Selective Induction of Cell Death in Melanoma Cell Lines through Targeting of Mcl-1 and A1.

PLoS One. 2012;7(1):e30821

Authors: Senft D, Berking C, Graf SA, Kammerbauer C, Ruzicka T, Besch R

Abstract
Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies.

PMID: 22292048 [PubMed - in process]

A software program designed to educate patients on age-related skin changes of facial and exposed extrafacial regions: the results of a validation study.

Clin Cosmet Investig Dermatol. 2012;5:23-31

Authors: Goodman GJ, Halstead MB, Rogers JD, Borzillo D, Ryan E, Riley N, Wlodarczyk J

Abstract
BACKGROUND: A software program called "HOYS" has been developed to depict various aspects and degrees of aging at 35 constituent subregions of seven distinct facial or exposed extrafacial regions. This program is underpinned by five-point photonumeric Likert scales characterizing skin surface and volume changes across five decades for each of the 35 subregions, and features an interactive skin-age assessment with a treatment-prioritization tool. In this study, the reliability and reproducibility of these scales was evaluated.
METHODS: Eleven physicians and 19 non-physicians participated in this study. The five images from each of the 35 Likert scales in the HOYS program were shown on a total of 43 display boards, with selected subregions presented at rest or with movement, consistent with this program. Each image was randomly labeled between "A-E," corresponding to a range of skin ages by decade from 20-69 years. Each rater was asked to rank these images from youngest to oldest (or least to most severe deficit) for each scale and to repeat this exercise 2 hours later, with the intra- and inter-rater reliability evaluated. The raters were also asked to estimate the age of a single randomly allocated image on each scale for the purposes of internal validation.
RESULTS: The overall inter-rater reliability of the raters was high at the first ranking session (weighted kappa: 0.78; 95% confidence intervals [95% CI]: 0.77-0.79) and this was confirmed when repeated 2 hours later (0.82; 95% CI: 0.81-0.83), with an intra-rater reliability of 0.76 (95% CI: 0.75-0.77). There was no significant difference in the physicians' and non-physicians' rankings. The raters also accurately estimated the actual age of the single randomly allocated image from each of the 43 stations (0.72; 95% CI: 0.70-0.74). A very similar pattern was observed when the ratings of a constituent of one of the seven regions, the perioral/lower face, were analyzed for expounding purposes.
CONCLUSION: The high reliability and reproducibility of the ranking in this validation study suggests that the five-point photonumeric Likert scales used in the HOYS program are an accurate depiction of age-related changes over five decades in the seven facial and extrafacial regions represented in this program, from the ages of 20-69 years.

PMID: 22291477 [PubMed - in process]

Eponyms in dermatology literature linked to Japan.

Clin Cosmet Investig Dermatol. 2012;5:15-21

Authors: Al Aboud A, Al Aboud K

Abstract
There are many different eponyms in common use in dermatology today, originating from a variety of countries worldwide. This review discusses a selection of dermatological eponyms that are linked to Japan.

PMID: 22291476 [PubMed - in process]

Inhibition of angiogenesis as a new therapeutic target in the treatment of lepromatous leprosy.

Clin Cosmet Investig Dermatol. 2012;5:1-6

Authors: El-Khalawany M, Shaaban D, Sultan M, Abd Alsalam F

Abstract
BACKGROUND: Angiogenesis was suggested to have a significant role in the pathogenesis of leprosy. However, the benefit of inhibiting angiogenesis in lepromatous leprosy patients has not previously been studied. The purpose of this study was to evaluate angiogenesis in leprosy patients before and after treatment with multidrug therapy (MDT) with and without minocycline.
METHODS: A total of 40 patients with lepromatous leprosy were enrolled in this study. They were categorized into two equal groups (A and B), each formed of 20 patients. Group A received World Health Organization MDT, and Group B received MDT combined with minocycline, which has a known antiangiogenic effect. Microvascular density (MVD) in dermal granuloma was evaluated in both groups by immunostaining with CD31 and CD34 markers before and after 6 months of treatment.
RESULTS: With CD31 immunostaining, the mean MVD in Group A significantly decreased from 39.1 ± 3.1 vessels (v)/high power field (HPF) to 16.5 ± 2.7 v/HPF, and in Group B it significantly decreased from 38.3 ± 2.5 v/HPF to 7.6 ± 1.9 v/HPF. CD34 immunostaining also showed a significant decrease of MVD from 42.2 ± 3.1 v/HPF to 18.8 ± 2.4 v/HPF in Group A, and in Group B it significantly decreased from 43.7 ± 2.3 v/HPF to 11.5 ± 1.6 v/HPF. The reduction of MVD was significantly higher in Group B compared with in Group A (P < 0.0001). Moreover, there was a significant reduction in bacterial density (assessed by bacterial index) in the cutaneous lesions of in Group B (decreased from 4.9 ± 0.3 to 1.4 ± 0.2) compared with in Group A (decreased from 5.1 ± 0.4 to 2.3 ± 0.4).
CONCLUSION: The synergistic effect of MDT and minocycline seems to be promising in the treatment of lepromatous leprosy. It significantly reduces angiogenesis and rapidly eliminates lepra bacilli from the skin that enables a rapid control and elimination of the disease.

PMID: 22291474 [PubMed - in process]

Regression of metastatic melanoma in a patient by antibody targeting of cancer stem cells.

Oncotarget. 2012 Jan 28;

Authors: Schlaak M, Schmidt P, Bangard C, Kurschat P, Mauch C, Abken H

Abstract
Current therapeutic regimens attempt to eliminate all malignant cells of a melanoma lesion; pre-clinical data, however, indicate that melanoma, once established, is maintained by a minor, non-random subset of cancer cells which are characterized by CD20 expression. We asked to eliminate those cells in a progressing, chemotherapy-refractory metastatic melanoma patient by lesional injections of the anti-CD20 therapeutic antibody rituximab and concomitant low dose systemic dacarbazine treatment. Although the frequencies of CD20+ melanoma cells within the tumor lesions were initially about 2% and the bulk of tumor cells did not express CD20, rituximab treatment produced lasting remission of treated tumor lesions in the long-term. Remission was accompanied by a decline of the melanoma serum marker S-100 to physiological levels. Detailed in-depth-analyses revealed a switch of serum cytokines from a T helper-2 to a pro-inflammatory T helper-1 cell profile. Apart from B cell elimination and decline in gammaglobulin levels, no grade 3/4 toxicity related to treatment was observed. Data provide the first clinical evidence that targeting the minor subset of CD20+ "melanoma sustaining cells" produces regression of chemotherapy-refractory melanoma and highlight the potency of selective cancer cell targeting in the treatment of melanoma.

PMID: 22289880 [PubMed - as supplied by publisher]

Loss of nuclear pro-IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma.

J Clin Invest. 2011 Dec 1;121(12):4838-49

Authors: Curiel-Lewandrowski C, Yamasaki H, Si CP, Jin X, Zhang Y, Richmond J, Tuzova M, Wilson K, Sullivan B, Jones D, Ryzhenko N, Little F, Kupper TS, Center DM, Cruikshank WW

Abstract
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined. Here, we demonstrate that loss of nuclear localization of pro-IL-16 facilitates CTCL cell proliferation by causing a decrease in expression of the cyclin dependent-kinase inhibitor p27Kip1. The decrease in p27Kip1 expression was directly attributable to an increase in expression of S-phase kinase-associated protein 2 (Skp2). Regulation of Skp2 is in part attributed to the nuclear presence of the scaffold protein pro-IL-16. T cells isolated from 11 patients with advanced CTCL, but not those from healthy controls or patients with T cell acute lymphocytic leukemia (T-ALL), demonstrated reduction in nuclear pro-IL-16 levels. Sequence analysis identified the presence of mutations in the 5' end of the PDZ1 region of pro-IL-16, a domain required for association of pro-IL-16 with the nuclear chaperone HSC70 (also known as HSPA8). HSC70 knockdown led to loss of nuclear translocation by pro-IL-16 and subsequent increases in Skp2 levels and decreases in p27Kip1 levels, which ultimately enhanced T cell proliferation. Thus, our data indicate that advanced CTCL cell growth is facilitated, at least in part, by mutations in the scaffold protein pro-IL-16, which directly regulates Skp2 synthesis.

PMID: 22080865 [PubMed - indexed for MEDLINE]

[Enlarging pigmented facial lesion.]

Hautarzt. 2012 Feb 1;

Authors: Haenssle HA

Abstract
A 75-year-old man presented after recurrence of a pigmented macule on his left cheek. Approximately 8 month before a seborrheic keratosis had been diagnosed clinically and treated with cryosurgery and curettage. Dermatoscopy of the recurrent lesion revealed a number of criteria associated with lentigo maligna including asymmetric pigmented follicular openings, streaks, rhomboidal structures, and homogeneous slate-gray areas. Histopathology confirmed a lentigo maligna melanoma with a Breslow tumor thickness of 0.3 mm.

PMID: 22290279 [PubMed - as supplied by publisher]

Alopecia Areata during Treatment of Psoriasis with Adalimumab and Leflunomide: A Case and Review of the Literature.

Skin Pharmacol Physiol. 2012 Jan 31;25(2):107-110

Authors: Navarro R, Daudén E, Gallo E, Santiago Sánchez-Mateos D, García-Diez A

Abstract
The pathogenesis of alopecia areata (AA) is not clear, even though it is believed to be an autoimmune mechanism which involves T lymphocytes and cytokines such as tumor necrosis factor α. We report the case of a 43-year-old man with psoriasis and psoriatic arthritis who developed AA during his treatment with adalimumab and leflunomide. We perform a review of the literature associating AA with biological therapy and leflunomide. We cannot exclude that the use of these therapies and the development of AA could be coincidental. However, we consider that case reports like ours are essential for clinicians as early alerts if similar observations occur.

PMID: 22301842 [PubMed - as supplied by publisher]

Acute Genital Ulcers in Nonsexually Active Young Girls: Case Series, Review of the Literature, and Evaluation and Management Recommendations.

Pediatr Dermatol. 2012 Feb 3;

Authors: Rosman IS, Berk DR, Bayliss SJ, White AJ, Merritt DF

Abstract
  Acute genital ulcers rarely occur in nonsexually active young girls. When present, they can cause significant physical and emotional distress for the patient and her parents, and prompt an evaluation for sexual abuse and sexually transmitted diseases. With this review, we aim to further characterize acute genital ulcers in nonsexually active young girls by reviewing the medical records of patients with this disorder and to offer an approach to the diagnosis, evaluation, and treatment of acute genital ulcers based on our understanding and knowledge of this condition. We retrospectively review our understanding and knowledge of acute genital ulcers in nonsexually active girls at a pediatric hospital. A review of the recent literature on acute genital ulcers and a multidisciplinary approach to the diagnosis, evaluation, and treatment of acute genital ulcers are also presented. Twelve patients presented with acute genital ulcers, 11 of which were hospitalized for evaluation and pain management. Extensive work-up failed to reveal a specific infectious or autoimmune etiology in all but one patient, who was diagnosed with acute mycoplasma pneumonia. Acute genital ulcers in nonsexually active young girls likely represent a form of idiopathic vulvar aphthosis. Evaluation of a first episode of acute genital ulcers with mild prodromal symptoms should be limited. Treatment consists primarily of supportive care and symptom relief.

PMID: 22300420 [PubMed - as supplied by publisher]

Bacterial Resistance and Impetigo Treatment Trends: A Review.

Pediatr Dermatol. 2012 Feb 3;

Authors: Bangert S, Levy M, Hebert AA

Abstract
  Impetigo is a common cutaneous infection that is especially prevalent in children. The prevalence of colonization and infection with resistant strains is continually increasing, forcing clinicians to reevaluate treatment strategies. Newer topical agents are effective in treating infections with resistant strains and may help minimize resistance and adverse effects from systemic agents. Use of topical disinfectants to decrease colonization is an important adjunctive measure. Physicians should be aware of local resistance patterns in impetigo to help guide therapy.

PMID: 22299710 [PubMed - as supplied by publisher]

Photopheresis in the treatment of cutaneous T-cell lymphoma: current status.

Curr Opin Oncol. 2012 Jan;24 Suppl 1:S1-10

Authors: Zic JA

Abstract
Cutaneous T-cell lymphoma is the overall name for a group of malignancies in which malignant T-lymphocytes localize at the skin. Of the current 20 recognized subtypes of the disease, the most common are mycosis fungoides and Sézary syndrome. Extracorporeal photopheresis (ECP), an immunomodulating procedure that treats pheresed blood with a photoactive agent, received US Food and Drug Administration approval in 1988 as a medical device for the treatment of CTCL patients, one of many treatment options for such patients. This was followed in 2003 by guidelines in the United Kingdom that recommended ECP for patients with advanced CTCL, particularly after skin-directed treatment options have failed. ECP is now under investigation for use in patients with earlier stages of CTCL. This article reviews the evolution of the ECP technique--for example, the most recent generation of the device requires a lower extracorporeal volume of blood than the previous version did, thus making it possible for more patients to be candidates for the procedure. In addition, there has been progress in understanding how ECP works at the cellular level.

PMID: 22157241 [PubMed - indexed for MEDLINE]

Actress Jennifer Aniston , who was recently named the Hottest Woman of All Time , shows off her age-defying beauty in the March 2012 issue of InStyle .

Tissue adhesives have been widely used for wound closure, especially in children, because they are painless, fast, and easy to use and result in minimal scarring.

To analyze the biocompatibility of an adhesive based on n-butyl-cyanoacrylate in the subcutaneous tissue of rats.

Two surgical sites were prepared (approximately 3 cm apart): one on the left side of the animal and the other on the right side); polyethylene tubes were implanted in each surgical site. The tube on the left was filled with n-butyl-cyanoacrylate (treated group) and the tube on the right side was unfilled (control group). After 7, 30, and 120 days, the animals were killed, and the specimens were processed for histologic analysis.

No significant inflammatory reaction occurred in the treated group, showing results similar to the control group.

This adhesive based on n-butyl-cyanoacrylate is biocompatible in the subcutaneous tissue of rats.

To improve skin appearance at the donor site of a split-thickness skin graft, part of the harvested skin was minced and grafted back onto the site in a process we named “recruited minced skin grafting.”

Thirteen Japanese patients who needed split-thickness skin grafts were treated with recruited minced skin grafting. Five patients were used as controls, in whom donor sites were treated with the traditional method. Part of the split-thickness skin was minced using two surgical blades (number 24) to an approximate particle size of less than 0.5 mm. Minced skin was spread and transplanted onto the donor site and covered with polyurethane foam. Twelve months after the operation, donor sites were scored for hypopigmentation, hyperpigmentation, redness, and disruption of skin texture. Gross appearance was evaluated according to total score.

Donor sites treated with recruited minced skin grafts had significantly better appearance than those of controls. Donor sites that had more than 5% of the total area treated tended to have better results.

Recruited minced skin grafting is a good method of improving the appearance of the donor site.