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Biomedical subjects

Barbara A Gilchrest

Publications and source records attributed to Barbara A Gilchrest.

At least 19 recordsLinked to original sources
PubMed2007

Sun protection and Vitamin D: three dimensions of obfuscation.

Ultraviolet (UV) radiation is a proven carcinogen, responsible for more than half of all human malignancies. It also compromises skin appearance and function. Since the UV action spectra for DNA damage, skin cancer and Vitamin D(3) (vit D) photosynthesis are identical and vit D is readily available from oral supplements, why has sun protection become controversial, now that some data suggest conventionally "sufficient" levels of vit D may be less than optimal for at least some population groups? First, the media and apparently some researchers are hungry for a new message. Nevertheless, after 50 years, UV exposure is still a major avoidable health hazard. Second, the controversy is fueled by a powerful special interest group: the indoor tanning industry. They target not the frail elderly or inner-city ethnic minorities, groups for whom evidence of vit D insufficiency is strongest, but rather fair-skinned teenagers and young adults, those at highest risk of UV photodamage. Third, evolution does not keep pace with civilization. When nature gave man the appealing capacity for vit D photosynthesis, the expected lifespan was far less than 40 years. Long-term photodamage was not a concern, and vit D was not available at the corner store. The medical community should avoid sensationalism and instead rigorously explore possible cause-and-effect relationships between vit D status and specific diseases while advocating the safest possible means of assuring vit D sufficiency.

Animals↗
PubMed2007

Visual screening for malignant melanoma: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of various melanoma screening strategies proposed in the United States. DESIGN: We developed a computer simulation Markov model to evaluate alternative melanoma screening strategies. PARTICIPANTS: Hypothetical cohort of the general population and siblings of patients with melanoma. Intervention We considered the following 4 strategies: background screening only, and screening 1 time, every 2 years, and annually, all beginning at age 50 years. Prevalence, incidence, and mortality data were taken from the Surveillance, Epidemiology, and End Results Program. Sibling risk, recurrence rates, and treatment costs were taken from the literature. MAIN OUTCOME MEASURES: Outcomes included life expectancy, quality-adjusted life expectancy, and lifetime costs. Cost-effectiveness ratios were in dollars per quality-adjusted life year (US dollars/QALY) gained. RESULTS: In the general population, screening 1 time, every 2 years, and annually saved 1.6, 4.4, and 5.2 QALYs per 1000 persons screened, with incremental cost-effectiveness ratios of US dollars 10,100/QALY, US dollars 80,700/QALY, and US dollars 586,800/QALY, respectively. In siblings of patients with melanoma (relative risk, 2.24 compared with the general population), 1-time, every-2-years, and annual screenings saved 3.6, 9.8, and 11.4 QALYs per 1000 persons screened, with incremental cost-effectiveness ratios of US dollars 4000/QALY, US dollars 35,500/QALY, and US dollars 257,800/QALY, respectively. In higher risk siblings of patients with melanoma (relative risk, 5.56), screening was more cost-effective. Results were most sensitive to screening cost, melanoma progression rate, and specificity of visual screening. CONCLUSIONS: One-time melanoma screening of the general population older than 50 years is very cost-effective compared with other cancer screening programs in the United States. Screening every 2 years in siblings of patients with melanoma is also cost-effective.

Boston↗
PubMed2007

Features that determine telomere homolog oligonucleotide-induced therapeutic DNA damage-like responses in cancer cells.

Cancer is the second leading cause of death in the USA, with metastatic disease proving a particular management challenge. Treatment modalities for patients with metastatic disease are limited, and survival beyond 5 years is uncommon. We have reported that an 11-base DNA oligonucleotide 100% homologous to the telomere 3' overhang can induce apoptosis, senescence and/or differentiation of several types of malignant cells in vitro and in vivo, while having minimal effect on normal cells. We now report that 22 oligonucleotides, 9-20 bases in length, with or without a 5' phosphate group and with varying homology (40-100%) to the 3' overhang, inhibit growth and induce apoptosis of human cell lines derived from breast cancers, pancreatic and ovarian carcinomas, and malignant melanoma, lines that lack p53 and/or p16 and harbor a variety of other abnormalities in key regulatory signaling pathways. Cytosine (C) content adversely affected oligonucleotide efficacy, decreasing their effect on cellular apoptosis by > or =80%. These data confirm and expand our earlier work suggesting that such telomere homolog oligonucleotides (T-oligos) target an innate anti-cancer defense system in human cells and may provide an effective treatment for cancers of multiple different cellular origins and genetic profile.

Aging↗
PubMed2006

A role for WRN in telomere-based DNA damage responses.

Telomeres cap the ends of eukaryotic chromosomes and prevent them from being recognized as DNA breaks. We have shown that certain DNA damage responses induced during senescence and, at times of telomere uncapping, also can be induced by treatment of cells with small DNA oligonucleotides homologous to the telomere 3' single-strand overhang (T-oligos), implicating this overhang in generation of these telomere-based damage responses. Here, we show that T-oligo-treated fibroblasts contain gammaH2AX foci and that these foci colocalize with telomeres. T-oligos with nuclease-resistant 3' ends are inactive, suggesting that a nuclease initiates T-oligo responses. We therefore examined WRN, a 3'-->5' exonuclease and helicase mutated in Werner syndrome, a disorder characterized by aberrant telomere maintenance, premature aging, chromosomal rearrangements, and predisposition to malignancy. Normal fibroblasts and U20S osteosarcoma cells rendered deficient in WRN showed reduced phosphorylation of p53 and histone H2AX in response to T-oligo treatment. Together, these data demonstrate a role for WRN in processing of telomeric DNA and subsequent activation of DNA damage responses. The T-oligo model helps define the role of WRN in telomere maintenance and initiation of DNA damage responses after telomere disruption.

Cells, Cultured↗
PubMed2006

A randomized trial to improve early detection and prevention practices among siblings of melanoma patients.

BACKGROUND: Identifying high-risk individuals for melanoma education and risk reduction may be a viable strategy to curb the incidence of melanoma, which has risen precipitously in the past 50 years. The first-degree relatives of melanoma patients represent a risk group who may experience a 'teachable moment' for enhanced education and risk reduction. METHODS: We report a randomized trial testing an intervention that provided personalized telephone counseling and individually tailored materials to siblings of recently-diagnosed melanoma patients. The purpose of this study was to test whether an intervention could lead to improvements in siblings' skin cancer risk reduction practices. Intervention condition participants received the following: (1) an initial motivational and goal-setting telephone intervention session delivered by the health educator; (2) three sets of computer-generated materials specifically tailored to individual responses from the baseline survey; (3) three telephone counseling sessions with the health educator, timed to follow receipt of the mailed materials; and (4) linkages to free screening programs. Families in the usual care arm received the suggestion from the physician that patients diagnosed with melanoma notify the family members about their diagnosis and encourage the family members to be screened. RESULTS: 494 siblings were recruited to the study and 403 siblings remained in the study through at least 6 months. At 12 months, intervention siblings were more likely to examine all moles, including those on the back (OR, 1.76; 95% CI, 1.06-2.91). Compared with baseline, the number of participants in both groups that had received a skin cancer examination more than doubled, with no differences between groups. At 12 months, two-thirds of siblings in both groups reported routine use of sunscreen, but there were no differences in change over baseline between the two groups. CONCLUSIONS: This study is the one of the first, to our knowledge, to address skin cancer risk-reduction strategies in a sample of individuals who have a recent family diagnosis of melanoma. Diagnosis of melanoma in a family member provides an important opportunity to intervene with others in that family. The components of the intervention may provide a useful foundation for future efforts to target the more than half million siblings at risk for melanoma, a lethal but preventable disease.

Adolescent↗
PubMed2006

T-oligos augment UV-induced protective responses in human skin.

We have shown that DNA oligonucleotides substantially homologous to the telomere 3-prime overhang sequence (T-oligos) increase DNA repair capacity (DRC) in cultured human cells and decrease UV-induced mutation rate and photocarcinogenesis in mouse skin. To investigate the protective effects of T-oligos in intact human skin, paired skin explants obtained from adult donors were treated with T-oligos or diluent alone for 24 h, then UVB- or sham-irradiated, and processed after 6, 24, 48, 72, and 96 h for histological analysis. After UV irradiation apoptotic epidermal cells were comparable in diluent- and T-oligo-treated skin. Proliferating (Ki67+) cells were sparse in sham-irradiated skin and for 24 h after UV in both diluent- and T-oligo-treated specimens. However, compared to diluent controls, at 48 and 72 h T-oligos significantly inhibited UV-induced rebound hyperproliferation. Maximum and comparable cyclobutane pyrimidine dimers (CPDs) were detected immediately after UV irradiation in diluent- and T-oligo-treated skin, but CPDs were strikingly reduced in T-oligo- vs. diluent-treated skin at 24, 48, and 72 h. Total and activated p53 protein was increased in T-oligo- vs. diluent-pretreated skin at the time of irradiation, and up to 3-fold increases persisted for 24 h post-UV. Over 5 days, UV irradiation and T-oligo comparably increased expression of melanogenic proteins and each increased epidermal melanin content 3- to 5-fold, with distinct nuclear capping in many keratinocytes. In combination, these findings predict that T-oligo treatment will increase melanogenesis, prolong epidermal arrest, and increase DNA repair rate after UV irradiation, thus decreasing the severity of acute and chronic photodamage in human skin. Moreover, the data document an inducible SOS-like response consisting of increased melanogenesis and increased DNA repair capacity in human skin following UV-induced damage that is also produced by T-oligos in the absence of initial damage.

Adult↗
PubMed2006

Bone morphogenetic protein-4, a novel modulator of melanogenesis.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta family, signal in many cells including neural precursors. Two receptors, types 1 and 2, coordinately mediate BMP signaling, and type 1 receptor has two forms: A and B. Using RT-PCR we found that neural crest-derived human melanocytes express BMP receptor-1A, -1B, and -2. Furthermore, melanocytes and the surrounding keratinocytes express BMP-4, suggesting both autocrine and paracrine effects of this molecule. Moreover, BMP-4 supplementation of cultured human melanocytes decreases melanin synthesis, tyrosinase mRNA, and protein. The mechanism of this BMP-4 effect on tyrosinase and ultimately on melanogenesis involves modest decreases of tyrosinase transcription rate and mRNA stability. Moreover, ultraviolet irradiation, the best recognized environmental stimulator of melanogenesis, down-regulated the mRNA of BMP receptor-1B in melanocytes. Our data provide evidence of a novel regulatory pathway for melanogenesis in human skin.

Apoptosis↗
PubMed2006

MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes.

The cAMP-dependent pathway up-regulates MITF (microphthalmia-associated transcription factor), important for key melanogenic proteins such as tyrosinase, TRP-1 (tyrosinase-related protein 1) and TRP-2. We asked whether MITF is also a key transcription factor for PKC-beta (protein kinase C-beta), required to phosphorylate otherwise inactive tyrosinase. When paired cultures of human melanocytes were treated with isobutylmethylxanthine, known to increase intracellular cAMP, both protein and mRNA levels of PKC-beta were induced by 24 h. To determine whether MITF modulates PKC-beta expression, paired cultures of human melanocytes were transfected with dn-MITF (dominant-negative MITF) or empty control vector. By immunoblotting, PKC-beta protein was reduced by 63+/-3.7% within 48 h. Co-transfection of an expression vector for MITF-M, the MITF isoform specific for pigment cells, or empty control vector with a full-length PKC-beta promoter-CAT (chloramphenicol acetyltransferase) reporter construct (PKC-beta/CAT) into Cos-7 cells showed >60-fold increase in CAT activity. Melanocytes abundantly also expressed MITF-A, as well as the MITF-B and MITF-H isoforms. However, in contrast with MITF-M, MITF-A failed to transactivate co-expressed PKC-beta/CAT or CAT constructs under the control of a full-length tyrosinase promoter. Together, these results demonstrate that MITF, specifically MITF-M, is a key transcription factor for PKC-beta, linking the PKC- and cAMP-dependent pathways in regulation of melanogenesis.

1-Methyl-3-isobutylxanthine↗
PubMed2006

The vitamin D questions: how much do you need and how should you get it?

UV radiation is a well-documented human carcinogen, indisputably linked to the current continued increased rate of skin cancer. UV radiation is also responsible for cutaneous synthesis of vitamin (vit) D3, a substance that is then sequentially hydroxylated in the liver and kidney to yield 1,25(OH)2 vit D, a hormone critical for calcium homeostasis and skeletal maintenance. Because the UV action spectra for DNA damage leading to skin cancer and for vit D photosynthesis are virtually identical, the harmful and beneficial effects of UV irradiation are inseparable. This has given rise to the argument that sun avoidance, with a goal of skin cancer prevention, may compromise vit D sufficiency. Public interest in this matter has been heightened in recent years by multiple studies correlating the level of 25-OH vit D, the readily measurable "storage" precursor form of the vit, with a variety of benefits separate from skeletal health. Although the studies are of variable quality and all alleged treatment benefits are based on dietary supplementation with vit D, not on increased sun exposure, they have been interpreted by some as support for advocating increased sun exposure of the public at large. The goal of this review is to provide a detailed, balanced, and referenced discussion of the complex literature underlying the current popular interest in vit D and sun exposure for the purpose of increasing vit D photosynthesis. We review the nomenclature, metabolism, and established functions of vit D; the evidence supporting the less well-established but purported vit D effects; the concept of vit D insufficiency; populations at risk for vit D deficiency; and finally the risk/benefit of obtaining vit D from cutaneous photosynthesis versus diet or supplementation.

DNA Damage↗
PubMed2006

Skin cancer examination teaching in US medical education.

OBJECTIVE: To determine physician preparation for performing the skin cancer examination (SCE). DESIGN: We evaluated medical students' observation, training, and practice of the SCE; hours spent in a dermatology clinic; and self-reported skill level for the SCE by a self-administered survey. PARTICIPANTS: Graduating students at 7 US medical schools during the 2002-2003 academic year. MAIN OUTCOME MEASURES: Percentages of students reporting SCE skill observation, training, and practice. RESULTS: Of 934 students, 659 (70.6%) completed surveys. Twenty-three percent of students had never observed an SCE, 26.7% had never been trained to perform an SCE, and 43.4% had never examined a patient for skin cancer. Only 28.2% rated themselves as somewhat or very skilled in the SCE. This rate dropped to 19.7% among 553 students who had not completed a dermatology elective. Compared with students without training, students who had been trained at least once in the SCE were 7 times more likely to rate themselves as being somewhat or very skilled in the SCE. Sixty-nine percent of students agreed that insufficient emphasis in their medical training was placed on learning about the SCE. CONCLUSIONS: This survey documents the need for more consistent training of medical students in SCE. Even brief curricular additions would augment students' perceived skill levels and improve practice patterns and competencies of future physicians. More frequent and improved SCEs might result in earlier detection of melanoma and nonmelanoma skin cancers by nondermatologists, with significant public health benefits.

Adult↗
PubMed2006

Detection of UV-induced pigmentary and epidermal changes over time using in vivo reflectance confocal microscopy.

In vivo reflectance confocal microscopy (RCM) provides high-resolution optical sections of the skin in its native state, without needing to fix or section the tissue. Melanin provides an excellent contrast for RCM, giving a bright signal in the confocal images. The pigmented guinea-pig is a common animal model to study human pigment induction and modulation, as its tanning response is comparable to human tanning after exposure to ultraviolet radiation (UVR). We investigated the applicability of RCM to detecting UVR-induced pigmentary changes in this model. Animals were exposed to solar simulator radiation for 7 days. RCM was performed during the irradiation and follow-up period. Compared to non-irradiated skin, an increase in melanocyte size, dendricity, and number, as well as increased pigment in keratinocytes, was seen in the irradiated epidermis. Interestingly, these changes could be detected even before a tanning response was clinically visible. UVR-induced epidermal hyperplasia could also be detected and quantified. In conclusion, in vivo RCM is a sensitive non-invasive imaging technique that can repeatedly measure epidermal pigmentation and thickness, as demonstrated in the guinea-pig model. This technique should greatly enhance our appreciation of dynamic pigmentary changes in human or animal skin over time and in response to specific stimuli.

Animals↗
PubMed2006

Broad area photodynamic therapy for treatment of multiple basal cell carcinomas in a patient with nevoid basal cell carcinoma syndrome.

We report a case of a 73-year-old man with nevoid basal cell carcinoma syndrome who was referred to us with multiple basal cell carcinomas on his face and chest. The patient underwent photodynamic therapy utilizing a 1-hour incubation of Levulan Kerastick delta-aminolevulinic acid 20% topical solution applied to the full face and illumination with a BLU-U blue light source (10 J/cm2) every 2 to 3 months for a total of 4 treatments. This treatment strategy resulted in multiple benefits, including reducing the number and size of his existing basal cell carcinomas, improving the appearance of previous surgical scars, and decreasing the rate of tumor development.

Aged↗
PubMed2005

T-oligo treatment decreases constitutive and UVB-induced COX-2 levels through p53- and NFkappaB-dependent repression of the COX-2 promoter.

Chronically irradiated murine skin and UV light-induced squamous cell carcinomas overexpress the inducible isoform of cyclooxygenase (COX-2), and COX-2 inhibition reduces photocarcinogenesis in mice. We have reported previously that DNA oligonucleotides substantially homologous to the telomere 3'-overhang (T-oligos) induce DNA repair capacity and multiple other cancer prevention responses, in part through up-regulation and activation of p53. To determine whether T-oligos affect COX-2 expression, human newborn keratinocytes and fibroblasts were pretreated with T-oligos or diluent alone for 24 h, UV-irradiated, and processed for Western blotting. In both cell types, T-oligos transcriptionally down-regulated base-line and UV light-induced COX-2 expression, coincident with p53 activation. In fibroblasts with wild type versus dominant negative p53 (p53(WT) versus p53(DN)), T-oligos decreased constitutive expression of a COX-2 reporter plasmid by >50%. We then examined NFkappaB, a known positive regulator of COX-2 transcription. In p53(WT) but not in p53(DN) fibroblasts and in human keratinocytes, T-oligos decreased readout of an NFkappaB promoter-driven reporter plasmid and decreased NFkappaB binding to DNA. After T-oligo treatment and subsequent UV irradiation, binding of the transcriptional co-activator protein p300 to NFkappaB was decreased, whereas binding of p300 to p53 was increased. Human skin explants provided with T-oligos had markedly decreased COX-2 immunostaining both at base-line and post-UV light, coincident with increased p53 immunostaining. We conclude that T-oligos transcriptionally down-regulate COX-2 expression in human skin via activation and up-regulation of p53, at least in part by inhibiting NFkappaB transcriptional activation. Decreased COX-2 expression may contribute to the observed ability of T-oligos to reduce photocarcinogenesis.

Acetyltransferases↗
PubMed2005

Psychosocial aspects of aging skin.

Many older individuals use products and procedures to conceal or delay the signs of aging. For most, this provides a helpful ego boost, but some suffer from pathologies such as eating disorders and body dysmorphic disorder. The impact of aging skin may include social anxiety and social isolation. Poor self-image is associated with chronic illness and fewer preventive health behaviors, such as exercise. Aged appearance, especially in women, is also associated with workplace discrimination. Patients should therefore be offered treatments for aging skin, ensured that society's negative views not be unnecessarily reinforced, and maintain a realistic treatment expectations.

Humans↗