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PubMed2006

Engineered antibody Fc variants with enhanced effector function.

Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcgamma receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcgamma receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.

Alemtuzumab↗
PubMed2006

Structural basis for ligand promiscuity in cytochrome P450 3A4.

Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes and contributes to the metabolism of approximately 50% of marketed drugs. It is also the isoform most often involved in unwanted drug-drug interactions. A better understanding of the molecular mechanisms governing CYP3A4-ligand interaction therefore would be of great importance to any drug discovery effort. Here, we present crystal structures of human CYP3A4 in complex with two well characterized drugs: ketoconazole and erythromycin. In contrast to previous reports, the protein undergoes dramatic conformational changes upon ligand binding with an increase in the active site volume by >80%. The structures represent two distinct open conformations of CYP3A4 because ketoconazole and erythromycin induce different types of coordinate shifts. The binding of two molecules of ketoconazole to the CYP3A4 active site and the clear indication of multiple binding modes for erythromycin has implications for the interpretation of the atypical kinetic data often displayed by CYP3A4. The extreme flexibility revealed by the present structures also challenges any attempt to apply computational design tools without the support of relevant experimental data.

Crystallography↗
PubMed1999

Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease.

We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site-the properties that must be conserved in any mutant protease to retain the ability to bind and cleave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possible.

Amino Acid Sequence↗
PubMed2004

Mediterranean Adequacy Index of Italian diets.

OBJECTIVE: To assess, particularly in longitudinal studies, how close or far the food intakes of population groups are from a reference dietary pattern. DESIGN: Computation of an index, called the Mediterranean Adequacy Index (MAI), by dividing the sum of the percentage of total energy from typical Mediterranean food groups by the sum of the percentage of total energy from non-typical Mediterranean food groups. The reference Italian-Mediterranean diet utilised was that of subjects from Nicotera in 1960. SETTING: Different areas in Italy. SUBJECTS: Men aged 45-65 years at the start of the study from rural areas of Italy in the Seven Countries Study followed for 26 years (Crevalcore and Montegiorgio), elderly men and women from Perugia followed for 11 years, men and women from Pollica (Salerno) followed for 32 years, and families from Rofrano (Salerno) followed for 41 years. RESULTS: The median value of MAI among 40-59-year-old men from Nicotera in 1960 was 7.2; in Crevalcore it was 2.9 in 1965 and 2.2 in 1991; and in Montegiorgio, 5.6 in 1965 and 3.9 in 1991. In Pollica, the values in men ranged from 5.6 to 6.3 in 1967 and from 2.4 to 4.5 in 1999; for women, the corresponding ranges were 4.2-7.2 and 2.7-4.1. In elderly men of Perugia, median MAI value was 4.9 in 1976 and 3.2 in 1987; for women, the corresponding values were 3.1 and 2.6. CONCLUSIONS: The diet of these Italian population groups has changed over the last four decades, progressively abandoning the nutritional characteristics of the reference Italian-Mediterranean diet. The MAI proposed is simple to compute; it has satisfactory discriminating power particularly for longitudinal dietary data with only a few limitations.

Adolescent↗
PubMed2004

An audit of outpatient antipsychotic usage in the three health sectors of Auckland, New Zealand.

OBJECTIVE: To examine antipsychotic usage in outpatients in three community mental health centres. METHOD: A retrospective chart review was conducted for all outpatient files that were active in March 2000 at all community mental health services in Auckland (population 1.3 million). All patients prescribed an antipsychotic had information entered into a specifically designed computer software program. The antipsychotic, dose and route of administration were recorded. The diagnosis, number of hospitalizations, ethnicity and gender were also collected. RESULTS: 6558 community files were audited and 3254 people were prescribed antipsychotics; 3178 (97.6%) files had adequate information for study inclusion. The mean antipsychotic daily dose in chlorpromazine equivalents (CPZe) was 360 mg. Most of the population (76.6%) was prescribed an oral antipsychotic alone, 14.9% were prescribed depot antipsychotic only and 8.4% were on a depot and oral antipsychotic. The average daily dose prescribed for people on antipsychotic polypharmacy was 601 mg CPZe compared with 312 mg CPZe for those on a single antipsychotic. There were 2300 patients with schizophrenia (72.5% of cohort) and 585 patients with bipolar affective disorder (18.5%). The mean total daily dose in CPZe was significantly higher for schizophrenia than any other psychotic diagnoses. Regional analysis showed differences in the doses and type of antipsychotics prescribed; one health sector had significantly higher daily doses while another was significantly more likely to prescribe atypical antipsychotics and correspondingly fewer depot antipsychotics. CONCLUSIONS: There is a significant variation in the prescribing of antipsychotics across the three Auckland health sectors. The variation relates to dosage used, type of antipsychotics prescribed and effect of multiple antipsychotic prescribing. Combination therapy of more than one oral antipsychotic or a combination of oral and depot antipsychotics leads to a significant trend of higher doses in excess of best practice guidelines.

Adult↗
PubMed2001

Improved efficiency of mutation detection by denaturing high-performance liquid chromatography using modified primers and hybridization procedure.

The addition of a 20-base GC-clamp to a DNA fragment enabled mutations to be detected by denaturing high-performance liquid chromatography (DHPLC) in the higher melting domain of the two-domain fragment DYS271. The mutations were undetectable in the absence of the GC-clamp. The heteroduplex yield was greatly decreased by the presence of mutations in the high melting domain, presumably because this region anneals first during cooling, leading to selection of the more stable homoduplexes. Suppression of sequence-dependent melting behavior using betaine increased the heteroduplex yield almost four-fold. Mutations in the high melting domain were detected at 60 degrees C, whereas mutations in the low melting domain were detected at 56 degrees C. Computer modeling of the melting behavior agreed well with the experimental results, facilitating computer design of DHPLC amplicons.

Base Pair Mismatch↗
PubMed2003

ddbRNA: detection of conserved secondary structures in multiple alignments.

MOTIVATION: Structured non-coding RNAs (ncRNAs) have a very important functional role in the cell. No distinctive general features common to all ncRNA have yet been discovered. This makes it difficult to design computational tools able to detect novel ncRNAs in the genomic sequence. RESULTS: We devised an algorithm able to detect conserved secondary structures in both pairwise and multiple DNA sequence alignments with computational time proportional to the square of the sequence length. We implemented the algorithm for the case of pairwise and three-way alignments and tested it on ncRNAs obtained from public databases. On the test sets, the pairwise algorithm has a specificity greater than 97% with a sensitivity varying from 22.26% for Blast alignments to 56.35% for structural alignments. The three-way algorithm behaves similarly. Our algorithm is able to efficiently detect a conserved secondary structure in multiple alignments.

Algorithms↗
PubMed2005

Residue-rotamer-reduction algorithm for the protein side-chain conformation problem.

MOTIVATION: The protein side-chain conformation problem is a central problem in proteomics with wide applications in protein structure prediction and design. Computational complexity results show that the problem is hard to solve. Yet, instances from realistic applications are large and demand fast and reliable algorithms. RESULTS: We propose a new global optimization algorithm, which for the first time integrates residue reduction and rotamer reduction techniques previously developed for the protein side-chain conformation problem. We show that the proposed approach simplifies dramatically the topology of the underlining residue graph. Computations show that our algorithm solves problems using only 1-10% of the time required by the mixed-integer linear programming approach available in the literature. In addition, on a set of hard side-chain conformation problems, our algorithm runs 2-78 times faster than SCWRL 3.0, which is widely used for solving these problems. AVAILABILITY: The implementation is available as an online server at http://eudoxus.scs.uiuc.edu/r3.html

Algorithms↗
PubMed1991

Comparison of selective arginine vasopressin V1 and V2 receptor antagonists on burn shock in the rat.

STUDY OBJECTIVE: Two selective V1 and V2 receptor antagonists of arginine vasopressin, d(CH2)5Tyr(Me)AVP and d(CH2)5[D-Ile2, Ile4, Ala9-NH2]AVP, were given intravenously in burn shocked rats to investigate the respective effects of V1 and V2 receptor blockade on the haemodynamic variables in burn shock. DESIGN: Computer assisted on line real time measurements of mean arterial blood pressure, diastolic blood pressure, left ventricular systolic pressure, dP/dtmax, and heart rate were used to study the effects of the receptor antagonists during burn shock. In addition, the radioactive microsphere method was used to measure the changes of cardiac output and regional blood flows to heart, kidney, and liver in response to the antagonists during burn shock. Third degree burns extending over 30% of body surface area were made by dipping the rat's shaved back into water at 100 degrees C for 20 s. EXPERIMENTAL MATERIAL: Male Sprague-Dawley rats (250-300 g) were used in groups of 6-9 per experiment. MEASUREMENTS AND MAIN RESULTS: Mean and diastolic arterial blood pressures, left ventricular systolic pressure, dP/dtmax and heart rate were measured for 8 h after burns. Cardiac output and regional blood flow were measured at 3 h and 8 h postburn. Results showed that blockade of V1 receptor lowered mean and diastolic arterial blood pressures throughout the 8 h period, and raised left ventricular systolic pressure and dP/dtmax only during the early phase of shock. Cardiac output and blood flows to heart, kidney, and liver were increased by the V1 antagonist at 3 h but not at 8 h postburn. The V2 receptor antagonist increased mean and diastolic arterial blood pressures, left ventricular systolic pressure, and dP/dtmax both during the early and during the late phases of burn shock. It also improved cardiac output and blood flows to the heart, kidney, and liver during the early and late phases of burn shock. However, heart rate was not affected by V1 and V2 receptor antagonists. CONCLUSIONS: The V2 like receptor may be the dominating receptor mediating vasopressin's inhibitory effect on the heart. V1 receptor mediated coronary vasoconstriction contributes to the myocardial depression possibly only at the compensatory phase of shock. In addition V1 receptor mediated vasoconstriction is important in maintaining blood pressure during burn shock.

Angiotensin Receptor Antagonists↗
PubMed1993

Prospective evaluation of an EDB-based diagnostic program to be used in patients admitted to hospital with acute chest pain.

A recently designed computer based decision support system (DSP), almost exclusively based on case history data, was developed to facilitate immediate differentiation between patients with and without urgent need for coronary care unit (CCU) transferral from the emergency room, and additionally to distinguish between patients with and without acute myocardial infarction (MI). One-year's prospective testing in a consecutive series of 1252 patients with acute chest pain revealed that the DSP, used in addition to ECG and clinical examination, demonstrated a sensitivity of 96% in the detection of patients in need of CCU observation (MI-sensitivity of 98%), and a specificity of 56% in excluding patients who were not in need of CCU observation. The proportion of referrals to the CCU judged to be unnecessary was only 17% of the total number of patients seen in the emergency room.

Angina, Unstable↗
PubMed1993

Project Safety Net: a health screening outreach and assessment program.

Although comprehensive geriatric assessment (CGA) has been conducted in many settings, its use in community-based outreach programs has been limited. We have developed Project Safety Net, a program that identifies low-income urban-dwelling frail elderly persons and provides CGA and appropriate referral. The program uses validated screening instruments and makes extensive use of a custom-designed computer program to provide information to the interdisciplinary team and for research purposes. During an 8 month period, 814 older persons were screened including high proportions who were widowed (51%) and who lived alone (66%). The effectiveness of this program remains to be determined in a randomized clinical trial.

Aged↗
PubMed2005

Audiometric threshold shift definitions: simulations and suggestions.

OBJECTIVES: Determine (1) whether pure-tone average (PTA) or "any frequency" (AF) definitions of significant threshold shift (STS) are more accurate under different conditions; (2) whether STS definitions applied twice are more accurate than when applied once; (3) whether three surrogate analysis methods applicable to real-world audiometric data can appropriately measure the accuracy of STS definitions; and (4) whether evidence from previous studies supports a change in the current STS definition used by the Occupational Safety and Health Administration (OSHA); (5) make recommendations for future research. DESIGN: Computer simulation of periodic audiograms, with typical test-retest variability, from seven groups of individuals (N = 1000 each), with or without threshold shifts of different sizes at different frequencies; receiver operating characteristic area analysis to determine relative accuracy of PTA and AF decision variables, applied once or twice; testing of surrogate methods (confirmation, variability, and comparison) against receiver operating characteristic areas in estimation of accuracy of decision variables; review of previous studies, considering the limitations of the surrogate methods that were used. RESULTS: Either AF or PTA definitions may be preferable, depending on whether the genuine threshold shift has occurred at a single frequency or across a range of frequencies. Including too few or too many frequencies degrades the performance of both AF and PTA variables. An STS decision variable performs only slightly better when applied twice than when applied once. The surrogate methods can be useful, but all have important caveats: The comparison method is best, but only when an appropriate control group is available; the variability method is intermediate but requires that each decision variable be tested at multiple criterion values for reliable results. The confirmation method, which was the least accurate in assessing true performance, also requires testing at multiple levels. Even when this is done, it markedly exaggerates the benefit of applying an STS definition twice and makes STS definitions that identify large numbers of individuals falsely appear to be more accurate than definitions that identify smaller numbers of individuals. Taking these caveats into account, previous studies do not offer convincing evidence for a change in the current OSHA STS definition. CONCLUSIONS: Choice of an STS definition requires three judgments that cannot be made based on the type of analysis discussed in this report: The range of frequencies to be tested, whether to require that an STS definition be applied twice, and the acceptable magnitude of false-positive error. Once these judgments have been made, the techniques discussed here can assist in selecting the appropriate decision variable (typically PTA or AF) and a criterion value that yields an acceptable false-positive rate. Additional research using the techniques described in this report with either new or old audiometric databases could help determine whether any STS definition is significantly better than the current OSHA definition.

Audiometry, Pure-Tone↗
PubMed1997

A prioritization and analysis strategy for environmental surveillance results.

DOE facilities are required to conduct environmental surveillance to verify that facility operations are operated within the approved risk envelope and have not caused undue risk to the public and the environment. Given a reduced budget, a strategy for analyzing environmental surveillance data was developed to set priorities for sampling needs. The radiological and metal data collected at Sandia National Laboratories, New Mexico, were used to demonstrate the analysis strategy. Sampling locations were prioritized for further investigation and the needs for routine sampling. The process of data management, analysis, prioritization, and presentation has been automated through a custom-designed computer tool. Data collected over years can be analyzed and summarized in a short table format for prioritization and decision making.

Cesium Radioisotopes↗
PubMed2003

The effect of sacral fracture malreduction on the safe placement of iliosacral screws.

OBJECTIVES: To determine the effects of cranial displacement on the safe placement of iliosacral screws for zone II sacral fractures. DESIGN: Computer imaging and dimensional analysis of a human cadaveric sacral fracture model. SETTING: Cadaveric dissection, Orthopaedic Research Laboratories, Newark, New Jersey. MAIN OUTCOME MEASUREMENTS: Six cadaveric pelves with simulated zone II sacral fractures were imaged with computed tomography at controlled cranial displacements of 5, 10, 15, and 20 mm. The area of contact at the fracture site and volume of bone available for iliosacral screw placement was graphically measured using both two- and three-dimensional computer modeling. Areas of contact were also represented in terms of the maximal number of 7.0-mm screws that could be simultaneously implanted. RESULTS: Cross-sectional contact area was decreased by 30%, 56%, 81%, and 90% at 5, 10, 15 and 20 mm of displacement, respectively. Volume of bone was decreased by 21%, 25%, 26%, and 34% for 5, 10, 15 and 20 mm of displacement, respectively. In 50% of the specimens at 15 mm and 66% of the specimens with 20 mm displacement, two iliosacral screws could not be contained simultaneously within bone. In 17% of the specimens displaced 15 mm and 50% of the specimens displaced 20 mm, the cross-sectional area was insufficient to contain a single iliosacral screw. CONCLUSIONS: Although previous authors have accepted up to 15 mm of cranial displacement, the data demonstrate substantial compromise of available screw space with displacements greater than 1 cm. Fracture reduction is mandatory, as screw placement with residual displacement of 10 mm or more can endanger adjacent neural and vascular structures.

Aged↗
PubMed1994

Osteology of the pediatric skull. Considerations of halo pin placement.

STUDY DESIGN: Computed tomography scans of the heads of 48 normal children were measured for skull thickness in areas of routine halo pin placement. The thickest and thinnest areas were noted. OBJECTIVES: The head computed tomography scans were measured to identify consistently thin areas in the pediatric skull that should be avoided when pins are placed. SUMMARY OF BACKGROUND DATA: Complications of halo pin placement in children are common, including loosening and dislodgment, infection and penetration. METHODS: Normal head computed tomography scans of 48 normal children, 10 years old and under, were divided into four age groups. Total skull thickness was measured in five areas at the level of halo insertion. RESULTS: There was a trend toward increasing skull thickness with age. There was a large variation in skull thickness at each area within and between age groups. None of the standard pin sites was consistently thicker. Even up to 10 years of age, the average thinnest area was only 1.9 mm. CONCLUSIONS: There is no "safe area" for halo pin placement in the pediatric skull. Limited preoperative head computed tomography scans are recommended to determine safe areas for pin placement.

Bone Nails↗
PubMed2004

Long-term effects of connective tissue cancer treatment.

In 1999, we began a study to assess the long-term effect of connective tissue cancer treatment on clinical, social, and psychologic aspects of the lives of surviving patients. A specially designed computer program generated an 85-item questionnaire, which was sent to more than 2000 patients with malignant bone and soft tissue neoplasms. Twelve hundred forty-four patients responded. The data were entered into a computer system and were correlated with the clinical information already contained in the system for the individual patients. Although there are many possible uses for these data, we chose to do a study comparing the lifestyle and physical and sociologic problems for 144 patients treated with chemotherapy and surgery for high-grade osteosarcoma against a control population consisting of 61 patients treated surgically for benign giant cell tumors of bone. The data show a remarkable degree of compensation on the part of the patients with the malignant tumors in terms of some problems but some significant differences particularly in physical status and functional limitations.

Activities of Daily Living↗
PubMed2004

Survival data for 648 patients with osteosarcoma treated at one institution.

During the past 30 years, the orthopaedic oncology group at the Massachusetts General Hospital has treated 648 patients with osteosarcoma centrally located in the bone. Using records maintained in a specifically designed computer system, a study was done to assess the factors that seemed to influence the survival outcome. The overall survival for the entire series was 68% at an average followup of 6 +/- 4 years. Death occurred at a mean of 3 +/- 3 years. Patient gender had no effect, but age of the patient was correlated with survival data, with the poorest survival for the older patients. Surgical treatment had no effect on outcome, but the Musculoskeletal Tumor Society stage of the lesion, the presence of metastases or local recurrence, and the chemotherapeutic treatment (very dependent on the drugs available and adjuvant versus neoadjuvant administration at various decades) all had a profound effect. In addition, anatomic location, size of the tumor, and percentage of tumor cells killed after neoadjuvant chemotherapy all had an effect on outcome.

Adolescent↗
PubMed2003

Buckling and bone modeling as factors in the development of idiopathic scoliosis.

STUDY DESIGN: Computational analysis using the finite-element method was used to examine a possible etiology of idiopathic scoliosis. OBJECTIVES: To compare changes in the coronal and the transverse planes of idiopathic thoracic scoliosis with changes produced in a finite-element buckling model, and to investigate the influence of bone modeling on the buckling spine. SUMMARY OF BACKGROUND DATA: Although it is now widely accepted that growth is related strongly to the onset and progression of scoliosis, the pathomechanism or etiology of idiopathic scoliosis still is not clear. A previous study showed that a buckling phenomenon caused by anterior spinal overgrowth can produce scoliosis, and that the fourth buckling mode matched the clinical characteristics associated with the thoracic type of idiopathic scoliosis. The fourth buckling mode occurs when the first, second, and third buckling modes are prevented. METHODS: The spinal finite-element model used in this study consisted of 68,582 elements and 84,603 nodes. The transverse changes seen in the computed tomography images of 41 patients with idiopathic thoracic scoliosis (apex, T8; average Cobb angle, 52.5 degrees) were compared with those produced in the fourth buckling mode. Bone modeling (bone formation and resorption) was simulated as heat deformation caused by changes in temperature. The bone formation and resorption were simulated, respectively, by positive and negative volume changes in proportion to the stress that occurred in the buckling spine. RESULTS: Computed tomography images of scoliosis show that as the scoliosis becomes more severe, the thoracic cage decreases on the convex side of the curve and increases on the concave side. The opposite thoracic cage deformation was obtained in the fourth buckling mode. In patients with scoliosis, the sternum essentially remains in its original position with respect to the vertebrae, but in the linear buckling model, it shifted in the direction of vertebral body rotation. In contrast to clinical data, the incremental deformation resulting from bone formation corrected the original curve, and the thoracic cage distorted. On the other hand, incremental deformation resulting from bone resorption worsened the original curve, and the thoracic cage distorted in a manner similar to that described by the clinical data. CONCLUSIONS: This computational investigation suggests that scoliotic changes in the spinal column triggered by the buckling phenomenon are counteracted by bone formation, but worsened by bone resorption. The authors hypothesized that scoliosis progressed with resorption of loaded bone. However, it is unclear whether this hypothesis applies to a living body in practice because of the effects from additional factors.

Bone Resorption↗