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Biomedical subjects

M Duvic

Publications and source records attributed to M Duvic.

At least 73 records · Page 4Linked to original sources
PubMed1998

Tumor necrosis factor-alpha and interferon-gamma, but not HTLV-I tax, are likely factors in the epidermotropism of cutaneous T-cell lymphoma via induction of interferon-inducible protein-10.

We have previously shown that Interferon-Inducible Protein-10 (IP-10), a cytokine chemotactic for CD4-positive lymphocytes, is overexpressed by lesional epidermal keratinocytes and probably accounts for the epidermotropism of cutaneous T-cell lymphoma (CTCL). The tax gene of human T-lymphotropic virus-I (HTLV-I) immortalizes CD4-positive lymphocytes, induces IFN-gamma, and has been detected in patients with classical CTCL who are seronegative for HTLV-I. TNF-alpha is synergistic with IFN-gamma for the induction of IP-10. We therefore decided to define the presence of tax, IFN-gamma, TNF-alpha, and IP-10 in lesions of 19 adults with classical CTCL who were seronegative for HTLV-I. Lesional mRNAs for actin, TNF-alpha, IFN-gamma, and tax were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) amplification. In addition IP-10, TNF-alpha, and IFN-gamma were detected and localized with immunocytochemistry of frozen sections. In agreement with previous observations IP-10 was overexpressed in lesional keratinocytes of all 19 patients. By RT-PCR, mRNA for IFN-gamma was detected in lesions of 8, and for TNF-alpha in lesions of 13 patients. By immunocytochemistry, TNF-alpha was expressed by lesional keratinocytes in 10 of 13 tested patients, whereas IFN-gamma was focally expressed by lesional lymphocytes and faintly by lesional keratinocytes in 9 of 13 tested patients. tax mRNA was not detected in lesions of any patient, but was easily detectable in cutaneous lesions or peripheral blood of control patients who were seropositive for HTLV-I. We conclude that TNF-alpha and IFN-gamma may cause epidermotropism by inducing IP-10. However, the tax gene of HTLV-I does not appear to be involved in the pathogenesis of classical CTCL.

Adult↗
PubMed1998

Pharmacologic profile of tazarotene.

The majority of patients with psoriasis exhibit a mild to moderate form of the disease. While topically applied agents represent the ideal therapeutic approach for these patients, our treatment options have been hampered by their inconsistent or limited efficacy, expense, and cosmetic properties. Furthermore, some of the topically applied preparations have the potential for systemic absorption and associated adverse events. Tazarotene is the first synthetically developed retinoid indicated for the topical treatment of patients with psoriasis. Pharmacologically, tazarotene affects the three primary abnormalities associated with psoriasis: it normalizes epidermal differentiation, it exhibits a potent antiproliferative effect, and it decreases epidermal inflammation. Following topical application, tazarotene is rapidly metabolized in the skin to tazarotenic acid, its primary and active metabolite. While tazarotenic acid achieves measurable levels in the systemic circulation, no drug-related hematologic, ophthalmologic, or metabolic adverse events have been observed. Only a minimal amount of tazarotene is absorbed into the circulation. While animal studies have found tazarotene to be nonmutagenic and nonteratogenic, women of child-bearing potential should be counseled regarding the potential risks of retinoid use during pregnancy. In summary, animal and clinical patient trials have found tazarotene to be effective, safe, and well-tolerated. The availability of such an agent in a topical formulation is a welcome treatment alternative for the management of patients with psoriasis.

Administration, Topical↗
PubMed1997

Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen.

Ehlers-Danlos syndrome (EDS) type VII results from defects in the conversion of type I procollagen to collagen as a consequence of mutations in the substrate that alter the protease cleavage site (EDS type VIIA and VIIB) or in the protease itself (EDS type VIIC). We identified seven additional families in which EDS type VII is either dominantly inherited (one family with EDS type VIIB) or due to new dominant mutations (one family with EDS type VIIA and five families with EDS type VIIB). In six families, the mutations alter the consensus splice junctions, and, in the seventh family, the exon is deleted entirely. The COL1A1 mutation produced the most severe phenotypic effects, whereas those in the COL1A2 gene, regardless of the location or effect, produced congenital hip dislocation and other joint instability that was sometimes very marked. Fractures are seen in some people with EDS type VII, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. These new findings expand the array of mutations known to cause EDS type VII and provide insight into genotype/phenotype relationships in these genes.

Adult↗
PubMed1997

Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.

Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection. Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor V beta repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific V beta gene, whereas 10 had oligoclonal or polyclonal expansion of several V beta families. All patients with TSST-1+ S aureus had overexpansion of V beta Z in blood and/or skin lesions. These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.

Adult↗
PubMed1997

Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect.

BACKGROUND: Topical therapy providing initial improvement and maintenance of effect after treatment of the large majority of patients with limited, mild to moderate psoriasis is not presently available. Previous topical retinoids have generally been either ineffective or too irritating for therapy of psoriasis. OBJECTIVE: Our purpose was to evaluate a new topical retinoid, tazarotene, in the treatment of stable plaque psoriasis during treatment and posttreatment periods. METHODS: In a double-blind manner, 324 patients were randomly selected to receive tazarotene 0.1% or 0.05% gel, or vehicle control, once daily for 12 weeks and were then followed up for 12 weeks after treatment. RESULTS: Of the total, 318 patients could be evaluated. Tazarotene gels were superior (p < 0.05) to vehicle, often as early as treatment week 1, in all efficacy measures: plaque elevation, scaling, and erythema; treatment response; percentage treatment success (patients with > or = 50% improvement); and time to initial success. Efficacy was equivalent on target lesion sites (trunk or limbs and knees or elbows) and overall. A sustained therapeutic effect was observed for 12 weeks after treatment. Tazarotene gel was cosmetically acceptable. There was low systemic absorption, limiting toxicity to local irritation. CONCLUSION: Once-daily tazarotene was effective and safe as a topical monotherapy for plaque psoriasis, providing rapid reduction of signs and symptoms.

Administration, Topical↗
PubMed1997

Follicular mucinosis associated with scarring alopecia, oligoclonal T-cell receptor V beta expansion, and Staphylococcus aureus: when does follicular mucinosis become mycosis fungoides?

A diagnosis of alopecia mucinosa, occurring as a single scalp lesion, was made in a 40-year-old white woman who had a history of trauma. Follicular mucinosis, Staphylococcus aureus, and oligoclonal expansion of the T-cell receptor V beta chain genes 6 and 7 were present in the skin. Epidermotropic T-cell skin diseases with oligoclonal T-cell proliferations may be the result of HLA- and cytokine-determined reaction patterns to persistent antigens.

Adult↗
PubMed1997

HIV-related psoriasis and Reiter's syndrome.

Infection with the human immunodeficiency virus (HIV) is associated with the development of psoriasis and related disorders, including psoriatic arthritis, dactylitis and enthesitis, and Reiter's syndrome. The etiologic mechanisms remain unclear but most likely represent a combination of genetic and environmental factors. Therapy for these diseases in the setting of HIV infection is often difficult not only because of their characteristically increased severity, but also because the use of conventionally effective immunosuppressive agents may be counterproductive in this patient population.

Arthritis↗
PubMed1997

Epidermolytic acanthomas: clinical characteristics and immunohistochemical features.

Epidermolytic hyperkeratosis in bullous congenital ichthyosiform erythroderma results from mutations in the K1 and K10 genes. Epidermolytic acanthomas are solitary or multiple lesions with microscopic features that are identical to those in bullous congenital ichthyosiform erythroderma. In this study, the clinical and epidemiologic characteristics of epidermolytic acanthomas were summarized, and the expression of keratins (using antibodies to K1, K6, K10, K14, K16, and K19) in five solitary epidermolytic acanthomas was determined using immunohistochemistry techniques. The intensity of staining for K1 and K10 was (a) less in the altered granular layer, as compared to the adjacent nonaltered granular layer of the lesional skin, and (b) less in the lesional skin as compared to the perilesional, histologically normal-appearing skin. Expression of K6 and K16 was noted not only in the basal layer and suprabasal layers of the lesions, but also in the corresponding layers of the adjacent normal skin. Staining for K14 was also observed in the basal layers and suprabasal layers of the lesional and adjacent normal epidermis; within the lesional and perilesional normal skin, the intensity of positive staining for K14 was greater in the basal layers than in the suprabasal layers of the epidermis. The specimens did not stain for K19. In conclusion, using immunohistochemistry techniques on solitary epidermolytic acanthomas, we were able to demonstrate (1) an abnormality in K1 and K10 expression in the lesional skin as compared to the adjacent, histologically normal-appearing skin and (b) the expression of hyperproliferative keratins not only with the lesional skin, but also in the perilesional normal skin. We hypothesize that the pathogenesis of epidermolytic hyperkeratosis in lesions of solitary epidermolytic acanthomas results from mutations in the K1 and K10 genes.

Adult↗
PubMed1997

Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin.

Retinoids exert their biologic effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroid hormone nuclear receptors. By using a subtraction hybridization approach, we have identified a cDNA sequence TIG2 (Tazarotene-induced gene 2), whose expression is up-regulated by the treatment of skin raft cultures by an RAR beta/gamma-selective anti-psoriatic synthetic retinoid tazarotene [AGN 190168/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate]. The retinoid-mediated up-regulation in the expression of TIG2 was confirmed by Northern blot analysis. Upon sequencing, TIG2 was found to be a cDNA whose complete sequence was not in the GenBank and EMBL data bases. The TIG2 cDNA is 830 bp long and encodes a putative protein product of 164 amino acids. TIG2 is neither expressed nor induced by tazarotene in primary keratinocyte and fibroblast cultures. Thus, TIG2 is expressed and induced by tazarotene only when keratinocytes and fibroblasts form a tissue-like 3-dimensional structure. We further demonstrate that RAR-specific retinoids increase TIG2 mRNA levels. In contrast, neither RXR-specific retinoids nor 1,25-dihydroxyvitamin D3 increased TIG2 levels. Finally, we demonstrate that TIG2 is expressed at high levels in nonlesional psoriatic skin but at lower levels in the psoriatic lesion and that its expression is up-regulated in psoriatic lesions after topical application of tazarotene.

Administration, Topical↗
PubMed1997

Lichen amyloidosis presenting as a papular pruritus syndrome in a human-immunodeficiency-virus-infected man.

A human-immunodeficiency-virus (HIV)-positive man presented with pruritic erythematous and flesh-colored papules on his arms and trunk of 1 year's duration. The lesions had previously been treated with oral ketoconazole and topical emollients with no improvement. Microscopic evaluation of lesional skin from his left forearm showed lichen amyloidosis. The patient was started on ultraviolet B phototherapy which he received for 2 weeks without improvement. Lichen amyloidosis should be added to the differential diagnosis of papular pruritus syndrome in HIV-positive individuals.

Administration, Oral↗
PubMed1997

Tazarotene: a review of its pharmacological profile and potential for clinical use in psoriasis.

Psoriasis appears to be a T-cell-mediated, HLA-associated genetic skin disease that profoundly alters epidermal differentiation in a reversible manner. The topical treatment of mild-to-moderate stable plaque psoriasis is limited by side-effects, cosmetic problems, and often by unsatisfactory efficacy, while systemic therapy is usually not warranted because of safety concerns. Tazarotene is the first member of a novel acetylenic and non-isomerisable class of retinoids to undergo extensive clinical testing. Tazarotene therapy regulates gene transcription via interaction with specific nuclear retinoic acid receptors (RARs), thereby modulating the three key pathogenic factors in psoriasis. Systemic absorption is minimal and, in contrast to some other retinoids, elimination is rapid. The results of Phase II and Phase III controlled clinical studies have shown tazarotene to be an effective treatment for psoriasis. The clinical response is rapid, and in many patients was sustained for several weeks following discontinuation of therapy. Adverse effects are generally limited to mild-to-moderate local effects, as seen with other topical retinoid therapies. Convenient once-daily application of tazarotene gel is effective first-line monotherapy for mild-to-moderate plaque psoriasis, providing rapid and sustained benefits, while minimal systemic absorption and rapid elimination appear to limit the potential for systemic side-effects.

Journal Article↗
PubMed1997

Long-range amplification of genomic DNA detects the t(2;5)(p23;q35) in anaplastic large-cell lymphoma, but not in other non-Hodgkin's lymphomas, Hodgkin's disease, or lymphomatoid papulosis.

DESIGN: Determine the frequency of t(2;5)(p23;q35) in anaplastic large-cell lymphoma (ALCL), non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), and lymphomatoid papulosis (LP). PATIENTS AND METHODS: The t(2;5) was detected with a long-range nested polymerase chain reaction (PCR) using 0.5 microgram of DNA (60,000-80,000 cells), 5'-primers from the NPM gene, 3'-primers from the ALK gene, agarose electrophoresis, hybridization, and autoradiography. Patients were evaluable if a 3016 base pair amplicon could be generated from tumor DNA with beta-globin primers. RESULTS: Amplicons were detected by PCR of genomic DNA from three ALCL cell lines and four primary ALCLs known to t(2;5) positive. DNA from t(2;5)-positive cell lines diluted 10(4)-fold or 10(5)-fold generated amplicons in 100% or 20% of reactions, respectively. Archival tumor DNA from 144 patients was amplifiable by beta-globin amplicons in 126 (88%) who are considered evaluable for this study. Twenty-two had ALCL, 69 other NHLs, 30 HD, and five LP. Genomic DNA PCR detected the t(2;5) in 5 of 22 with ALCL (23%, 95% confidence intervals [95% CI] 8%-45%) but not in those with NHLs, HD, or LP. Among ALCLs the t(2;5) was confined to 5 of 20 with nodal presentations (25%, 95% CI 9%-49%), among whom it was seen in 5 of 15 with T-cell or null-cell phenotype (33%, 95% CI 12%-62%), in 4 of 11 with age < 40 years (36%, 95% CI 11%-69%), and in 4 of 9 with nodal presentations, T-cell or null-cell phenotype, and age < 40 years (44%, 95% CI 14%-79%). Amplicon sizes were different between cell lines and patients, reflecting unique genomic DNA breakpoints, as confirmed by DNA sequencing, and served as an internal control against specimen cross-contamination in the laboratory. CONCLUSIONS: Long-range PCR of genomic DNA detects t(2;5) only in ALCL, but not in other NHLs, HD, or LP. Long-range PCR may be useful in establishing diagnosis, determining prognosis, and monitoring minimal residual disease in ALCL.

Adolescent↗
PubMed1997

Molecular mechanisms of tazarotene action in psoriasis.

Psoriasis is a chronic immune-mediated disease that is characterized by the hyperproliferation and abnormal differentiation of keratinocytes and by inflammation. The epidermal changes associated with psoriasis may be due to the infiltration of inflammatory T lymphocytes and the release of cytokines in response to antigenic stimulation. Tazarotene is a retinoic acid receptor-specific retinoid with demonstrated efficacy in the topical treatment of psoriasis. Tazarotene down-regulates markers of keratinocyte differentiation, keratinocyte proliferation, and inflammation. The drug also up-regulates three novel genes TIG-1 (tazarotene-induced gene-1), TIG-2, and TIG-3, which may mediate an antiproliferative effect. The effect of tazarotene on these markers is probably a direct effect on gene expression rather than an indirect effect associated with disease improvement.

Cell Differentiation↗
PubMed1997

Interferon-inducible protein 10 as a possible factor in the pathogenesis of cutaneous T-cell lymphomas.

Human IFN-gamma-inducible protein 10 (IP-10), a C-X-C chemokine secreted by IFN-gamma-stimulated keratinocytes, is chemotactic for normal CD4-positive lymphocytes and inhibits the proliferation of early subsets of normal and of leukemic hemopoietic progenitors. Cutaneous T-cell lymphoma (CTCL) is an indolent lymphoproliferative disorder of CD4-positive lymphocytes that remain confined to the skin for many years before visceral dissemination. Because IFN-gamma mRNA was detected in the epidermis of CTCL lesions, we decided to investigate the role of IP-10 in the epidermotropism of CTCL by determining its expression in normal skin and in CTCL lesions. Using purified recombinant IP-10 (rIP-10) or a recombinant fusion protein between IP-10 and the straight phi10 protein of phage T7, we generated rabbit antisera that recognized and neutralized rIP-10. Immunoperoxidase staining of normal epidermis demonstrated that IP-10 was expressed by basal keratinocytes but not by the more differentiated cells. In the often hyperplastic epidermis overlying CTCL lesions, IP-10 immunostaining was enhanced compared to normal skin and extended to the suprabasal keratinocytes in 28 of 29 patients for a frequency of 97% and a 95% confidence interval of 82-100%. However, IP-10 was detectable in the dermal or epidermal lymphoid infiltrates in only 3 of 29 patients (10%; 95% confidence interval, 2-29%). Skin clinically free of CTCL demonstrated normal IP-10 immunostaining. In one patient who had matching biopsies performed before and after treatment, IP-10 was overexpressed before treatment but was normally expressed at remission. The in vitro proliferation of primary normal human keratinocytes was inhibited in a dose-dependent manner by rIP-10. These results suggest that IP-10 plays a role in the epidermotropism of CTCL. Additional work is needed to determine whether IP-10 stimulates or inhibits CTCL proliferation. A better understanding of the growth controls operating in CTCL may be useful in the development of curative strategies for this disorder.

Adult↗
PubMed1996

Amplification of genomic DNA demonstrates the presence of the t(2;5) (p23;q35) in anaplastic large cell lymphoma, but not in other non-Hodgkin's lymphomas, Hodgkin's disease, or lymphomatoid papulosis.

Anaplastic large cell lymphoma (ALCL) is a distinct clinicopathologic variant of intermediate grade non-Hodgkin's lymphomas (NHL) composed of large pleomorphic cells that usually express the CD30 antigen and interleukin (IL)-2 receptors, and is characterized by frequent cutaneous and extranodal involvement. With variable frequency ALCL bear the t(2;5)(p23;q35) chromosomal translocation that fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a novel protein kinase gene, Anaplastic Lymphoma Kinase (ALK), on chromosome 2p23. We determined the frequency of this translocation with a novel DNA polymerase chain reaction (PCR) technique using 0.5 microgram of genomic DNA, 5'-primers derived from the NPM gene and 3'-primers derived from the ALK gene and hybridization with internal probes. The presence of amplifiable DNA in the samples was tested with the inclusion in the PCR reaction of oligonucleotide primers designed to amplify a 3016-bp fragment from the beta-globin locus. NMP-ALK fusion amplicons were detected using DNA isolated either from all three ALCL cell lines tested, or from all four primary ALCL tumors known to contain the t(2;5)(p23;q35) translocation. Nested amplicons were detected by hybridization in 100% of specimens diluted 10(4)-fold and in 20% of those diluted 10(5)-fold. We subsequently examined archival genomic DNA from 20 patients with ALCL, 39 with diffuse large cell, 2 with mantle cell, 20 with peripheral T cell, 13 with low-grade NHL, 31 with Hodgkin's disease (HD), and 6 with lymphomatoid papulosis. Fusion of the NPM and ALK genes was detected in three of 18 patients with ALCL who had amplifiable DNA (17%, 95% confidence intervals 4% to 41%), but not in any patients with other NHL, HD, or lymphomatoid papulosis. The amplicon sizes were different in all cell lines and patients reflecting unique genomic DNA breakpoints. We conclude that with genomic DNA-PCR the rearrangement of the NPM and ALK loci is restricted to patients with ALCL. Further studies are needed to determine the prognostic significance of the NPM-ALK rearrangement, to determine whether its detection can aid in the differential diagnosis between ALCL. Hodgkin's disease, and lymphomatoid papulosis, and to establish the usefulness of the genomic DNA PCR in the monitoring of minimal residual disease in those patients whose tumors bear the t(2;5).

Adolescent↗
PubMed1996

A dimorphic Alu Sb-like insertion in COL3A1 is ethnic-specific.

Alu elements are a class of repetitive DNA sequences found throughout the human genome that are thought to be duplicated via an RNA intermediate in a process termed retroposition. Recently inserted Alu elements are closely related, suggesting that they are derived from a single source gene or closely related source genes. Analysis of the type III collagen gene (COL3A1) revealed a polymorphic Alu insertion in intron 8 of the gene. The Alu insertion in the COL3A1 gene had a high degree of nucleotide identity to the Sb family of Alu elements, a family of older Alu elements. The Alu sequence was less similar to the consensus sequence for the PV or Sb2 subfamilies, subfamilies of recently inserted Alu elements. These data support the observations that at least three source genes are active in the human genome, one of which is distinct from the PV and Sb2 subfamilies and predates either of these two subfamilies. Appearance of the Alu insertion in different ethnic populations suggests that the insertion may have occurred in the last 100,000 years. This Alu insert should be a useful marker for population studies and for marking COL3A1 alleles.

Alleles↗
PubMed1996

Localized scleroderma in breast cancer patients treated with supervoltage external beam radiation: radiation port scleroderma.

BACKGROUND: An association between systemic scleroderma, radiation, and breast cancer has been recognized. However, localized scleroderma in the radiation port of breast cancer patients has been rarely described. OBJECTIVE: Our purpose was to describe the concurrence of localized scleroderma, supervoltage radiation, and breast carcinoma. METHODS: Patients were prospectively evaluated in a tertiary care cancer center, and the literature was reviewed. RESULTS: We describe six patients with breast cancer in whom localized scleroderma developed within their radiation port. CONCLUSION: Radiation port localized scleroderma can be a sequela of supervoltage radiation therapy in patients with breast cancer. Recognition is important because localized scleroderma can clinically mimic recurrent breast carcinoma.

Breast Neoplasms↗