Keyoumars Soltani

Iontophoresis in dermatology: A review

Iontophoresis, the process of increasing the penetration of drugs into surface tissues by the application of an electric current, has been applied to a great many disease conditions over its 200-year history. Although its greatest success has been in the treatment of hyperhidrosis, it is steadily finding new applications. Many aspects of the mechanisms of iontophoresis have yet to be studied before the technic is both fully understood and maximally utilized. In this article we review the literature on iontophoresis as it pertains to dermatology, including the basic principles, engineering aspects.

Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C

Disruption of the nucleotide excision repair (NER) pathway by mutations can cause xeroderma pigmentosum, a syndrome predisposing affected individuals to development of skin cancer. The xeroderma pigmentosum C (XPC) protein is essential for initiating global genome NER by recognizing the DNA lesion and recruiting downstream factors. Here we show that inhibition of the deacetylase and longevity factor SIRT1 impairs global genome NER through suppressing the transcription of XPC in a SIRT1 deacetylase-dependent manner. SIRT1 enhances XPC expression by reducing AKT-dependent nuclear localization of the transcription repressor of XPC. Finally, we show that SIRT1 levels are significantly reduced in human skin tumors from Caucasian patients, a population at highest risk. These findings suggest that SIRT1 acts as a tumor suppressor through its role in DNA repair.

Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor

The Ras–Raf–MEK–ERK signalling pathway is frequently dysregulated in human malignancies, as is angiogenesis and the vascular endothelial growth factor receptor (VEGF/VEGFR) pathway. These kinases are therefore important anticancer targets. The novel, oral treatment sorafenib (BAY 43–9006), has been shown to be an inhibitor of VEGFR, Raf and platelet‐derived growth factor in clinical trials against a variety of cancers, with the greatest activity to date observed in metastatic renal cancer. Although side‐effects with this targeted therapy are usually not dose‐limiting, they frequently involve the skin, and consist of a maculopapular rash, palmar–plantar dysaesthesia, alopecia and xerosis. In this report, we present two patients in whom treatment with sorafenib resulted in inflammation of actinic keratosis, which in some cases progressed to invasive squamous cell carcinoma. This side‐effect is of clinical importance, as early recognition is critical for early treatment and may represent a source of additional morbidity to these patients.

Trigerninal trophic syndrome: A case and review

A 26-year-old woman developed a well-circumscribed, bleeding ulcer at the right nasolabial area 28 months after the recurrence of a posterior fossa meningioma. To our knowledge, this is the first reported case of trigeminal trophic syndrome following an intracranial meningioma. Clinical data from sixty-three cases of trigeminal trophic syndrome in the English literature are reviewed, and etiologic factors are discussed.

Liver abnormalities in patients with lichen planus: A retrospective case-control study

A retrospective case-control study of 136 patients with lichen planus and 272 paired controls demonstrated a significantly higher occurrence of liver abnormalities in this dermatosis. There is currently no good explanation for the high occurrence rate of such abnormalities in lichen planus. Factors that alter epidermal cell antigenicity may induce reactions that can damage keratinocytes as well as hepatocytes.

PTEN Positively Regulates UVB-Induced DNA Damage Repair

Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCCs, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin through its ability to positively regulate XPC-dependent GG-NER following DNA damage.

Unilateral linear nevoidal syringoma

We here report the unusual occurrence of syringoma in a unilateral linear nevoid distribution in a 32-year-old woman. The papules were located on the right side of the chest and right arm. These lesions need to be distinguished from other linear papular eruptions.

Inhibition of histamine-induced pruritus by topical tricyclic antidepressants

Frequent antihistaminic side effects noted during treatment of depression by tricyclic drugs, as well as the high affinity of tricyclic antidepressants for H1 receptors in mouse neuroblastoma cells, suggest possible useful antihistaminic properties. We investigated the antipruritic activity of topically applied 5% solutions of doxepin hydrochloride (Adapin; Sinequan) and amitriptyline hydrochloride (Elavil) and compared such activity to that of a 5% solution of diphenhydramine and vehicle alone. Test solutions were applied to 25-cm2 areas on the flexor forearms of forty subjects, and the development of itch to single drops of eight dilutions of histamine phosphate instilled in each area was reported over a 3-minute period. The lowest concentration of histamine able to elicit unequivocal itching in each treated area was the histamine itch threshold (HIT). Doxepin, amitriptyline, and diphenhydramine all produced significantly higher mean and median HITs (p less than 0.01 than did vehicle control. Sixty-eight percent of subjects had a HIT greater than or equal to 2 x 10(-4) mg/ml in doxepin-treated areas versus 58% for amitriptyline, 53% for diphenhydramine, and 25% for vehicle. Our data suggest that tricyclic antidepressants are effective topical antipruritic agents.

UVB induced ERK/AKT-dependent PTEN suppression promotes survival of epidermal keratinocytes

Ultraviolet (UV) radiation in sunlight is the major environmental cause of skin cancer. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a proven critical tumor suppressor. We report here that UVB downregulates PTEN in primary human keratinocytes, human HaCaT keratinocytes and mouse skin. As compared with normal skin, PTEN levels are reduced in human actinic keratosis, a precancerous skin lesion caused by solar UV. PTEN downregulation is mediated by two mechanisms: (1) PTEN is cleaved by active caspase in apoptotic cells in which AKT activation is reduced; and (2) PTEN transcription is suppressed in surviving cells, and this suppression is independent of caspase activation and occurs in parallel with increased ERK and AKT activation. We report here that the combination of ERK and AKT activation is crucial for PTEN suppression in surviving cells following UVB irradiation. AKT activation is higher in UVB-irradiated surviving cells as compared with unirradiated cells. The ERK and AKT pathways are involved in sustaining PTEN suppression in UVB-exposed cells. Increasing PTEN expression enhances apoptosis of keratinocytes in response to UVB irradiation. Our findings indicate that (1) UVB radiation suppresses PTEN expression in keratinocytes; and (2) the ERK/AKT/PTEN axis may form a positive feedback loop following UVB irradiation. Our identification of PTEN as a critical molecular target of UVB provides new insights into the pathogenesis of skin cancer.

Increased frequency of diabetes mellitus in patients with bullous pemphigoid: A case-control study

A case-control study was designed to assess the occurrence rate of primary diabetes mellitus (DM) in patients with bullous pemphigoid (BP) by retrospectively reviewing the records of our thirty histopathologically and immunopathologically proved cases of BP from the past 10 years. One hundred twenty patients were selected as controls, which included two names immediately before and two names immediately after each case of BP in our histopathology record book. The occurrence rate of primary DM prior to the administration of systemic corticosteroids was significantly higher in patients with BP than in the controls (20% and 2.5%, respectively; p = 0.004). Among patients over 50 years of age, this occurrence rate was again higher in patients with BP than in the controls (23% and 3.6% respectively; p = 0.02). This study suggests a higher than chance association of BP and primary DM.