Steven Chan - Academia.edu (original) (raw)

Papers by Steven Chan

ANZ Journal of Surgery

The size of thyroid nodules as measured by ultrasound (ultrasound size, USS) is routinely used in... more The size of thyroid nodules as measured by ultrasound (ultrasound size, USS) is routinely used in clinical decision-making. Reports of discrepancy between USS and pathological size (PS) evaluation have not analysed their systematic differences. The objective of this study was to uncover the lack of agreement (bias) between USS and PS measurements. A retrospective study was performed on 121 patients who had a total or hemi-thyroidectomy for a solitary nodule. Ordinary least product regression was used to detect and distinguish constant and proportional bias in unidimensional size measurements between USS and PS evaluation. Three-dimensional volume measurements were compared in a subgroup of 31 patients. Pre-specified acceptable limits of interchange were defined as 20% difference. Ordinary least product regression demonstrated no constant or proportional bias between the two methods; regression equation: USS = (0.863) + (1.040) × PS. When nodules were grouped by size, discrepancies between the two methods were observed in nodules <10 mm (P = 0.004). However, potential overtreatment of patients with USS >10 mm but PS <10 mm only accounted for 4.1% of total patients. Subgroup analysis of volume measurements showed no bias between USS and PS evaluation. USS and PS measurements were interchangeable, as there was no evidence of constant or proportional bias between the two measurements. However, USS may misclassify the size for smaller nodules and potentially lead to unnecessary workup and treatment. Discrepancy in size measurements between USS and PS should be taken into account in clinical practice, particularly in smaller nodules.

Cancer discovery, Oct 20, 2017

We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and the... more We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their super-enhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong super-enhancer at the retinoic acid receptor alpha (RARA) gene locus. Presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of APL treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiatio...

Nature communications, May 31, 2017

Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single de... more Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology ...

Clinical Cancer Research, 2017

Oncotarget, Jan 6, 2016

The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We... more The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.

Nature Genetics, 2016

We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood ce... more We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, we enable 'enhancer cytometry' for enumeration of pure cell types from complex populations. We identify regulators governing hematopoietic differentiation and further show the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility uncovers unique regulatory evolution in cancer cells with a progressively increasing mutation burden. Single AML cells exhibit distinctive mixed regulome profiles corresponding to disparate developmental stages. A method to account for this regulatory heterogeneity identified cancer-specific deviations and implicated HOX factors as key regulators of preleukemic hematopoietic stem cell characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.

Journal of Cataract and Refractive Surgery, Sep 1, 2010

To evaluate the precision of the axial length (AL), keratometry (K), anterior chamber depth (ACD)... more To evaluate the precision of the axial length (AL), keratometry (K), anterior chamber depth (ACD), astigmatism, and minus astigmatic cylinder axis measurements by a partial coherence interferometry (PCI)-keratometry device. Private practice, Lynwood, California. This prospective comparative observational study analyzed measurements in the second eye to have cataract surgery. Before surgery in the first eye, AL, K, ACD, astigmatism, and cylinder axis in both eyes were measured with an IOLMaster PCI device. The measurements were repeated approximately 1 month later, before second eye-surgery. The 2 sets of measurements were compared. The study evaluated 121 eyes of 121 patients. The interclass correlation coefficient (ICC) for AL was 0.999 in all 3 signal-to-noise ratio (SNR) categories; the highest difference range was with an SNR below 100. Astigmatism, K, and cylinder axis had a high correlation in flat corneas (K reading <42.0 diopters [D]) (ICC = 0.994, 0.978, and 0.918, respectively) and a poorer correlation with K readings between 42.0 D and 44.0 D (ICC = 0.905, 0.774, and 0.456, respectively) and K readings above 44.0 D (ICC = 0.988, 0.729 and 0.446, respectively). The precision of the PCI measurements was extremely high for AL with low fluctuations (95% limits of agreement [LoA], 0.06 mm) and was relatively high for K readings with higher fluctuations (95% LoA, 0.55 D) and for ACD (95% LoA, 0.2 mm). The precision of astigmatism and cylinder axis was high in flat corneas and relatively low in steeper corneas.

Radiotherapy and Oncology, Jan 5, 2011

Bju International, Jul 1, 2009

To test the hypothesis that urinary catheter balloons filled with sterile water, saline or glycin... more To test the hypothesis that urinary catheter balloons filled with sterile water, saline or glycine have equivalent rates of failure to deflate. This was an in vitro equivalence study designed to test whether saline or glycine are neither substantially worse nor substantially better than water in terms of balloon-deflation failure rates. Glycine was chosen as the third arm, as it is readily available during endoscopic procedures and would be useful to use in such situations. We hypothesised that balloon-deflation failure rates using saline or glycine were no worse than water by 10%. We calculated the sample size for equivalence testing; 600 catheters were randomized by computer-generated random numbers to receive 10 mL of water, saline or glycine, and then immersed in a heated artificial urine solution for 6 weeks. The catheter balloons were then deflated, noting any failures to deflate and recording the deflation volumes. There was no failure to deflate in all 600 catheters. The median deflation volume for water, saline and glycine was 9.0, 9.2 and 9.1 mL, respectively (P < 0.001 Kruskal-Wallis test). Post-hoc pair-wise comparisons showed that the deflation volume difference between water and saline was significant (P < 0.001), as was that between water and glycine (P < 0.001). The practical implication of this difference is not apparent from this study. The use of saline or glycine in catheter balloons has an equivalent deflation failure rate to using water, which in this study was zero.

Cell Stem Cell, 2015

Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoieti... more Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.

AJNR. American journal of neuroradiology, 1996

To investigate the phenomenon of reversible increased signal intensity of medial temporal lobe st... more To investigate the phenomenon of reversible increased signal intensity of medial temporal lobe structures and cerebral neocortex seen on MR images of six patients with recent prolonged seizure activity. After excluding patients with known causes of reversible signal abnormalities (such as hypertensive encephalopathy), we retrospectively reviewed the clinical findings and MR studies of six patients whose MR studies showed reversible signal abnormalities. MR pulse sequences included T2-weighted spin-echo coronal views or conventional short-tau inversion-recovery coronal images of the temporal lobes. All six MR studies showed increased signal intensity within the medial temporal lobe, including the hippocampus in five studies. All follow-up MR examinations showed partial or complete resolution of the hyperintensity within the medial temporal lobe and the neocortex. In one patient, results of a brain biopsy revealed severe cerebral cortical gliosis. Temporal lobectomy performed 4 years ...

Journal of andrology

The results of routine semen analyses, the zona-free hamster oocyte penetration test, the hypoosm... more The results of routine semen analyses, the zona-free hamster oocyte penetration test, the hypoosmotic swelling test, and semen adenosine triphosphate levels were studied in 66 fertile and 130 infertile men. Multivariate discriminant analysis demonstrated that routine semen parameters including semen volume, sperm count, percent sperm motility, and percent normal spermatozoa in combination could predict the fertility of these patients with 70.4% accuracy. Of the three sperm function tests evaluated, the zona-free hamster oocyte penetration test and the hypoosmotic swelling test were selected by the multivariate discriminant analysis as variables capable of providing significant information on the fertility status of the patients. However, the addition of the results of these two tests to the routine semen analysis did not significantly improve the predictability of fertility. The overall correct prediction rate was 77.6% after incorporation of the results of these two sperm function ...

Journal of andrology

Multivariate discriminant analysis was used to evaluate the usefulness of computer image analysis... more Multivariate discriminant analysis was used to evaluate the usefulness of computer image analysis of sperm movement characteristics and differential patterns of sperm tail swelling after hypoosmotic treatment for predicting the human sperm in vitro fertilizing capacity assessed by the zona-free hamster egg penetration assay. Fifty-five semen samples, mostly normospermic, from untreated infertility clinic patients were analyzed. The % normal sperm morphology, linearity of seminal sperm movement, seminal sperm head beat frequency, mean and maximum amplitudes of lateral head displacement, and hypoosmotic sperm tail swelling patterns c, d and f were selected by multivariate discriminant analysis to be capable of discriminating the samples exhibiting the presence or the absence of sperm in vitro fertilizing capacity. The % total sperm tail swelling did not give additional information about in vitro fertilizing capacity. These preliminary data suggest that computer image analysis of sperm...

Journal of andrology

The authors studied hyperactivated motility of human spermatozoa as a method of evaluating capaci... more The authors studied hyperactivated motility of human spermatozoa as a method of evaluating capacitation by examining its relationship to results of zona-free hamster oocyte sperm penetration assays (SPA) of semen samples from 50 men attending the infertility clinic. Hyperactivated motility was assessed in the seminal plasma and after swim-up preparation of spermatozoa at 1, 3, and 24 hours of incubation in capacitation media using a computer-assisted semen analysis system equipped with a hyperactivation module. Hyperactivated motility reached a peak at 1 hour and plateaued at 3 hours. The percentage of spermatozoa in seminal plasma with star-spin hyperactivated motility was significantly lower in the group showing no penetration in the SPA. The hyperactivated motility characteristics did not differ in the groups with positive or negative penetration. Correlation analysis failed to show any significant relationship between the hyperactivated motility parameters and SPA score. When th...

Psychiatry Research: Neuroimaging, 2000

L.S. Kegeles 0925-4927r00r$ -see front matter ᮊ 2000 Elsevier Science Ireland Ltd. All rights res... more L.S. Kegeles 0925-4927r00r$ -see front matter ᮊ 2000 Elsevier Science Ireland Ltd. All rights reserved. Ž . PII: S 0 9 2 5 -4 9 2 7 0 0 0 0 0 4 4 -5 ( ) L.S. Kegeles et al. r Psychiatry Research: Neuroimaging 98 2000 163᎐175 164

Blood, Jan 8, 2015

Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many ca... more Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many cases do not bear mutations in known regulators of cytosine guanine dinucleotide (CpG) methylation. We found that mutations in WT1, IDH2, and CEBPA were strongly linked to DNA hypermethylation in AML using a novel integrative analysis of The Cancer Genome Atlas data based on Boolean implications, if-then rules that identify all individual CpG sites that are hypermethylated in the presence of a mutation. Introduction of mutant WT1 (WT1mut) into wild-type AML cells induced DNA hypermethylation, confirming mutant WT1 to be causally associated with DNA hypermethylation. Methylated genes in WT1mut primary patient samples were highly enriched for polycomb repressor complex 2 (PRC2) targets, implicating PRC2 dysregulation in WT1mut leukemogenesis. We found that PRC2 target genes were aberrantly repressed in WT1mut AML, and that expression of mutant WT1 in CD34(+) cord blood cells induced myeloid ...

Supplements to Clinical Neurophysiology, 2009

We prospectively studied 64 patients with motor neuron disease (amyotrophic lateral sclerosis (AL... more We prospectively studied 64 patients with motor neuron disease (amyotrophic lateral sclerosis (ALS), familial ALS (fALS), progressive muscular atrophy (PMA) and primary lateral sclerosis (PLS)) using multiple point stimulation motor unit number estimation (MUNE), transcranial magnetic stimulation (TMS), proton magnetic resonance spectroscopic imaging (1H MRSI), diffusion tensor imaging (MRDTI), and clinical measures at baseline and every 3 months thereafter for 15 months. Substantial differences in MUNE were noted among the motor neuron disease subgroups (P = 0.0005) and mean values for each motor neuron disease subgroup were significantly lower vs. controls (ALS = 76, fALS = 80, PMA = 29, and PLS = 174) vs. the normal control average (267). MUNE correlated well with % FVC (r = 0.32; P = 0.01), manual muscle testing (r = 0.52; P < 0.0005), grip strength (r = 0.34; P = 0.007), and pinch strength (r = 0.49; P < 0.0005). Overall, MUNE showed the greatest significant change over time of any measure, clinical or otherwise, tested in this study (-2.35 linear trend % change per month, mean). MUNE clearly delineates lower motor neuron dysfunction, strongly correlates with important clinical functions (such as strength and respiration) and is a highly sensitive marker of disease progression over time. These features make MUNE an important tool for both the study of the pathophysiology of the motor neuron diseases, as well as an important measure for incorporation into future clinical trials.

Nature medicine, Jan 19, 2015

Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute my... more Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likel...

Stroke, 1999

Background and Purpose-Although numerous families with cerebral autosomal dominant arteriopathy w... more Background and Purpose-Although numerous families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported, our understanding of the disease remains incomplete. Thus, we performed this study to investigate the phenotypic range and natural history of CADASIL. Methods-We performed a pooled analysis of previously published cases.

Schizophrenia Research, 1995

Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To ... more Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To test the hypothesis that these abnormalities were related, CT scans from 164 psychotic patients (80 with schizophrenia) were reviewed. Neurodevelopmental abnormalities were observed in 11%. Abnormalities were equally prevalent in schizophrenia and other psychotic disorders. Cortical sulcal enlargement was observed in 39% of patients with schizophrenia, and was not associated with developmental abnormalities. Different mechanisms may contribute to distinct structural abnormalities.

ANZ Journal of Surgery

The size of thyroid nodules as measured by ultrasound (ultrasound size, USS) is routinely used in... more The size of thyroid nodules as measured by ultrasound (ultrasound size, USS) is routinely used in clinical decision-making. Reports of discrepancy between USS and pathological size (PS) evaluation have not analysed their systematic differences. The objective of this study was to uncover the lack of agreement (bias) between USS and PS measurements. A retrospective study was performed on 121 patients who had a total or hemi-thyroidectomy for a solitary nodule. Ordinary least product regression was used to detect and distinguish constant and proportional bias in unidimensional size measurements between USS and PS evaluation. Three-dimensional volume measurements were compared in a subgroup of 31 patients. Pre-specified acceptable limits of interchange were defined as 20% difference. Ordinary least product regression demonstrated no constant or proportional bias between the two methods; regression equation: USS = (0.863) + (1.040) × PS. When nodules were grouped by size, discrepancies between the two methods were observed in nodules <10 mm (P = 0.004). However, potential overtreatment of patients with USS >10 mm but PS <10 mm only accounted for 4.1% of total patients. Subgroup analysis of volume measurements showed no bias between USS and PS evaluation. USS and PS measurements were interchangeable, as there was no evidence of constant or proportional bias between the two measurements. However, USS may misclassify the size for smaller nodules and potentially lead to unnecessary workup and treatment. Discrepancy in size measurements between USS and PS should be taken into account in clinical practice, particularly in smaller nodules.

Cancer discovery, Oct 20, 2017

We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and the... more We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their super-enhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong super-enhancer at the retinoic acid receptor alpha (RARA) gene locus. Presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of APL treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiatio...

Nature communications, May 31, 2017

Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single de... more Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology ...

Clinical Cancer Research, 2017

Oncotarget, Jan 6, 2016

The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We... more The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.

Nature Genetics, 2016

We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood ce... more We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, we enable 'enhancer cytometry' for enumeration of pure cell types from complex populations. We identify regulators governing hematopoietic differentiation and further show the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility uncovers unique regulatory evolution in cancer cells with a progressively increasing mutation burden. Single AML cells exhibit distinctive mixed regulome profiles corresponding to disparate developmental stages. A method to account for this regulatory heterogeneity identified cancer-specific deviations and implicated HOX factors as key regulators of preleukemic hematopoietic stem cell characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.

Journal of Cataract and Refractive Surgery, Sep 1, 2010

To evaluate the precision of the axial length (AL), keratometry (K), anterior chamber depth (ACD)... more To evaluate the precision of the axial length (AL), keratometry (K), anterior chamber depth (ACD), astigmatism, and minus astigmatic cylinder axis measurements by a partial coherence interferometry (PCI)-keratometry device. Private practice, Lynwood, California. This prospective comparative observational study analyzed measurements in the second eye to have cataract surgery. Before surgery in the first eye, AL, K, ACD, astigmatism, and cylinder axis in both eyes were measured with an IOLMaster PCI device. The measurements were repeated approximately 1 month later, before second eye-surgery. The 2 sets of measurements were compared. The study evaluated 121 eyes of 121 patients. The interclass correlation coefficient (ICC) for AL was 0.999 in all 3 signal-to-noise ratio (SNR) categories; the highest difference range was with an SNR below 100. Astigmatism, K, and cylinder axis had a high correlation in flat corneas (K reading <42.0 diopters [D]) (ICC = 0.994, 0.978, and 0.918, respectively) and a poorer correlation with K readings between 42.0 D and 44.0 D (ICC = 0.905, 0.774, and 0.456, respectively) and K readings above 44.0 D (ICC = 0.988, 0.729 and 0.446, respectively). The precision of the PCI measurements was extremely high for AL with low fluctuations (95% limits of agreement [LoA], 0.06 mm) and was relatively high for K readings with higher fluctuations (95% LoA, 0.55 D) and for ACD (95% LoA, 0.2 mm). The precision of astigmatism and cylinder axis was high in flat corneas and relatively low in steeper corneas.

Radiotherapy and Oncology, Jan 5, 2011

Bju International, Jul 1, 2009

To test the hypothesis that urinary catheter balloons filled with sterile water, saline or glycin... more To test the hypothesis that urinary catheter balloons filled with sterile water, saline or glycine have equivalent rates of failure to deflate. This was an in vitro equivalence study designed to test whether saline or glycine are neither substantially worse nor substantially better than water in terms of balloon-deflation failure rates. Glycine was chosen as the third arm, as it is readily available during endoscopic procedures and would be useful to use in such situations. We hypothesised that balloon-deflation failure rates using saline or glycine were no worse than water by 10%. We calculated the sample size for equivalence testing; 600 catheters were randomized by computer-generated random numbers to receive 10 mL of water, saline or glycine, and then immersed in a heated artificial urine solution for 6 weeks. The catheter balloons were then deflated, noting any failures to deflate and recording the deflation volumes. There was no failure to deflate in all 600 catheters. The median deflation volume for water, saline and glycine was 9.0, 9.2 and 9.1 mL, respectively (P < 0.001 Kruskal-Wallis test). Post-hoc pair-wise comparisons showed that the deflation volume difference between water and saline was significant (P < 0.001), as was that between water and glycine (P < 0.001). The practical implication of this difference is not apparent from this study. The use of saline or glycine in catheter balloons has an equivalent deflation failure rate to using water, which in this study was zero.

Cell Stem Cell, 2015

Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoieti... more Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.

AJNR. American journal of neuroradiology, 1996

To investigate the phenomenon of reversible increased signal intensity of medial temporal lobe st... more To investigate the phenomenon of reversible increased signal intensity of medial temporal lobe structures and cerebral neocortex seen on MR images of six patients with recent prolonged seizure activity. After excluding patients with known causes of reversible signal abnormalities (such as hypertensive encephalopathy), we retrospectively reviewed the clinical findings and MR studies of six patients whose MR studies showed reversible signal abnormalities. MR pulse sequences included T2-weighted spin-echo coronal views or conventional short-tau inversion-recovery coronal images of the temporal lobes. All six MR studies showed increased signal intensity within the medial temporal lobe, including the hippocampus in five studies. All follow-up MR examinations showed partial or complete resolution of the hyperintensity within the medial temporal lobe and the neocortex. In one patient, results of a brain biopsy revealed severe cerebral cortical gliosis. Temporal lobectomy performed 4 years ...

Journal of andrology

The results of routine semen analyses, the zona-free hamster oocyte penetration test, the hypoosm... more The results of routine semen analyses, the zona-free hamster oocyte penetration test, the hypoosmotic swelling test, and semen adenosine triphosphate levels were studied in 66 fertile and 130 infertile men. Multivariate discriminant analysis demonstrated that routine semen parameters including semen volume, sperm count, percent sperm motility, and percent normal spermatozoa in combination could predict the fertility of these patients with 70.4% accuracy. Of the three sperm function tests evaluated, the zona-free hamster oocyte penetration test and the hypoosmotic swelling test were selected by the multivariate discriminant analysis as variables capable of providing significant information on the fertility status of the patients. However, the addition of the results of these two tests to the routine semen analysis did not significantly improve the predictability of fertility. The overall correct prediction rate was 77.6% after incorporation of the results of these two sperm function ...

Journal of andrology

Multivariate discriminant analysis was used to evaluate the usefulness of computer image analysis... more Multivariate discriminant analysis was used to evaluate the usefulness of computer image analysis of sperm movement characteristics and differential patterns of sperm tail swelling after hypoosmotic treatment for predicting the human sperm in vitro fertilizing capacity assessed by the zona-free hamster egg penetration assay. Fifty-five semen samples, mostly normospermic, from untreated infertility clinic patients were analyzed. The % normal sperm morphology, linearity of seminal sperm movement, seminal sperm head beat frequency, mean and maximum amplitudes of lateral head displacement, and hypoosmotic sperm tail swelling patterns c, d and f were selected by multivariate discriminant analysis to be capable of discriminating the samples exhibiting the presence or the absence of sperm in vitro fertilizing capacity. The % total sperm tail swelling did not give additional information about in vitro fertilizing capacity. These preliminary data suggest that computer image analysis of sperm...

Journal of andrology

The authors studied hyperactivated motility of human spermatozoa as a method of evaluating capaci... more The authors studied hyperactivated motility of human spermatozoa as a method of evaluating capacitation by examining its relationship to results of zona-free hamster oocyte sperm penetration assays (SPA) of semen samples from 50 men attending the infertility clinic. Hyperactivated motility was assessed in the seminal plasma and after swim-up preparation of spermatozoa at 1, 3, and 24 hours of incubation in capacitation media using a computer-assisted semen analysis system equipped with a hyperactivation module. Hyperactivated motility reached a peak at 1 hour and plateaued at 3 hours. The percentage of spermatozoa in seminal plasma with star-spin hyperactivated motility was significantly lower in the group showing no penetration in the SPA. The hyperactivated motility characteristics did not differ in the groups with positive or negative penetration. Correlation analysis failed to show any significant relationship between the hyperactivated motility parameters and SPA score. When th...

Psychiatry Research: Neuroimaging, 2000

L.S. Kegeles 0925-4927r00r$ -see front matter ᮊ 2000 Elsevier Science Ireland Ltd. All rights res... more L.S. Kegeles 0925-4927r00r$ -see front matter ᮊ 2000 Elsevier Science Ireland Ltd. All rights reserved. Ž . PII: S 0 9 2 5 -4 9 2 7 0 0 0 0 0 4 4 -5 ( ) L.S. Kegeles et al. r Psychiatry Research: Neuroimaging 98 2000 163᎐175 164

Blood, Jan 8, 2015

Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many ca... more Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many cases do not bear mutations in known regulators of cytosine guanine dinucleotide (CpG) methylation. We found that mutations in WT1, IDH2, and CEBPA were strongly linked to DNA hypermethylation in AML using a novel integrative analysis of The Cancer Genome Atlas data based on Boolean implications, if-then rules that identify all individual CpG sites that are hypermethylated in the presence of a mutation. Introduction of mutant WT1 (WT1mut) into wild-type AML cells induced DNA hypermethylation, confirming mutant WT1 to be causally associated with DNA hypermethylation. Methylated genes in WT1mut primary patient samples were highly enriched for polycomb repressor complex 2 (PRC2) targets, implicating PRC2 dysregulation in WT1mut leukemogenesis. We found that PRC2 target genes were aberrantly repressed in WT1mut AML, and that expression of mutant WT1 in CD34(+) cord blood cells induced myeloid ...

Supplements to Clinical Neurophysiology, 2009

We prospectively studied 64 patients with motor neuron disease (amyotrophic lateral sclerosis (AL... more We prospectively studied 64 patients with motor neuron disease (amyotrophic lateral sclerosis (ALS), familial ALS (fALS), progressive muscular atrophy (PMA) and primary lateral sclerosis (PLS)) using multiple point stimulation motor unit number estimation (MUNE), transcranial magnetic stimulation (TMS), proton magnetic resonance spectroscopic imaging (1H MRSI), diffusion tensor imaging (MRDTI), and clinical measures at baseline and every 3 months thereafter for 15 months. Substantial differences in MUNE were noted among the motor neuron disease subgroups (P = 0.0005) and mean values for each motor neuron disease subgroup were significantly lower vs. controls (ALS = 76, fALS = 80, PMA = 29, and PLS = 174) vs. the normal control average (267). MUNE correlated well with % FVC (r = 0.32; P = 0.01), manual muscle testing (r = 0.52; P < 0.0005), grip strength (r = 0.34; P = 0.007), and pinch strength (r = 0.49; P < 0.0005). Overall, MUNE showed the greatest significant change over time of any measure, clinical or otherwise, tested in this study (-2.35 linear trend % change per month, mean). MUNE clearly delineates lower motor neuron dysfunction, strongly correlates with important clinical functions (such as strength and respiration) and is a highly sensitive marker of disease progression over time. These features make MUNE an important tool for both the study of the pathophysiology of the motor neuron diseases, as well as an important measure for incorporation into future clinical trials.

Nature medicine, Jan 19, 2015

Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute my... more Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likel...

Stroke, 1999

Background and Purpose-Although numerous families with cerebral autosomal dominant arteriopathy w... more Background and Purpose-Although numerous families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported, our understanding of the disease remains incomplete. Thus, we performed this study to investigate the phenotypic range and natural history of CADASIL. Methods-We performed a pooled analysis of previously published cases.

Schizophrenia Research, 1995

Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To ... more Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To test the hypothesis that these abnormalities were related, CT scans from 164 psychotic patients (80 with schizophrenia) were reviewed. Neurodevelopmental abnormalities were observed in 11%. Abnormalities were equally prevalent in schizophrenia and other psychotic disorders. Cortical sulcal enlargement was observed in 39% of patients with schizophrenia, and was not associated with developmental abnormalities. Different mechanisms may contribute to distinct structural abnormalities.