Inhibition of Melanoma Angiogenesis by Telomere Homolog Oligonucleotides

Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1α. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P<.004) total tumor microvascular density and the functional vessels density by 80% (P <.002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.National Institutes of Health (CA10515); American Skin Associatio

Aging Skin: Nourishing from Out-In. Lessons from Wound Healing

Skin lesion therapy, peculiarly in the elderly, cannot be isolated from understanding that the skin is an important organ consisting of different tissues. Furthermore, dermis health is fundamental for epidermis integrity, and so adequate nourishment is mandatory in maintaining skin integrity. The dermis nourishes the epidermis, and a healthy epidermis protects the dermis from the environment, so nourishing the dermis through the epidermal barrier is a technical problem yet to be resolved. This is also a consequence of the laws and regulations restricting cosmetics, which cannot have properties that pass the epidermal layer. There is higher investment in cosmetics than in the pharmaceutical industry dealing with skin therapies, because the costs of drug registration are enormous and the field is unprofitable. Still, wound healing may be seen as an opportunity to “feed” the dermis directly. It could also verify whether providing substrates could promote efficient healing and test optimal skin integrity maintenance, if not skin rejuvenation, in an ever aging population

Adventurous Physical Activity Environments: A Mainstream Intervention for Mental Health

Adventurous physical activity has traditionally been considered the pastime of a small minority of people with deviant personalities or characteristics that compel them to voluntarily take great risks purely for the sake of thrills and excitement. An unintended consequence of these traditional narratives is the relative absence of adventure activities in mainstream health and well-being discourses and in large-scale governmental health initiatives. However, recent research has demonstrated that even the most extreme adventurous physical activities are linked to enhanced psychological health and well-being outcomes. These benefits go beyond traditional ‘character building’ concepts and emphasize more positive frameworks that rely on the development of effective environmental design. Based on emerging research, this paper demonstrates why adventurous physical activity should be considered a mainstream intervention for positive mental health. Furthermore, the authors argue that understanding how to design environments that effectively encourage appropriate adventure should be considered a serious addition to mainstream health and well-being discourse

Inhibition of Melanoma Angiogenesis by Telomere Homolog Oligonucleotides

Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1α. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment

Inhibition of Melanoma Angiogenesis by Telomere Homolog Oligonucleotides

Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1α. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment

Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls

Background Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude

Reduced Apaf-1 expression in human cutaneous melanomas

Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio- and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15–20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (χ2=6.02, P=0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma