Journal of chemical information and modeling, Jan 15, 2015
Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem c... more Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic x...
Arthritis & rheumatology (Hoboken, N.J.), Jan 21, 2015
One in four Medicare beneficiaries with rheumatoid arthritis (RA) use high cost biologic disease ... more One in four Medicare beneficiaries with rheumatoid arthritis (RA) use high cost biologic disease modifying drugs (DMARDs), and spending for these drugs has risen sharply for Medicare Part D. We conducted the first systematic, national investigation of how Part D plans cover biologic DMARDs and patients' financial burden under current cost-sharing structures. We performed a cross-sectional analysis of Part D plans' formularies (n=2,737) in 50 states and Washington, DC using the January 2013 Centers for Medicare and Medicaid Services Prescription Drug Plan Formulary and Pharmacy Network Files. We calculated the percentage of plans covering each DMARD, prior authorization (PA) requirements, and copayments charged. We also compared biologic drug coverage in Medicare Advantage plans to stand-alone Part D plans. All plans covered at least 1 biologic DMARD, but the vast majority required PAs (95%). Nearly all plans (81% to 100%) required a percentage coinsurance (average 29.6% of.d...
-Early studies showed beneficial effects of phosphodiesterase 5 inhibitors (PDE5i) on cardiovascu... more -Early studies showed beneficial effects of phosphodiesterase 5 inhibitors (PDE5i) on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction (HFpEF). -A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular (LV) contractility was assessed by peak power index (PWR/EDV) and stroke work index (SW/EDV). Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure (PASP). Endothelial function was assessed by reactive hyperemia index (RHI) following upper arm cuff occlusion. Compared to placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28mmHg/ml vs +0.02±0.29, p=0.008) and tended to improve RHI (+0.30±0.45 vs -0.17±0.30, p=0.054). In contrast, LV contractility was reduced by 11-16% with sildenafil compared to placebo (ΔPWR/EDV -52±70 vs +0±40 mmHg/s, p=0.006; ΔSW/EDV +0.3±5.8 vs -6.0±5.1 mmHg, p=0.04). Sildenafil had no effect on PASP. -In subjects with HFpEF, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of PDE5i in the systemic vasculature and endothelium were insufficient to improve clinical status, or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HFpEF in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.
Recent evidence suggests that blocking aberrant Hedgehog pathway signaling may be a potential the... more Recent evidence suggests that blocking aberrant Hedgehog pathway signaling may be a potential therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid natural product, is an antagonist of the Hedgehog pathway and was used as a starting point for the development of new Hedgehog pathway antagonists. Herein, we describe the synthesis of D-homo cyclopamine analogs by a sequence of chemoselective cyclopropanation followed by stereoselective acid-catalyzed rearrangement. These D-homo analogs are more stable to acid-catalyzed degradation than the natural product. Further modifications of the A-ring generated three new series of analogs, which were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926, a novel semi-synthetic cyclopamine analog with improved pharmaceutical properties and potency, and a superior plasma pharmacokinetic profile relative t...
Early diagnosis of malignant mixed mesodermal tumors of the ovary is very difficult because of th... more Early diagnosis of malignant mixed mesodermal tumors of the ovary is very difficult because of the rarity and the insidious onset. The purpose of this report is to review the magnetic resonance imaging features of an ovarian malignant mixed mesodermal tumor, which occurred in a 52-year-old woman, aiding in the differential diagnosis.
Despite the proven efficacy of decision aids as interventions for increasing patient engagement a... more Despite the proven efficacy of decision aids as interventions for increasing patient engagement and facilitating shared decision making, they are not used routinely in clinical care. Findings from a project designed to achieve such integration, conducted at five primary care practices in 2010-12, document low rates of distribution of decision aids to eligible patients due for colorectal cancer screening (9.3 percent) and experiencing back pain (10.7 percent). There were also no lasting increases in distribution rates in response to training sessions and other promotional activities for physicians and clinic staff. The results of focus groups, ethnographic field notes, and surveys suggest that major structural and cultural changes in health care practice and policy are necessary to achieve the levels of use of decision aids and shared decision making in routine practice envisioned in current policy. Among these changes are ongoing incentives for use, physician training, and a team-ba...
Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercis... more Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E/e', 16; deceleration time, 185 ms; left atrial volume, 44 mL/m(2)) and increased arterial load (arterial elast...
Right heart function is not well characterized in patients with heart failure and preserved eject... more Right heart function is not well characterized in patients with heart failure and preserved ejection fraction (HFpEF). The goal of this study was to examine the haemodynamic, clinical, and prognostic correlates of right ventricular dysfunction (RVD) in HFpEF. Heart failure and preserved ejection fraction patients (n = 96) and controls (n = 46) underwent right heart catheterization, echocardiographic assessment, and follow-up. Right and left heart filling pressures, pulmonary artery (PA) pressures, and right-sided chamber dimensions were higher in HFpEF compared with controls, while left ventricular size and EF were similar. Right ventricular dysfunction (defined by RV fractional area change, FAC <35%) was present in 33% of HFpEF patients and was associated with more severe symptoms and greater comorbidity burden. Right ventricular function was impaired in HFpEF compared with controls using both load-dependent (FAC: 40 ± 10 vs. 53 ± 7%, P < 0.0001) and load-independent indices ...
The transcriptional repressor B-cell Lymphoma 6 (Bcl6) was recently identified in a profile of ge... more The transcriptional repressor B-cell Lymphoma 6 (Bcl6) was recently identified in a profile of genes regulated in adipocytes, suggesting a relationship between Bcl6 and metabolic regulation. As a representative target gene repressed by Bcl6, Suppressor of Cytokine Signaling (Socs) 2 expression was elevated in Bcl6 deficient (KO) mice, including metabolic tissues liver, adipose tissue and muscle, as well as in spleen and thymus. Bcl6 occupied the Socs2 promoter in wild-type, but not Bcl6 KO mice, suggesting direct regulation of Socs2 by Bcl6 in vivo. Mice deficient in Bcl6 were found to exhibit multiple features of dysregulated lipid metabolism. Adipose tissue mass was dramatically reduced or absent in Bcl6 KO mice. Further, hepatic and serum triglycerides were low. Bcl6 deficiency was accompanied by decreased hepatic expression of Stearoyl-CoA desaturase 1 (Scd1) and Fatty acid synthase (Fasn) genes which encode lipogenic enzymes. Expression of the gene for the transcription factor ...
Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which ob... more Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which obliterate the lumen of pulmonary venules, leading to pulmonary hypertension, right ventricular failure, and death. This condition has no effective treatment and a 5-year survival of <5%. Understanding the mechanism of this disease and designing effective therapies are urgently needed. We show that mice with homozygous deletion of the Ets transcription factor Erg die between embryonic day 16.5 and 3 months of age as a result of pulmonary veno-occlusive disease, capillary hemorrhage, and pancytopenia. We demonstrate that Erg binds to and serves as a transcriptional activator of the G-protein-coupled receptor gene Aplnr, the expression of which is uniquely specific for venous endothelium and that knockout of either Erg or Aplnr results in pulmonary venule-specific endothelial proliferation in vitro. We show that mice with either homozygous-global or endothelium-directed deletion of Aplnr ...
Expression of the Growth Hormone (GH)-stimulated gene Socs2 (Suppressor of Cytokine Signaling 2) ... more Expression of the Growth Hormone (GH)-stimulated gene Socs2 (Suppressor of Cytokine Signaling 2) is mediated by the transcription activator STAT5 (Signal Transducer and Activator of Transcription 5) and the transcription repressor BCL6 (B-Cell Lymphoma 6). ChIP-Sequencing identified Cish (Cytokine-Inducible SH2-containing protein) and Bcl6 as having similar patterns of reciprocal occupancy by BCL6 and STAT5 in response to GH, though GH stimulates Cish and inhibits Bcl6 expression. The co-activator p300 occupied Socs2, Cish and Bcl6 promoters, and enhanced STAT5-mediated activation of Socs2 and Cish. In contrast, on Bcl6, p300 functioned as a repressor and inhibited in conjunction with STAT5 or BCL6. The co-repressor HDAC3 (Histone deacetylase 3) inhibited the Socs2, Cish and Bcl6 promoters in the presence of STAT5. Thus transcriptional outcomes on GH-regulated genes occupied by BCL6 and STAT5 are determined in a promoter-specific fashion by co-regulatory proteins which mediate the d...
International Journal of Pediatric Otorhinolaryngology, 2011
ObjectiveThe purpose of this study is to assess the language ability between early-intervention a... more ObjectiveThe purpose of this study is to assess the language ability between early-intervention and later-intervention Mandarin-speaking deaf children, who have normal cognition and high family involvement.
Extensive molecular profiling of leukemias and preleukemic diseases has revealed that distinct cl... more Extensive molecular profiling of leukemias and preleukemic diseases has revealed that distinct clinical entities, like acute myeloid (AML) and T-lymphoblastic leukemia (T-ALL), share similar pathogenetic mutations. It is not well understood how the cell of origin, accompanying mutations, extracellular signals or structural differences in a mutated gene determine the phenotypic identity of leukemias. We dissected the functional aspects of different protein regions of the MN1 oncogene and their effect on the leukemic phenotype, building on the ability of MN1 to induce leukemia without accompanying mutations. We found that the most C-terminal region of MN1 was required to block myeloid differentiation at an early stage, and deletion of an extended C-terminal region resulted in loss of myeloid identity and cell differentiation along the T-cell lineage in vivo. Megakaryocytic/erythroid lineage differentiation was blocked by the N-terminal region. In addition, the N-terminus was required ...
Journal of chemical information and modeling, Jan 15, 2015
Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem c... more Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic x...
Arthritis & rheumatology (Hoboken, N.J.), Jan 21, 2015
One in four Medicare beneficiaries with rheumatoid arthritis (RA) use high cost biologic disease ... more One in four Medicare beneficiaries with rheumatoid arthritis (RA) use high cost biologic disease modifying drugs (DMARDs), and spending for these drugs has risen sharply for Medicare Part D. We conducted the first systematic, national investigation of how Part D plans cover biologic DMARDs and patients' financial burden under current cost-sharing structures. We performed a cross-sectional analysis of Part D plans' formularies (n=2,737) in 50 states and Washington, DC using the January 2013 Centers for Medicare and Medicaid Services Prescription Drug Plan Formulary and Pharmacy Network Files. We calculated the percentage of plans covering each DMARD, prior authorization (PA) requirements, and copayments charged. We also compared biologic drug coverage in Medicare Advantage plans to stand-alone Part D plans. All plans covered at least 1 biologic DMARD, but the vast majority required PAs (95%). Nearly all plans (81% to 100%) required a percentage coinsurance (average 29.6% of.d...
-Early studies showed beneficial effects of phosphodiesterase 5 inhibitors (PDE5i) on cardiovascu... more -Early studies showed beneficial effects of phosphodiesterase 5 inhibitors (PDE5i) on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction (HFpEF). -A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular (LV) contractility was assessed by peak power index (PWR/EDV) and stroke work index (SW/EDV). Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure (PASP). Endothelial function was assessed by reactive hyperemia index (RHI) following upper arm cuff occlusion. Compared to placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28mmHg/ml vs +0.02±0.29, p=0.008) and tended to improve RHI (+0.30±0.45 vs -0.17±0.30, p=0.054). In contrast, LV contractility was reduced by 11-16% with sildenafil compared to placebo (ΔPWR/EDV -52±70 vs +0±40 mmHg/s, p=0.006; ΔSW/EDV +0.3±5.8 vs -6.0±5.1 mmHg, p=0.04). Sildenafil had no effect on PASP. -In subjects with HFpEF, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of PDE5i in the systemic vasculature and endothelium were insufficient to improve clinical status, or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HFpEF in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.
Recent evidence suggests that blocking aberrant Hedgehog pathway signaling may be a potential the... more Recent evidence suggests that blocking aberrant Hedgehog pathway signaling may be a potential therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid natural product, is an antagonist of the Hedgehog pathway and was used as a starting point for the development of new Hedgehog pathway antagonists. Herein, we describe the synthesis of D-homo cyclopamine analogs by a sequence of chemoselective cyclopropanation followed by stereoselective acid-catalyzed rearrangement. These D-homo analogs are more stable to acid-catalyzed degradation than the natural product. Further modifications of the A-ring generated three new series of analogs, which were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926, a novel semi-synthetic cyclopamine analog with improved pharmaceutical properties and potency, and a superior plasma pharmacokinetic profile relative t...
Early diagnosis of malignant mixed mesodermal tumors of the ovary is very difficult because of th... more Early diagnosis of malignant mixed mesodermal tumors of the ovary is very difficult because of the rarity and the insidious onset. The purpose of this report is to review the magnetic resonance imaging features of an ovarian malignant mixed mesodermal tumor, which occurred in a 52-year-old woman, aiding in the differential diagnosis.
Despite the proven efficacy of decision aids as interventions for increasing patient engagement a... more Despite the proven efficacy of decision aids as interventions for increasing patient engagement and facilitating shared decision making, they are not used routinely in clinical care. Findings from a project designed to achieve such integration, conducted at five primary care practices in 2010-12, document low rates of distribution of decision aids to eligible patients due for colorectal cancer screening (9.3 percent) and experiencing back pain (10.7 percent). There were also no lasting increases in distribution rates in response to training sessions and other promotional activities for physicians and clinic staff. The results of focus groups, ethnographic field notes, and surveys suggest that major structural and cultural changes in health care practice and policy are necessary to achieve the levels of use of decision aids and shared decision making in routine practice envisioned in current policy. Among these changes are ongoing incentives for use, physician training, and a team-ba...
Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercis... more Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E/e', 16; deceleration time, 185 ms; left atrial volume, 44 mL/m(2)) and increased arterial load (arterial elast...
Right heart function is not well characterized in patients with heart failure and preserved eject... more Right heart function is not well characterized in patients with heart failure and preserved ejection fraction (HFpEF). The goal of this study was to examine the haemodynamic, clinical, and prognostic correlates of right ventricular dysfunction (RVD) in HFpEF. Heart failure and preserved ejection fraction patients (n = 96) and controls (n = 46) underwent right heart catheterization, echocardiographic assessment, and follow-up. Right and left heart filling pressures, pulmonary artery (PA) pressures, and right-sided chamber dimensions were higher in HFpEF compared with controls, while left ventricular size and EF were similar. Right ventricular dysfunction (defined by RV fractional area change, FAC <35%) was present in 33% of HFpEF patients and was associated with more severe symptoms and greater comorbidity burden. Right ventricular function was impaired in HFpEF compared with controls using both load-dependent (FAC: 40 ± 10 vs. 53 ± 7%, P < 0.0001) and load-independent indices ...
The transcriptional repressor B-cell Lymphoma 6 (Bcl6) was recently identified in a profile of ge... more The transcriptional repressor B-cell Lymphoma 6 (Bcl6) was recently identified in a profile of genes regulated in adipocytes, suggesting a relationship between Bcl6 and metabolic regulation. As a representative target gene repressed by Bcl6, Suppressor of Cytokine Signaling (Socs) 2 expression was elevated in Bcl6 deficient (KO) mice, including metabolic tissues liver, adipose tissue and muscle, as well as in spleen and thymus. Bcl6 occupied the Socs2 promoter in wild-type, but not Bcl6 KO mice, suggesting direct regulation of Socs2 by Bcl6 in vivo. Mice deficient in Bcl6 were found to exhibit multiple features of dysregulated lipid metabolism. Adipose tissue mass was dramatically reduced or absent in Bcl6 KO mice. Further, hepatic and serum triglycerides were low. Bcl6 deficiency was accompanied by decreased hepatic expression of Stearoyl-CoA desaturase 1 (Scd1) and Fatty acid synthase (Fasn) genes which encode lipogenic enzymes. Expression of the gene for the transcription factor ...
Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which ob... more Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which obliterate the lumen of pulmonary venules, leading to pulmonary hypertension, right ventricular failure, and death. This condition has no effective treatment and a 5-year survival of <5%. Understanding the mechanism of this disease and designing effective therapies are urgently needed. We show that mice with homozygous deletion of the Ets transcription factor Erg die between embryonic day 16.5 and 3 months of age as a result of pulmonary veno-occlusive disease, capillary hemorrhage, and pancytopenia. We demonstrate that Erg binds to and serves as a transcriptional activator of the G-protein-coupled receptor gene Aplnr, the expression of which is uniquely specific for venous endothelium and that knockout of either Erg or Aplnr results in pulmonary venule-specific endothelial proliferation in vitro. We show that mice with either homozygous-global or endothelium-directed deletion of Aplnr ...
Expression of the Growth Hormone (GH)-stimulated gene Socs2 (Suppressor of Cytokine Signaling 2) ... more Expression of the Growth Hormone (GH)-stimulated gene Socs2 (Suppressor of Cytokine Signaling 2) is mediated by the transcription activator STAT5 (Signal Transducer and Activator of Transcription 5) and the transcription repressor BCL6 (B-Cell Lymphoma 6). ChIP-Sequencing identified Cish (Cytokine-Inducible SH2-containing protein) and Bcl6 as having similar patterns of reciprocal occupancy by BCL6 and STAT5 in response to GH, though GH stimulates Cish and inhibits Bcl6 expression. The co-activator p300 occupied Socs2, Cish and Bcl6 promoters, and enhanced STAT5-mediated activation of Socs2 and Cish. In contrast, on Bcl6, p300 functioned as a repressor and inhibited in conjunction with STAT5 or BCL6. The co-repressor HDAC3 (Histone deacetylase 3) inhibited the Socs2, Cish and Bcl6 promoters in the presence of STAT5. Thus transcriptional outcomes on GH-regulated genes occupied by BCL6 and STAT5 are determined in a promoter-specific fashion by co-regulatory proteins which mediate the d...
International Journal of Pediatric Otorhinolaryngology, 2011
ObjectiveThe purpose of this study is to assess the language ability between early-intervention a... more ObjectiveThe purpose of this study is to assess the language ability between early-intervention and later-intervention Mandarin-speaking deaf children, who have normal cognition and high family involvement.
Extensive molecular profiling of leukemias and preleukemic diseases has revealed that distinct cl... more Extensive molecular profiling of leukemias and preleukemic diseases has revealed that distinct clinical entities, like acute myeloid (AML) and T-lymphoblastic leukemia (T-ALL), share similar pathogenetic mutations. It is not well understood how the cell of origin, accompanying mutations, extracellular signals or structural differences in a mutated gene determine the phenotypic identity of leukemias. We dissected the functional aspects of different protein regions of the MN1 oncogene and their effect on the leukemic phenotype, building on the ability of MN1 to induce leukemia without accompanying mutations. We found that the most C-terminal region of MN1 was required to block myeloid differentiation at an early stage, and deletion of an extended C-terminal region resulted in loss of myeloid identity and cell differentiation along the T-cell lineage in vivo. Megakaryocytic/erythroid lineage differentiation was blocked by the N-terminal region. In addition, the N-terminus was required ...
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