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| 2. |
- Bruce, Benjamin, et al.
(författare)
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Expression of the cytoskeleton linker protein ezrin in human cancers
- 2007
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Ingår i: Clinical and Experimental Metastasis. - : Springer Science and Business Media LLC. - 1573-7276 .- 0262-0898. ; 24:2, s. 69-78
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Tidskriftsartikel (refereegranskat)abstract
- Expression of the metastasis-associated protein, ezrin, in over 5,000 human cancers and normal tissues was analyzed using tissue microarray immunohistochemistry. Ezrin staining was compared between cancers and their corresponding normal tissues, between cancers of epithelial and mesenchymal origin, in the context of the putative inhibitor protein, merlin, and against clinicopathological data available for breast, lung, prostate cancers and sarcomas. Ezrin was found in most cancers and normal tissues at varying levels of intensity. In general ezrin was expressed at higher levels in sarcomas than in carcinomas. By normalizing the expression of ezrin in each cancer using ezrin expression found in the corresponding normal tissue, significant associations between ezrin were found in advancing histological grade in sarcomas (P = 0.02) and poor outcome in breast cancer (P = 0.025). Clinicopathologic associations were not changed by simultaneous assessment of ezrin and merlin in each patient sample for the cancer types examined. These data support a role for ezrin in the biology of human cancers and the need for additional studies in breast cancer and sarcoma patients that may validate ezrin as a marker of cancer progression and as a potential target for cancer therapy.
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| 3. |
- Denton, Christopher P., et al.
(författare)
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Recombinant human anti-transforming growth factor beta 1 antibody therapy in systemic sclerosis - A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 56:1, s. 323-333
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta 1 (TGF beta 1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). Methods. Patients with SSc duration of < 18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mglkg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGF beta 1 and TGF beta 2. Results. Forty-five patients were enrolled. There was significant morbidity and mortality, including I death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). Conclusion. We report the first evaluation of a systemically administered and repeatedly dosed anti-TGF beta 1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.
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- Friedman, James S., et al.
(författare)
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Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa
- 2009
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 84:6, s. 792-800
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G -> A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch Subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.
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| 5. |
- Merkel, Peter A, et al.
(författare)
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Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial
- 2008
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 59:5, s. 699-705
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine the validity, reliability, and feasibility of durometer measurements of skin hardness as an outcome measure in clinical trials of scleroderma. Methods. Skin hardness was measured during a multicenter treatment trial for scleroderma using handheld digital durometers with a continuous scale. Skin thickness was measured by modified Rodnan skin score (MRSS). Other outcome data collected included the Scleroderma Health Assessment Questionnaire. In a reliability exercise in advance of the trial, 9 investigators examined the same 5 scleroderma patients by MRSS and durometry. Results. Forty-three patients with early diffuse cutaneous systemic sclerosis were studied at 11 international centers (mean age 49 years [range 24-76], median disease duration 6.4 months [range 0.3-23], and median baseline MRSS 22 [range 11-38]). The reliability of durometer measurements was excellent, with high interobserver intraclass correlation coefficients (ICCs) (0.82-0.92), and each result was greater than the corresponding skin site ICCs for MRSS (0.54-0.85). Baseline durometer scores correlated well with MRSS (r = 0.69, P < 0.0001), patient self-assessments of skin disease (r = 0.69, P < 0.0001), and Health Assessment Questionnaire (HAQ) disability scores (r = 0.34, P = 0.03). Change in durometer scores correlated with change in MRSS (r = 0.70, P < 0.0001.), change in patient self-assessments of skin disease (r = 0.52, P = 0.003), and change in HAQ disability scores (r = 0.42, P = 0.017). The effect size was greater for durometry than for MRSS or patient self-assessment. Conclusion. Durometer measurements of skin hardness in patients with scleroderma are reliable, simple, accurate, demonstrate good sensitivity to change compared with traditional skin scoring, and reflect patients' self-assessments of their disease. Durometer measurements are valid, objective, and scalable, and should be considered for use as a complementary outcome measure to skin scoring in clinical trials of scleroderma.
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