John K. Vries

The medical archival system: an information retrieval system based on distributed parallel processing

Abstract The Medical ARchival System (MARS) is an information retrieval system utilizing distributed parallel processing. It features a modular design, machine independence, and a Boolean query interface, based in a UNIX environment. Developed at the University of Pittsburgh in response to the information needs of a large academic health center, MARS integrates textual data from a wide variety of sources to create a single, comprehensive medical records information system. It currently contains 850,000 medical reports, 2,500,000 medical references, and 500,000,000 indexed words. This paper describes the software design of MARS and its implementation as a practical system for large-scale information management.

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

Significance Most cancers are characterized by increased STAT3 activation where phosphorylated STAT3 levels are associated with reduced survival. The molecular mechanisms underlying aberrant STAT3 phosphorylation/activation in human malignancies have been elusive. Our findings provide a mechanistic basis for tumor-specific STAT3 hyperactivation in head and neck squamous cell carcinoma (HNSCC). We demonstrate that receptor-like protein tyrosine phosphatases, encoded by PTPR genes, including PTPRT, are commonly mutated in HNSCC where PTPR mutations are associated with increased phosphorylation of STAT3 in tumors. Several cancer-related PTPRT mutations localize to the substrate interaction surface of the enzyme catalytic domains. Expression of mutated PTPRT in HNSCC models markedly increases STAT3 activation, promoting cellular survival. PTPRT mutations may therefore serve as predictive biomarkers for STAT3 pathway inhibitors, suggesting new therapeutic opportunities. The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a “driver” phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine–substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.

Stereotactic implantation of deep brain electrodes using computed tomography

The selection of intracranial targets for stereotactic functional neurosurgical procedures traditionally has relied on information derived from pooled brain atlases and supplemented by contrast encephalographic or angiographic data from the individual patient. The integration of stereotaxy with computed tomography (CT) has permitted direct identification of intracranial targets based on multiplanar reformatted CT images from each individual patient. Four patients underwent the CT stereotactic implantation of a single deep brain electrode for the control of chronic pain (two cases) or of multiple depth electrodes for long term electroencephalographic recordings in the management of seizure disorders (two cases). In all patients, accurate and precise electrode placement was achieved from CT images alone. The use of CT permitted detailed anatomical stereotactic study of each patients brain, the preplotting of electrode trajectories before probe insertion, and the rapid confirmation of precise electrode placement. Intraoperative contrast encephalography was not necessary. Functional neurosurgery was performed successfully and advantageously using CT stereotactic technique alone.

A Sequence Alignment-Independent Method for Protein Classification

Annotation of the rapidly accumulating body of sequence data relies heavily on the detection of remote homologues and functional motifs in protein families. The most popular methods rely on sequence alignment. These include programs that use a scoring matrix to compare the probability of a potential alignment with random chance and programs that use curated multiple alignments to train profile hidden Markov models (HMMs). Related approaches depend on bootstrapping multiple alignments from a single sequence. However, alignment-based programs have limitations. They make the assumption that contiguity is conserved between homologous segments, which may not be true in genetic recombination or horizontal transfer. Alignments also become ambiguous when sequence similarity drops below 40%. This has kindled interest in classification methods that do not rely on alignment. An approach to classification without alignment based on the distribution of contiguous sequences of four amino acids (4-grams) was developed. Interest in 4-grams stemmed from the observation that almost all theoretically possible 4-grams (204) occur in natural sequences and the majority of 4-grams are uniformly distributed. This implies that the probability of finding identical 4-grams by random chance in unrelated sequences is low. A Bayesian probabilistic model was developed to test this hypothesis. For each protein family in Pfam-A and PIR-PSD, a feature vector called a probe was constructed from the set of 4-grams that best characterised the family. In rigorous jackknife tests, unknown sequences from Pfam-A and PIR-PSD were compared with the probes for each family. A classification result was deemed a true positive if the probe match with the highest probability was in first place in a rank-ordered list. This was achieved in 70% of cases. Analysis of false positives suggested that the precision might approach 85% if selected families were clustered into subsets. Case studies indicated that the 4-grams in common between an unknown and the best matching probe correlated with functional motifs from PRINTS. The results showed that remote homologues and functional motifs could be identified from an analysis of 4-gram patterns.

The Image Engine HPCC project. A medical digital library system using agent-based technology to create an integrated view of the electronic medical record

This paper describes the Image Engine project supported by the National Library of Medicines (NLM) biomedical applications of High Performance Computing and Communications (BAA/HPCC) program. Image Engine is a multi-user, object-oriented, client server database system for the storage, retrieval, integration and sharing of a wide range of biomedical images. In addition, Image Engine uses agent-based technology to implement real-time links between medical images and associated data stored in external database systems. This project is a first step towards implementing a multimedia electronic medical record system. As a digital library architecture Image Engine has the potential to support innovative applications in the clinical, research and educational domains of medicine.

Radiologic automated diagnosis (RAD)

RAD is a program currently being developed to interpret neuroimages. Given the clinical information usually available on the imaging request, RAD will analyze the scan directly from the data generated by the scanning machine to produce a differential diagnostic list explaining any lesions it discovers. RAD uses a computerized three-dimensional stereotaxic atlas of the nervous system as a model of normal structures in the analysis of scans.

The relationship between N-gram patterns and protein secondary structure

An n‐gram pattern (NP{n,m}) in a protein sequence is a set of n residues and m wildcards in a window of size n+m. Each window of n+m amino acids is associated with a collection of NP{n,m} patterns based on the combinatorics of n+m objects taken m at a time. NP{n,m} patterns that are shared between sequences reflect evolutionary relationships. Recently the authors developed an alignment‐independent protein classification algorithm based on shared NP{4,2} patterns that compared favorably to PSI‐BLAST. Theoretically, NP{4,2} patterns should also reflect secondary structure propensity since they contain all possible n‐grams for 1 ≤ n ≤ 4 and a window of 6 residues is wide enough to capture periodicities in the 2 ≤ n ≤ 5 range. This sparked interest in differentiating the information content in NP{4,2} patterns related to evolution from the content related to local propensity. The probability of α‐, β‐, and coil components was determined for every NP{4,2} pattern over all the chains in the Protein Data Bank (PDB). An algorithm exclusively based on the Z‐values of these distributions was developed, which accurately predicted 71–76% of α‐helical segments and 62–67% of β‐sheets in rigorous jackknife tests. This provided evidence for the strong correlation between NP{4,2} patterns and secondary structure. By grouping PDB chains into subsets with increasing levels of sequence identity, it was also possible to separate the evolutionary and local propensity contributions to the classification process. The results showed that information derived from evolutionary relationships was more important for β‐sheet prediction than α‐helix prediction. Proteins 2007.

Influence of Closure Technique on Results in Myelomeningocele

The results of the repair of myelomeningoceles by, respectively, reconstitution of the neural tube and simple replacement of the placode within the dural sheath are examined. It is concluded that neither offers any significant advantages over the other. When no neurologic function is present below the upper level of the lesion, no method of repair is likely to result in improvement, while the mere preservation of reflex activity in the distal segment of cord may be counterproductive. It is suggested, therefore, that there is a place for immediate excision of the lesion in properly selected cases.

Cerebral fluid overproduction in the absence of tumor or villous hypertrophy of the choroid plexus

A case of cerebrospinal fluid overproduction in a 2.5-year-old child is reported. The rate of cerebrospinal fluid production was more than four times the expected amount. There was no evidence of tumor or villous hypertrophy of the choroid plexus. The child was successfully treated with a ventriculoatrial shunt.

Childhood oligodendrogliomas presenting with seizures and low‐density lesions on computed tomography

Three children with cerebral oligodendrogliomas causing partial complex or generalized seizures presented with completely normal neurologic examinations. CT showed low-density, nonenhancing surface lesions. Although these CT features are usually associated with infarcts or cysts, neoplasm was suspected because of irregularity of the margins and erosion of the adjacent inner table of the skull. Oligodendrogliomas often enlarge slowly and may cause seizures years before they produce focal neurologic signs. CT of all children with seizures not responsive to anticonvulsant medication and focal clinical or EEG abnormalities will hasten diagnosis of slowly growing intracranial mass lesions.