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OBJECTIVE: The Huntsman Cancer Institute Research Informatics Shared Resource (RISR), a software and database development core facility, sought to address a lack of published operational best practices for research informatics cores. It aimed to use those insights to enhance effectiveness after an increase in team size from 20 to 31 full-time equivalents coincided with a reduction in user satisfaction. MATERIALS AND METHODS: RISR migrated from a water-scrum-fall model of software development to agile software development practices, which emphasize iteration and collaboration. RISR's agile implementation emphasizes the product owner role, which is responsible for user engagement and may be particularly valuable in software development that requires close engagement with users like in science. RESULTS: All RISR's software development teams implemented agile practices in early 2020. All project teams are led by a product owner who serves as the voice of the user on the development team. Annual user survey scores for service quality and turnaround time recorded 9 months after implementation increased by 17% and 11%, respectively. DISCUSSION: RISR is illustrative of the increasing size of research informatics cores and the need to identify best practices for maintaining high effectiveness. Agile practices may address concerns about the fit of software engineering practices in science. The study had one time point after implementing agile practices and one site, limiting its generalizability. CONCLUSIONS: Agile software development may substantially increase a research informatics core facility's effectiveness and should be studied further as a potential best practice for how such cores are operated.

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OBJECTIVE: To assess the effects of treatment with rituximab plus methotrexate on patient-reported outcomes in patients with active rheumatoid arthritis (RA) who experienced inadequate response to anti-tumor necrosis factor therapy. METHODS: Patients with active RA were randomly assigned to rituximab (1,000 mg on days 1 and 15) or placebo. The primary end point was the proportion of patients with an American College of Rheumatology 20% response at week 24. Additional goals were to assess treatment effects on pain, fatigue, functional disability, health-related quality of life, and disease activity by comparing mean changes between groups. The analysis was conducted in the intent-to-treat population. The proportion of patients who achieved the minimum clinically important difference on the Health Assessment Questionnaire (HAQ) disability index (DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Short Form 36 (SF-36) was determined. RESULTS: Rituximab patients had statistically significantly greater pain relief. The FACIT-F showed significantly greater improvement in rituximab patients than placebo patients from weeks 12 through 24. Mean improvement from baseline in functional disability (measured by the HAQ DI) was significantly greater in rituximab patients from weeks 8 to 24. The mean +/- SD change from baseline for the SF-36 Physical Component Score was 6.64 +/- 8.74 for rituximab patients and 1.48 +/- 7.32 for placebo patients (P < 0.0001). The mean change from baseline for the SF-36 Mental Component Score was 5.32 +/- 12.41 for rituximab patients and 2.25 +/- 12.23 for placebo patients (P = 0.0269). CONCLUSION: Rituximab produced rapid, clinically meaningful, and statistically significant improvements in patient-reported pain, fatigue, functional disability, health-related quality of life, and disease activity. These effects were sustained throughout the study.

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OBJECTIVE: To identify the genetic mutation responsible for autosomal dominant spastic paraplegia (HSP) in a large family with a "pure" form of the disorder. BACKGROUND: The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21-p22. Some of these families have mutations in the splice-site or coding regions of the spastin gene (SPAST). METHODS: Linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by single-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods were used to investigate incongruous mobility shifts. RESULTS: The genomic sequence of SPAST showed a heterozygous four--base pair deletion (delTAAT) near the 3' splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes). CONCLUSIONS: This study identifies an atypical intronic microdeletion in SPAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.

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Tinea capitis is one of the most common infections of children. The standard treatment is griseofulvin. Itraconazole and terbinafine have in large part replaced griseofulvin in the treatment of onychomycosis and, in addition to fluconazole and ketoconazole, are evolving treatments for tinea capitis. The purpose of this review is to compare the efficacy, safety, and cost of oral antifungal agents for tinea capitis. Small, open-label studies of itraconazole, terbinafine, and fluconazole have reported encouraging results, suggesting that these drugs may be effective alternatives to griseofulvin; however, in large controlled studies griseofulvin continues to exhibit greater or equal efficacy. Ketoconazole appears to be the least efficacious. All five drugs appear relatively safe, however, only griseofulvin has a long track record of safety, is Food and Drug Administration (FDA) approved for the treatment of tinea capitis in children, and has the least known drug interactions. Fluconazole is FDA approved for use in children more than 6 months of age, yet not for the treatment of tinea capitis. Oral griseofulvin and terbinafine tablets are the least expensive of the antifungal agents; griseofulvin suspension is, however, more expensive than fluconazole suspension. For the combined reasons of efficacy, safety, and cost, and a long track record of use, we feel oral griseofulvin is still the present treatment of choice for tinea capitis. Newer antifungals are currently under investigation, and their role in treating tinea capitis in children is still being defined.

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OBJECTIVE: To establish genetic linkage between polymorphic microsatellite loci and a disease locus responsible for an autosomal recessive type of nonsyndromic mental retardation (MR). BACKGROUND: Although MR is the most common developmental disability in the United States, the etiologies of most nonsyndromic cases are not known. METHODS: A genealogic database provided information to reconstruct the relationships between 32 individuals from five nuclear families in a single pedigree with 10 affected individuals with nonsyndromic MR. To find a MR disease locus in this population, we performed a genome-wide search using genetic loci spaced at 10- to 20-cM intervals. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to localize the disease gene. RESULTS: Genetic linkage between a MR disease locus and locus D3S3050 on chromosome 3p25-pter was established with a Zmax = 9.18 at theta = 0.00. Fine mapping this region delimited a 13. 47-cM candidate interval defined by key recombinants at loci D3S3525 and D3S1304. Multipoint linkage analysis refined the critical region to a 6.71-cM interval flanked by loci D3S3525 and D3S1560. Evidence that a gene for MR resides in this location is supported by previous breakpoint deletion mapping studies performed in the chromosome 3p- syndrome. CONCLUSIONS: These results suggest that a gene on the subtelomeric region of chromosome 3p contributes to general intelligence. The genes for the cell adhesion L1-like molecule (CALL), the inositol triphosphate receptor (ITPR1), and the AD neuronal thread protein (AD7c-NTP) are leading positional candidates because of their role in brain development, neuronal signaling, and structure.

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Autosomal recessive posterior column ataxia and retinitis pigmentosa (PCARP) is a movement disorder that was genetically mapped to a disease locus (AXPC1) on chromosome 1q32-q31 in an inbred population of Dutch-German ancestry in the continental United States. We performed genetic linkage analysis and haplotype reconstruction on a different family from Spain with an identical phenotype to determine if the neurologic signs of an early-onset ataxia, retinitis pigmentosa, and a sensory neuropathy also mapped to the AXPC1 locus. The disease phenotype was linked in the candidate interval with a maximum lod score of 3.56 at a recombination fraction of 0.0 for locus D1S414. Haplotypes were discordant and suggested that the disease mutation arose independently from at least two populations. These results refine the classification of early-onset ataxia, abrogate a founder effect for this recessive disorder, and provide evidence that PCARP is a distinct, homogeneous, clinical, and genetic disorder.

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OBJECTIVE: To identify genetic mutations in the coding regions and the splice-donor sites of the tau gene on chromosome 17q in individuals with progressive supranuclear palsy (PSP). BACKGROUND: Several studies provide evidence for linkage disequilibrium between a PSP disease gene and allelic variants of the tau gene. However, a causative mutation has not been identified. METHODS: We designed a study to search for genetic mutations in 15 coding regions of the tau gene including the splice-donor sites in 22 patients with PSP by comparing the mobility shifts on single-strand conformation analysis with those of age-matched controls. Fragments with altered migration were sequenced directly and compared for differences in nucleotide composition. Restriction enzyme digests were used to confirm single base-pair substitutions. RESULTS: Significant differences in mobility shifts were found in exons 1, 4A, and 8 between affected individuals and age-matched controls. All individuals with PSP had a common extended haplotype characterized by a homozygous polymorphism in the 5' splice site untranslated region of exon 1, two missense mutations in exon 4A (Asp285Asn, Ala289Val), and a nonsense mutation in the 5' splice site of exon 8. CONCLUSIONS: This study demonstrates that 22 unrelated progressive supranuclear palsy (PSP) patients have four identical sequence variants within the tau gene that are not present in 24 age-matched controls. Although the functional significance of these results on tau protein expression is unknown, the presence of this "susceptibility" haplotype in individuals may place them at risk for developing PSP.

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Linkage disequilibrium studies suggest that progressive supranuclear palsy (PSP) is an autosomal recessive condition that maps to a polymorphism in the tau gene. These results provide evidence that homozygous mutations in the tau gene may cause PSP. Recently, a missense mutation in exon 13 of one tau allele (R406W) was found in a single family with an atypical clinicopathologic form of dominantly inherited PSP. The authors report that the R406W mutation is lacking in 25 unrelated individuals with PSP and in six unrelated individuals with another tauopathy-corticobasal degeneration.

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OBJECTIVE: To establish a genetic linkage between highly polymorphic microsatellite loci and the disease locus responsible for an autosomal recessive neurodegenerative syndrome that causes posterior column ataxia and retinitis pigmentosa. BACKGROUND: The authors reported previously a genetic syndrome that causes visual impairment, proprioceptive loss, sensory ataxia, and areflexia in affected individuals from a large, inbred family belonging to a sectarian population that has been genetically semi-isolated from mainstream society for several centuries. METHODS: To find the disease locus responsible for this condition, the authors performed a genome-wide search using genetic loci spaced at 10 to 20-cM intervals spanning human chromosomes (chr) 1-22. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to delineate the candidate region containing the disease gene. RESULTS: After testing 226 loci that covered the entire genome, the authors identified a maximum lod score of 8.94 at a recombination fraction of 0.00 for locus D1S2692. Additional analyses placed the disease gene, AXPC1, in an 8.3-cM interval flanked by markers D1S2692 and D1S414 on chr 1q31-q32. CONCLUSIONS: This study suggests that a single genetic mutation can cause selective degeneration of the posterior columns of the spinal cord and retina. Finding the gene responsible for this syndrome may increase our understanding of the molecular basis of diseases that affect sensory neurons.

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In this Journal, we previously reported genetic linkage between loci on chromosome (chr)2p(ETM) and dominantly inherited essential tremor (ET) in a large American kindred of Czech ancestry. Other investigators reported another ET susceptibility locus on chr 3q (FET1) which accounted for over half of the Icelandic families that were studied. We now report evidence for linkage to the ETM locus in three additional, unrelated American families with ET and exclude the FET1 locus in these families. Fine mapping results, using an "affecteds-only" model in all four American families, demonstrate positive combined pairwise lod scores (Z) at the ETM locus with aZ(max) = 5.94 at a recombination fraction (theta) = 0.00 for locus D2S220. Haplotype reconstruction places the ETM gene in a 9.10 cM interval between the D2S224 and D2S405 loci. Multipoint linkage analysis suggests that the ETM gene is in the 2.18 cM interval between loci D2S2150 and D2S220 with a Z(max) = 8.12. These findings may facilitate the search for a gene that causes ET and may further our understanding of other disorders that are associated with tremor [corrected].

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Sarcoidosis is a systemic granulomatous disease of unknown etiology in which CD4+ T cells seem to be critically involved. In the lungs of patients with pulmonary disease, CD4+ T cells accumulate in large numbers, and a subset of these cells is activated. By using both quantitative PCR and anti-V beta mAbs, we analyzed the TCR repertoire of total and activated bronchoalveolar lavage T cells, the latter subset being defined by the ability to proliferate in short-term culture supplemented with IL-2. Overall, there was little difference when TCR V beta expression of freshly isolated lung and peripheral blood cells was compared in individual patients. Some individuals did demonstrate a modest increase in a few V beta-expressing subsets. However, after 1 to 2 wk of in vitro growth in IL-2-supplemented media, bronchoalveolar lavage cells from most patients, but not from any healthy individuals, demonstrated a selective expansion of particular V beta-expressing subsets. Interestingly, different V beta-bearing subsets were expanded in different patients. Junctional region sequencing indicated that the proliferating T cells in culture were strikingly oligoclonal and were derived from T cell clones already selectively expanded in vivo. These results provide evidence for a disease process that involves recognition of local Ag(s) by specific subsets of CD4+ T cells. Analysis of the Ag specificity of these IL-2-expanded populations is likely to provide insight into the pathogenesis of this disease.

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Oncogenes in DNAs from human tumor cell lines have been detected by a new transformation assay. Cellular DNAs are transfected into NIH3T3 murine fibroblasts, and transformed cells are selected by maintaining cell cultures in a defined medium lacking platelet-derived or fibroblast growth factors. DNAs from eight of 17 human tumor cell lines have yielded transformants by this method. Activated cellular ras genes account for three of the transforming activities. The SAOS2 osteosarcoma cell line contains an activated oncogene distinct from 18 known oncogenes. Another cellular oncogene was detected as the consequence of a fortuitous transfection-mediated DNA rearrangement.

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Human pancreatic ductal adenocarcinoma Capan-2, derived from a 56-yr-old male Caucasian, has been studied in both tissue culture and the nude mouse. In tissue culture, tumor cells showed epithelial-like features, whereas in the nude mouse, the tumor grew as a well-differentiated adenocarcinoma, resembling histopathologically the original neoplasm. Ultrastructurally, the neoplastic cells showed characteristics of ductal epithelium. The allozyme phenotypic profile of Tumor Capan-2 was determined in eight genetically determined loci, and chromosome studies showed a hypotetraploid pattern with a number of morphological and numerical changes. Carcinoembryonic antigen was produced in trace amounts, and lactate dehydrogenase was represented only by Isoenzyme 5, regardless of environmental conditions. The characteristics of Capan-2 tumor make it a valuable addition to the small number of available pancreatic tumor lines in studies aiming at clarifying certain aspects of the biology of this type of malignancy.

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Sixteen established cell lines of simian virus 40 (SV40)-transformed human amnion cells were examined for SV40 production. Many of these lines produced SV40 for extensive periods. Virus production had not ceased for 2 lines after 18 months, for 3 lines after 12 months, and for 3 lines at 3 months after recovery from "crisis". Three lines became virus-free in the first month, 1 line in the second month, 1 in the third month, and 1 in the fourth month, and 2 lines stopped virus production between 6 and 11 months after recovery. The virus titers were relatively low. Inclusion body-containing cells were infrequent. In contrast, in most cultures of SV40-transformed human fibroblasts rescued from crisis, no infectious virus was demonstrated, although exceptions have been reported. Virus was produced after heterokaryon formation of cells of the virus-free amnion lines with CV-1 cells in the presence of inactivated Sendai virus, as observed for SV40-transformed human fibroblasts. During the crisis period, some of the SV40-transformed amnion cells produced substantial amounts of virus. Titers decreased during the later periods of crisis. The most pronounced decrease in titers was in cultures from which established lines were recovered.

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Numerous cell lines derived from human tumors are not HeLa contaminants. Of 192 lines established in this or other laboratories, 169 lines were found to be G6PD type B. Twenty-three lines were type A as HeLa; three of these were of Negroid origin. There is reasonable doubt that the remaining 20 lines will all be shown to be confounded with HeLa.

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