatients with various types of cancer were recruited from a clinical oncology ward. Taste threshold was measured using commercial flavors supplied by Firmenich (pork, beef) and the ascending forced-choice method. Results showed that taste threshold increased with age. No abnormality in taste threshold was observed in patients with chronic renal failure with and without dialysis, and in patients with cancer. However, altered taste occurred in a large number of these patients. Abnormal taste function is present in healthy elderly people, and in patients with chronic renal failure and cancer. The nature of the abnormality differs among these groups, consisting of elevation of taste threshold in the elderly, and dysgeusia in those with disease.

Adult↗
PubMed2004

A case series of 72 neonates with renal vein thrombosis. Data from the 1-800-NO-CLOTS Registry.

Neonatal renal vein thrombosis (RVT) is a well-recognized clinical entity which is associated with serious morbidity. However, current information regarding RVT has been restricted to case reports and small case series. In this study, it was our objective to describe patient demographics, clinical presentation, location and risk factors of RVT. For our study design, we looked at a case series of 72 neonates with RVT referred to the 1-800-NO-CLOTS consultation service between 9/1996 and 8/2001. Data on age, gender, associated conditions, prothrombotic disorders, family history, location of the thrombosis, diagnostic techniques, and treatment were prospectively recorded using a standardized form. Our results show that RVT affected males (65%, CI 52-76%) significantly more often than females (35%, CI 24-48%). Median age at presentation was 2 days (0-21 days). RVT was unilateral in 72% (left side: 67%,CI 49-81%; right side: 33%, CI 19-51%), and bilateral in 28%. The majority (83%) had at least one associated condition: Prematurity (54%), central venous lines (17%), a diabetic mother (13%), asphyxia (6%), infections (6%). Prothrombotic testing was performed in 21 neonates. Activated protein C resistance was found in 8 children (38%), other defects in three. This is the largest case series of neonatal RVT to date. Data from the study show that i) male infants are affected twice as often as females and ii) there appears to be a left-sided predominance of neonatal RVT. Neonatal RVT is only infrequently associated with the presence of a catheter as compared to thrombosis at other sites. The majority of infants have associated conditions with prematurity being most frequent. A small subset of neonates were screened for prothrombotic abnormalities and 50% of the children screened were positive.

Age Factors↗
PubMed2004

Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service.

Thromboembolism (TE) has recently been recognized as a clinical entity in children. Determining the clinical characteristics of pediatric TE is an important first step in dealing with this new disorder. The paper summarizes 1776 consecutive children with systemic TE referred to 1-800-NO-CLOTS telephone consultation service. 1-800-NO-CLOTS is a free consultation service for clinicians managing pediatric TE. Patient information was collected immediately using standardized forms. In children with systemic TE, infants under one year of age (47%) including neonates (26%) represented the largest distinct pediatric age group. Age-related differences were seen in TE locations, associated conditions, and risk factors. However, venous TE was the most frequent manifestation (74%). Neonates and children with cardiac disorders were more likely to have an arterial TE than a venous TE Beyond the neonatal period, venous TE associated with a central line is more likely to occur than arterial TE. Children with ALL were 5.7 times more likely to have a venous TE than an arterial TE. TE were infrequent in otherwise healthy children with 90% of children having at least one risk factor. Central catheters were the single most common risk factor associated with TE, present in 2/3 of children. Ultrasound was most frequently employed for diagnosis of TE. Finally, there was marked heterogeneity in treatment of children with TE. In children, neonates form the largest single group with TE. TE usually occur only in the presence of one or more risk factors with catheters being the single most important factor.

Adolescent↗
PubMed2004

Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This article about antithrombotic therapy in children is part of the 7th American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh the risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this article are the following. In neonates with venous thromboembolism (VTE), we suggest treatment with either unfractionated heparin or low-molecular-weight heparin (LMWH), or radiographic monitoring and anticoagulation therapy if extension occurs (Grade 2C). We suggest that clinicians not use thrombolytic therapy for treating VTE in neonates, unless there is major vessel occlusion that is causing the critical compromise of organs or limbs (Grade 2C). For children (ie, > 2 months of age) with an initial VTE, we recommend treatment with i.v. heparin or LMWH (Grade 1C+). We suggest continuing anticoagulant therapy for idiopathic thromboembolic events (TEs) for at least 6 months using vitamin K antagonists (target international normalized ratio [INR], 2.5; INR range, 2.0 to 3.0) or alternatively LMWH (Grade 2C). We suggest that clinicians not use thrombolytic therapy routinely for VTE in children (Grade 2C). For neonates and children requiring cardiac catheterization (CC) via an artery, we recommend i.v. heparin prophylaxis (Grade 1A). We suggest the use of heparin doses of 100 to 150 U/kg as a bolus and that further doses may be required in prolonged procedures (both Grade 2 B). For prophylaxis for CC, we recommend against aspirin therapy (Grade 1B). For neonates and children with peripheral arterial catheters in situ, we recommend the administration of low-dose heparin through a catheter, preferably by continuous infusion to prolong the catheter patency (Grade 1A). For children with a peripheral arterial catheter-related TE, we suggest the immediate removal of the catheter (Grade 2C). For prevention of aortic thrombosis secondary to the use of umbilical artery catheters in neonates, we suggest low-dose heparin infusion (1 to 5 U/h) (Grade 2A). In children with Kawasaki disease, we recommend therapy with aspirin in high doses initially (80 to 100 mg/kg/d during the acute phase, for up to 14 days) and then in lower doses (3 to 5 mg/kg/d for > or = 7 weeks) [Grade 1C+], as well as therapy with i.v. gammaglobulin within 10 days of the onset of symptoms (Grade 1A).

Child↗
PubMedDate not supplied

Chimpanzee (Pan troglodytes) spermatozoa osmotic tolerance and cryoprotectant permeability characteristics.

Osmotic properties of chimpanzee spermatozoa were studied at 22 degrees C. An electronic particle counter was used to determine the isosmotic cell volume, and the volume response after exposure to four commonly used cryoprotectants: dimethyl sulfoxide, glycerol, propylene glycol, and ethylene glycol. The data were analyzed to determine the hydraulic conductivity and the permeability coefficients for the four cryoprotectants. The osmotically inactive volume fraction was determined using a Boyle van't Hoff plot of cells exposed to sodium chloride solutions. A computer-assisted semen analysis system was used to determine the osmotic tolerance of chimp spermatozoa, as well as the effects of a one-step addition and removal of 1 M permeating cryoprotectant on sperm motility. The isosmotic volume of chimpanzee sperm is 27.7 microm3. The osmotically inactive cell fraction is 69%. Hydraulic conductivity was higher in the presence of ethylene glycol: 4.09 +/- 0.76 (mean +/- SEM) and propylene glycol: 3.91 +/- 0.71 as compared to dimethyl sulfoxide: 3.49 +/- 0.79 and glycerol: 2.83 +/- 0.40 microm/min per atmosphere. The permeability of chimpanzee sperm in ethylene glycol (2.18 +/- 0.40 x 10(-3) cm/min) and propylene glycol (1.75 +/- 0.17 x 10(-3) cm/min) was higher than in glycerol (1.42 +/- 0.12 x 10(-3) cm/min) and dimethyl sulfoxide (0.82 +/- 0.015 x 10(-3) cm/min). Although chimpanzee sperm tolerated osmotic stress in the range of 169-400 mOsm very well, loss of motility was observed as the solution concentrations diverged from isosmotic condition. Exposure to the four cryoprotectants at 1 M did not cause a significant reduction in sperm motility. This information on membrane permeability characteristics and cryoprotectant tolerance will aid in designing more reliable cryopreservation protocols for chimpanzee sperm.

Animals↗