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Biomedical subjects

E S Huang

Publications and source records attributed to E S Huang.

At least 19 recordsLinked to original sources
PubMed2006

The incremental costs of recommended therapy versus real world therapy in type 2 diabetes patients.

BACKGROUND: The goals of diabetes management have evolved over the past decade to become the attainment of near-normal glucose and cardiovascular risk factor levels. Improved metabolic control is achieved through optimized medication regimens, but costs specifically associated with such optimization have not been examined. OBJECTIVE: To estimate the incremental medication cost of providing optimal therapy to reach recommended goals versus actual therapy in patients with type 2 diabetes. METHODS: We randomly selected the charts of 601 type 2 diabetes patients receiving care from the outpatient clinics of Massachusetts General Hospital March 1, 1996-August 31, 1997 and abstracted clinical and medication data. We applied treatment algorithms based on 2004 clinical practice guidelines for hyperglycemia, hyperlipidemia, and hypertension to patients' current medication therapy to determine how current medication regimens could be improved to attain recommended treatment goals. Four clinicians and three pharmacists independently applied the algorithms and reached consensus on recommended therapies. Mean incremental medication costs, the cost differences between current and recommended therapies, per patient (expressed in 2004 dollars) were calculated with 95% bootstrap confidence intervals (CIs). RESULTS: Mean patient age was 65 years old, mean duration of diabetes was 7.7 years, 32% had ideal glucose control, 25% had ideal systolic blood pressure, and 24% had ideal low-density lipoprotein cholesterol. Care for these diabetes patients was similar to that observed in recent national studies. If treatment algorithm recommendations were applied, the average annual medication cost/patient would increase from 1525 to 2164 dollars. Annual incremental costs/patient increased by 168 dollars (95% CI 133-206 dollars) for antihyperglycemic medications, 75 dollars (57-93 dollars) for antihypertensive medications, 392 dollars (354-434 dollars) for antihyperlipidemic medications, and 3 dollars (3-4 dollars) for aspirin prophylaxis. Yearly incremental cost of recommended laboratory testing ranged from 77-189 dollars/patient. LIMITATIONS: Although baseline data come from the clinics of a single academic institution, collected in 1997, the care of these diabetes patients was remarkably similar to care recently observed nationally. In addition, the data are dependent on the medical record and may not accurately reflect patients' actual experiences. CONCLUSION: Average yearly incremental cost of optimizing drug regimens to achieve recommended treatment goals for type 2 diabetes was approximately 600 dollars/patient. These results provide valuable input for assessing the cost-effectiveness of improving comprehensive diabetes care.

Aged↗
PubMed2001

The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes mellitus.

PURPOSE: Cardiovascular complications account for over 50% of mortality among patients with type 2 diabetes mellitus. We quantify the cardiovascular benefit of lowering cholesterol, blood pressure, and glucose levels in these patients. METHODS: We conducted a meta-analysis of randomized controlled trials in type 2 diabetes or diabetes subgroups, comparing the cardiovascular effects of intensive medication control of risk factor levels in standard therapy or placebo. We identified trials by searching MEDLINE (1966 to 2000) and review articles. Treatment details, patient characteristics, and outcome events were obtained using a specified protocol. Data were pooled using fixed-effects models. RESULTS: Seven serum cholesterol-lowering trials, six blood pressure-lowering trials, and five blood glucose-lowering trials met eligibility criteria. For aggregate cardiac events (coronary heart disease death and nonfatal myocardial infarction), cholesterol lowering [rate ratio (RR) = 0.75; 95% confidence interval (CI): 0.61 to 0.93) and blood pressure lowering (RR = 0.73; 95% CI: 0.57 to 0.94) produced large, significant effects, whereas intensive glucose lowering reduced events without reaching statistical significance (RR = 0.87; 95% CI: 0.74 to 1.01). We observed this pattern for all individual cardiovascular outcomes. For cholesterol-lowering and blood pressure-lowering therapy, 69 to 300 person-years of treatment were needed to prevent one cardiovascular event. CONCLUSION: The evidence from these clinical trials demonstrates that lipid and blood pressure lowering in patients with type 2 diabetes is associated with substantial cardiovascular benefits. Intensive glucose lowering is essential for the prevention of microvascular disease, but improvements in cholesterol and blood pressure levels are central to reducing cardiovascular disease in these patients.

Anticholesteremic Agents↗
PubMed2001

Characterization of immunologic tolerance induced by transfusion of UV-B--irradiated allogeneic mononuclear leukocytes.

Transfusions of UV-B--irradiated peripheral blood mononuclear cells (UV-B--PBMCs) from BALB/c (H-2(d)) mice into CBA (H-2(k)) mice can induce humoral immune tolerance to H-2(d) antigens, and the induced tolerance is partially mediated by negative regulatory PBMCs. To further identify which subset of spleen mononuclear leukocytes (MNLs) in the tolerant CBA mice is responsible for the negative regulatory activity, adoptive transfer experiments were conducted using spleen MNLs from the tolerant CBA mice. Results showed that only CD4(+) T cells could transfer the negative regulatory activity in a dose-dependent manner. This negative regulatory activity was significantly reduced when CD25(+) helper T cells were removed. Further study suggested that inhibition of IL-12 production by UV-B--irradiated PBMCs played a role in the induction of immune tolerance. In vitro study of the cytokine production profile by CBA CD4(+) T cells, after stimulation with gamma-irradiated BALB/c spleen cells, revealed an enhanced production of the type 2 T-cell cytokines after tolerance induction. Induction of tolerance also prevented the development of cytotoxic T cells in CBA mice against BALB/c MNLs. Adoptive transfer study suggested that the cellular immune tolerance was also mediated by CD4(+) negative regulatory T cells. The induced immune tolerance was nullified after 400 cGy sublethal gamma irradiation. These results suggest that the ex vivo study of cytokine production by T cells may be used to monitor tolerance induction and the selection of gamma radiation dose is critical for potential clinical application of the tolerance induced by UV-B--PBMCs. (Blood. 2001;98:1239-1245)

Animals↗
PubMed2001

Antitumor agents. 207. Design, synthesis, and biological testing of 4beta-anilino-2-fluoro-4'-demethylpodophyllotoxin analogues as cytotoxic and antiviral agents.

2-Fluoropodophyllotoxin (11) and several 4beta-anilino-2-fluoro-4'-O-demethyl analogues were synthesized and evaluated in both antineoplastic and antiviral assays. These compounds were moderately active against some cancer cell lines, but they were less active than the corresponding nonfluorinated analogues. Compound 11 exhibited the best activity against KB carcinoma with a GI(50) of approximately 30 nM. Most compounds exhibited moderate activity against HCMV with ID(50) and ID(90) values in the range of 1 microM and 4 microM, respectively. Both 9 and 11 showed an unusual 10-fold selectivity for HSV-2 compared to HSV-1.

Animals↗
PubMed2001

Human CMV-IGIV (CytoGam) neutralizes human cytomegalovirus (HCMV) infectivity and prevents intracellular signal transduction after HCMV exposure.

Pretreatment of human cytomegalovirus (HCMV) with human hyperimmune globulin (CytoGam) in human embryonic lung (HEL) fibroblast culture showed successful inhibition of infectivity, and decreased extracellular viral titers and extracellular viral DNA. CytoGam prevented HCMV from inducing intracellular activation of NF-kappaB, Sp-1, and P13-K signaling pathways and the production of immediate-early (IE), early (E), and late (L) viral proteins. CytoGam neutralization of HCMV in this cell culture model prevented the earliest known signal transduction events (NF-kappaB, Sp-1, P13-K activation) after viral specific glycoproteins bind to their cognate cell membrane receptors, suggesting that this agent contains highly effective neutralizing antibodies against HCMV.

Antiviral Agents↗
PubMed2001

Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling.

Infection of quiescent fibroblasts with human cytomegalovirus (HCMV) was found to cause a rapid activation of cellular phosphatidylinositol 3-kinase (PI3-K). Maximum PI3-K activation occurred from 15 to 30 min postinfection. This activation was transient, and by 2 h postinfection (hpi), PI3-K activity had declined to preinfection levels. However, at 4 hpi, a second tier of PI3-K activation was detected, and PI3-K activity remained elevated relative to that of mock-infected cells for the remainder of infection. The cellular kinases Akt and p70S6K and the transcription factor NF-kappaB were activated in a PI3-K-dependent manner at similar times following HCMV infection. Analysis using UV-irradiated virus indicated that no viral protein synthesis was necessary for the first phase of PI3-K activation, but viral protein expression was required for the second tier of PI3-K activation. Treatment of infected fibroblasts with LY294002, a potent and specific inhibitor of PI3-K kinase activity, caused a 4-log decrease in viral titers. LY294002 did not inhibit viral entry, but it did decrease viral immediate-early gene expression. In addition, the protein levels of two viral early genes required for DNA replication, UL84 and UL44, were significantly lower in the presence of LY294002. Furthermore, viral DNA replication was strongly inhibited by LY294002 treatment. This inhibition of viral DNA replication could be reversed by adding back the products of PI3-K activity (PI-3,4-P(2) and PI-3,4,5-P(3)), demonstrating that the effect of LY294002 on the viral life cycle was specifically due to the inhibition of PI3-K activity. These results are the first to suggest that PI3-K mediates HCMV-induced activation of host cell mitogenic pathways. They also provide strong evidence that PI3-K activation is important for initiation of viral DNA replication and completion of the viral lytic life cycle.

Cell Line↗
PubMed2000

Ab initio construction of protein tertiary structures using a hierarchical approach.

We present a hierarchical method to predict protein tertiary structure models from sequence. We start with complete enumeration of conformations using a simple tetrahedral lattice model. We then build conformations with increasing detail, and at each step select a subset of conformations using empirical energy functions with increasing complexity. After enumeration on lattice, we select a subset of low energy conformations using a statistical residue-residue contact energy function, and generate all-atom models using predicted secondary structure. A combined knowledge-based atomic level energy function is then used to select subsets of the all-atom models. The final predictions are generated using a consensus distance geometry procedure. We test the feasibility of the procedure on a set of 12 small proteins covering a wide range of protein topologies. A rigorous double-blind test of our method was made under the auspices of the CASP3 experiment, where we did ab initio structure predictions for 12 proteins using this approach. The performance of our methodology at CASP3 is reasonably good and completely consistent with our initial tests.

Algorithms↗
PubMed2000

Fibroblast growth factor receptor-1 alpha-exon exclusion and polypyrimidine tract-binding protein in glioblastoma multiforme tumors.

Neoplastic transformation of glial cells alters inclusion of the alpha exon in human fibroblast growth factor receptor-1 (FGFR-1) mRNA transcripts. Although normal cells predominantly include the alpha exon, this exon is excluded in most glioblastoma cell transcripts, creating a high-affinity receptor form. In this study, we identified polypyrimidine tract-binding protein (PTB) as a regulator of FGFR-1 splicing. PTB interacted in a sequence-specific manner with the ISS-1 regulatory element in the intron upstream of the a exon. PTB expression was also strongly increased in seven malignant glioblastoma multiforme tumors relative to adjacent normal tissue, but not in a low-grade astrocytoma. These results suggest that increased expression of PTB may contribute to glial cell malignancy.

Cell Transformation, Neoplastic↗
PubMed2000

Constructing side chains on near-native main chains for ab initio protein structure prediction.

Is there value in constructing side chains while searching protein conformational space during an ab initio simulation? If so, what is the most computationally efficient method for constructing these side chains? To answer these questions, four published approaches were used to construct side chain conformations on a range of near-native main chains generated by ab initio protein structure prediction methods. The accuracy of these approaches was compared with a naive approach that selects the most frequently observed rotamer for a given amino acid to construct side chains. An all-atom conditional probability discriminatory function is useful at selecting conformations with overall low all-atom root mean square deviation (r.m.s.d.) and the discrimination improves on sets that are closer to the native conformation. In addition, the naive approach performs as well as more sophisticated methods in terms of the percentage of chi(1) angles built accurately and the all-atom r. m.s.d., between the native and near-native conformations. The results suggest that the naive method would be extremely useful for fast and efficient side chain construction on vast numbers of conformations for ab initio prediction of protein structure.

Amino Acids↗
PubMed2000

Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38.

Recent evidence indicates activated mitogen-activated protein kinase (MAPK) p38 has a critical function in human cytomegalovirus (HCMV) viral DNA replication in infected human fibroblasts. To elucidate the mechanism of HCMV-mediated p38 activation, we have performed a detailed analysis of p38 activation and the kinases associated with this activation at different times postinfection. We demonstrate that p38 kinase activity is strongly increased following viral infection. Inhibition of this activity significantly inhibited HCMV-induced hyperphosphorylation of pRb and phosphorylation of heat shock protein 27, suggesting that p38 activation is involved in virus-mediated changes in host cell metabolism throughout the course of infection. We then provide evidence that p38 activation is mediated by different mechanisms at early times versus later times of infection. At early times of infection (8 to 14 h postinfection [hpi]), when p38 activation is first observed, no significant activation of the three kinases which can directly phosphorylate p38 (namely, MKK3, MKK6, and MKK4) is detected. Using vectors which express dominant negative proteins, we demonstrate that basal MKK6 kinase activity is necessary for HCMV-mediated p38 activation at these early times of infection (12 hpi). Then, we use ATP depletion to show that at 12 hpi, HCMV inhibits dephosphorylation of activated p38. These two experiments suggest that HCMV activates p38 by inhibition of dephosphorylation of p38. In contrast to early times of infection, at later times of infection (48 to 72 hpi), increased MKK3/6, but not MKK4, activity is observed. These results indicate that at early times of HCMV infection, increased steady-state levels of activated p38 is mediated at least in part by inhibition of dephosphorylation of p38, while at later times of infection p38 activation is due to increased activity of the upstream kinases MKK3 and MKK6. These findings indicate that HCMV has developed multiple mechanisms to ensure activation of the MAPK p38, a kinase critical to viral infection.

Adenosine Triphosphate↗
PubMed2000

Probing structure-function relationships of the DNA polymerase alpha-associated zinc-finger protein using computational approaches.

We present the application of a method for protein structure prediction to aid the determination of structure-function relationships by experiment. The structure prediction method was rigourously tested by making blind predictions at the third meeting on the Critical Assessment of Protein Structure methods (CASP3). The method is a combined hierarchical approach involving exhaustive enumeration of all possible folds of a small protein sequence on a tetrahedral lattice. A set of filters, primarily in the form of discriminatory functions, are applied to these conformations. As the filters are applied, greater detail is added to the models resulting in a handful of all-atom "final" conformations. Encouraged by the results at CASP3, we used our approach to help solve a practical biological problem: the prediction of the structure and function of the 67-residue C-terminal zinc-finger region of the DNA polymerase alpha-associated zinc-finger (PAZ) protein. We discuss how the prediction points to a novel function relative to the sequence homologs, in conjunction with evidence from experiment, and how the predicted structure is guiding further experimental studies. This work represents a move from the theoretical realm to actual application of structure prediction methods for gaining unique insight to guide experimental biologists.

Amino Acid Sequence↗
PubMed1999

Redundant intronic repressors function to inhibit fibroblast growth factor receptor-1 alpha-exon recognition in glioblastoma cells.

The human fibroblast growth factor receptor-1 primary transcript is alternatively processed to produce receptor forms that vary in their affinity for fibroblast growth factor. The inclusion of a single exon (alpha) in normal brain glial cells produces a low affinity form of the receptor. Recognition of the alpha-exon is dysregulated during neoplastic transformation of glial cells to produce a high affinity receptor form. In this study, we have identified a second intronic repressor of RNA splicing located approximately 250 nucleotides upstream of the alpha-exon. Deletion or mutation of this sequence resulted in a significant increase in exon recognition in glioblastoma cells. This intronic repressor was found to share significant sequence homology with an intronic repressor element located downstream of the alpha-exon. The two repressor elements are functionally redundant in that they are capable of inhibiting alpha-exon recognition when positioned upstream or downstream of the exon. Finally, the elements were found to mediate enhanced exclusion of an unrelated exon, but only the repressors were placed flanking the exon. However, under these conditions, the cell-specific exon exclusion was no longer maintained. These results suggest that although the alpha-exon inclusion is actively repressed in glioblastomas, the absence of trans-activators appears to be key to the production of the high affinity form of fibroblast growth factor receptor-1 in glioblastomas.

Alternative Splicing↗
PubMed1999

Ab initio fold prediction of small helical proteins using distance geometry and knowledge-based scoring functions.

The problem of protein tertiary structure prediction from primary sequence can be separated into two subproblems: generation of a library of possible folds and specification of a best fold given the library. A distance geometry procedure based on random pairwise metrization with good sampling properties was used to generate a library of 500 possible structures for each of 11 small helical proteins. The input to distance geometry consisted of sets of restraints to enforce predicted helical secondary structure and a generic range of 5 to 11 A between predicted contact residues on all pairs of helices. For each of the 11 targets, the resulting library contained structures with low RMSD versus the native structure. Near-native sampling was enhanced by at least three orders of magnitude compared to a random sampling of compact folds. All library members were scored with a combination of an all-atom distance-dependent function, a residue pair-potential, and a hydrophobicity function. In six of the 11 cases, the best-ranking fold was considered to be near native. Each library was also reduced to a final ab initio prediction via consensus distance geometry performed over the 50 best-ranking structures from the full set of 500. The consensus results were of generally higher quality, yielding six predictions within 6.5 A of the native fold. These favorable predictions corresponded to those for which the correlation between the RMSD and the scoring function were highest. The advantage of the reported methodology is its extreme simplicity and potential for including other types of structural restraints.

Protein Folding↗
PubMed1999

Are predicted structures good enough to preserve functional sites?

BACKGROUND: A principal goal of structure prediction is the elucidation of function. We have studied the ability of computed models to preserve the microenvironments of functional sites. In particular, 653 model structures of a calcium-binding protein (generated using an ab initio folding protocol) were analyzed, and the degree to which calcium-binding sites were recognizable was assessed. RESULTS: While some model structures preserve the calcium-binding microenvironments, many others, including some with low root mean square deviations (rmsds) from the crystal structure of the native protein, do not. There is a very weak correlation between the overall rmsd of a structure and the preservation of calcium-binding sites. Only when the quality of the model structure is high (rmsd less than 2 A for atoms in the 7 A local neighborhood around calcium) does the modeling of the binding sites become reliable. CONCLUSIONS: Protein structure prediction methods need to be assessed in terms of their preservation of functional sites. High-resolution structures are necessary for identifying binding sites such as calcium-binding sites.

Animals↗
PubMed1999

Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression.

To continue our investigation of the cellular events that occur following human CMV (HCMV) infection, we focused on the regulation of cellular activation following viral binding to human monocytes. First, we showed that viral binding induced a number of immunoregulatory genes (IL-1beta, A20, NF-kappaB-p105/p50, and IkappaBalpha) in unactivated monocytes and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55) and gH (UL75), inhibited the induction of these genes. Next, we demonstrated that these viral ligands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors. We then investigated if HCMV binding also resulted in the translation and secretion of cytokines. Our results showed that HCMV binding to monocytes resulted in the production and release of IL-1beta protein. Because these induced gene products have NF-kappaB sites in their promoter regions, we next examined whether there was an up-regulation of nuclear NF-kappaB levels. These experiments showed that, in fact, NF-kappaB was translocated to the nucleus following viral binding or purified viral ligand binding. Changes in IkappaBalpha levels correlated with the changes in NF-kappaB translocation. Lastly, we demonstrated that p38 kinase activity played a central role in IL-1beta production and that it was rapidly up-regulated following infection. These results support our hypothesis that HCMV initiates a signal transduction pathway that leads to monocyte activation and pinpoints a potential mechanism whereby HCMV infection of monocytes can result in profound pathogenesis, especially in chronic inflammatory-type conditions.

Antibodies, Anti-Idiotypic↗