Robert T. Brodell

CD133+ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: Significance for melanoma treatment

According to the cancer stem-like cell (CSC) hypothesis, neoplastic clones are maintained by a small fraction of cells with stem cell properties. Also, melanoma resistance to chemo- and radiotherapy is thought to be attributed to melanoma stem-like cells (MSCs). Caffeic acid phenethyl ester (CAPE) is a bioactive molecule, whose antitumor activity is approved in different tumor types. CAPE induced both apoptosis and E2F1 expression in CD133(-), but not in CD133(+) melanoma subpopulations. The resistance of CD133(+) melanoma subpopulation is attributed to the enhanced drug efflux mediated by ATP-binding cassette sub-family B member 5 (ABCB5), since the knockdown of ABCB5 was found to sensitize CD133(+) cells to CAPE. CAPE-induced apoptosis is mediated by E2F1 as evidenced by the abrogation of apoptosis induced in response to the knockdown of E2F1. The functional analysis of E2F1 in CD133(+) melanoma subpopulation demonstrated the ability of E2F1 gene transfer to trigger apoptosis of CD133(+) cells and to enhance the activation of apoptosis signal-regulating kinase (ASK1), c-Jun N-terminal kinase and p38, and the DNA-binding activities of the transcription factors AP-1 and p53. Also, the induction of E2F1 expression was found to enhance the expression of the pro-apoptotic proteins Bax, Noxa and Puma, and to suppress the anti-apoptotic protein Mcl-1. Using specific pharmacological inhibitors we could demonstrate that E2F1 overcomes the chemo-resistance of MSCs/CD133(+) cells by a mechanism mediated by both mitochondrial dysregulation and ER-stress-dependent pathways. In conclusion, our data addresses the mechanisms of CAPE/E2F1-induced apoptosis of chemo-resistant CD133(+) melanoma subpopulation.

Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment

Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanomas extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment.

Imiquimod‐induced apoptosis of melanoma cells is mediated by ER stress‐dependent Noxa induction and enhanced by NF‐κB inhibition

Melanoma is characterized by dysregulated intracellular signalling pathways including an impairment of the cell death machinery, ultimately resulting in melanoma resistance, survival and progression. This explains the tumours extraordinary resistance to the standard treatment. Imiquimod is a topical immune response modifier (imidazoquinoline) with both antiviral and antitumour activities. The mechanism by which imiquimod triggers the apoptosis of melanoma cells has now been carefully elucidated. Imiquimod‐induced apoptosis is associated with the activation of apoptosis signalling regulating kinase1/c‐Jun‐N‐terminal kinase/p38 pathways and the induction of endoplasmic stress characterized by the activation of the protein kinase RNA‐like endoplasmic reticulum kinase signalling pathway, increase in intracellular Ca2+ release, degradation of calpain and subsequent cleavage of caspase‐4. Moreover, imiquimod triggers the activation of NF‐κB and the expression of the inhibitor of apoptosis proteins (IAPs) such as, X‐linked IAP (XIAP) together with the accumulation of reactive oxygen species (ROS). Also, imiquimod triggers mitochondrial dysregulation characterized by the loss of mitochondrial membrane potential (Δψm), the increase in cytochrome c release, and cleavage of caspase‐9, caspase‐3 and poly(ADP‐ribose) polymerase (PARP). Inhibitors of specific pathways, permit the elucidation of possible mechanisms of imiquimod‐induced apoptosis. They demonstrate that inhibition of NF‐kB by the inhibitor of nuclear factor kappa‐B kinase (IKK) inhibitor Bay 11‐782 or knockdown of XIAP induces melanoma apoptosis in cells exposed to imiquimod. These findings support the use of either IKK inhibitors or IAP antagonists as adjuvant therapies to improve the effectiveness topical imiquimod in the treatment of melanoma.

Anxiety Sensitivity in Dermatological Patients

BACKGROUND Anxiety symptoms commonly occur in dermatological patients and can affect the severity of dermatological symptoms. Anxiety sensitivity (AS), defined as the fear of anxiety symptoms, is a well-supported cognitive vulnerability factor that may be particularly significant in these patients. OBJECTIVE This study compared the severity of AS between patients with psychodermatological (e.g., psoriasis) and nonpsychodermatological disorders (e.g., skin cancer). It was predicted that individuals with psychodermatological disorders would evidence significantly greater AS compared to individuals with nonpsychodermatological disorders. METHOD Adults presenting to outpatient dermatology clinics with psychodermatological (n = 63) and nonpsychodermatological (n = 52) conditions completed self-report questionnaires assessing sociodemographic characteristics, general anxiety, and AS. RESULTS Individuals with psychodermatological conditions reported significantly greater AS compared to individuals with nonpsychodermatological conditions (p < 0.05). Social concerns of AS emerged as the only significant factor that differentiated these categories of dermatological diseases, odds ratio = 1.13, 95% CI: 1.02-1.24, after adjusting for general anxiety. CONCLUSIONS These findings contribute to an advancing area of research linking AS and physical health problems. The results suggest that adjunctive cognitive-behavioral treatments targeting AS reductions could help patients with psychodermatological conditions.

Concurrent treatment of chronic psoriasis and asthma with ustekinumab

A 56-year-old woman with a 40-year history of guttate flares of psoriasis associated with stress and infection as well as chronic asthma was treated with subcutaneous injections of ustekinumab, repeated after 1 month and then every 3 months. Her psoriasis completely resolved, and her capacity for exercise was markedly increased and asthma maintenance medications were no longer needed. Ustekinumab is a human monoclonal antibody that binds the p40 subunit of IL-12 and IL-23 to limit the progression of the Th1 and Th17 inflammatory immune responses that maintain many autoimmune and inflammatory diseases. Th17-related responses drive inflammation during late stages of chronic asthma and can also be blocked by ustekinumab. Blocking the underlying cytokine-mediated inflammatory responses for psoriasis with ustekinumab can also treat other chronic inflammatory diseases.

Stress and skin disease quality of life: the moderating role of anxiety sensitivity social concerns

Stress is an important factor in the onset, exacerbation and reoccurrence of many skin diseases. Little is known about psychological risk factors that affect the association between stress and dermatological conditions. One relevant factor that may modulate this link is anxiety sensitivity (AS) social concerns – the propensity to respond fearfully to anxiety‐related sensations (e.g. sweating, flushing) owing to perceived social consequences (e.g. rejection or humiliation).

Skin Protection Behaviors among Young Male Latino Day Laborers: An Exploratory Study Using a Social Cognitive Approach

Latino Day Laborers (LDLs) are employed in occupations where multiple work hazards exist. One such hazard is the overexposure to solar ultraviolet radiation for continuous periods of time. Regular sun exposure can put individuals at increased risk of developing skin cancers, especially without adequate protection. The purpose of this cross-sectional exploratory study was to use a social cognitive framework to assess skin protective behaviors among LDLs. A community-based nonrandom and purposive sample of LDLs was recruited in two states: Mississippi and Illinois. The study sample consisted of 137 male participants, of which the majority were of Mexican ancestry (72%). The average age was 35.40 (SD = 9.89) years. Results demonstrated that a substantial number of LDLs do not adequately practice sun protection behaviors on a regular basis. The skin cancer knowledge scores were very modest. The most frequently indicated barriers towards sun protection were “inconvenient,” “forget to use,” and “not being able to reapply sunscreen.” Overall, LDLs had moderate confidence in their abilities to adopt successful sun protection strategies. This study underscores the need for intervention programs aimed at LDLs to reduce extended time in the sun and increase use of sun protective measures when working outdoors.

Improving Dermatology Clinical Efficiency in Academic Medical Centers

Objective : Improve efficiency and profitability in academic medical centers Methods : Academic medical centers across the United States are experiencing lower payments with increasing work hours and patient volumes for many faculty physicians. Department chairpersons find themselves caught in the middle, trying to improve clinical efficiency and profitability while retaining satisfied physicians. During a meeting with the chairperson, one faculty member reported frustration with the inability to meet targets for incentive pay. He agreed to add six slots to his scheduling template each half day if he could have a second LPN/RN for support. The hypothesis: productivity as measured by charges, work relative value units, and collections would increase and be greater than the cost of the additional employee. Data was collected over eight months, with the physician having one assistant during the first half and two assistants during the second half. Results : There was a 30% increase in completed visits, 39% increase in wRVU’s, and 33% increase in gross payments received. Conclusion : This experiment demonstrated that, when allowed to have input regarding structure of their own clinics, physicians are predictably able to see more patients and generate more income.

Introducing a curriculum in ethics and professionalism for dermatology residencies

There is general agreement on what constitutes ethical reasoning and professional behavior, but standardized methods to teach these skills in dermatology residency are currently unavailable. We introduce a model curriculum designed to impart the knowledge and skills to meet the Accreditation Council for Graduate Medical Education Dermatology Milestones for Professionalism over a 3-year cycle.

Chronic verrucous sarcoidosis associated with human papillomavirus infection: Improvement with adalimumab

Fig 1. Lesion at initial presentation shows annular verrucous lesions overlying sarcoidal papules and plaques. To the Editor: Verrucous sarcoidosis is a rare variant of cutaneous sarcoidosis observed most commonly on the lower extremities of patients with severe pulmonary disease. A case of a skin-colored to violaceous verrucous hyperplasia overlying sarcoidal plaques associated with human papillomavirus (HPV) was previously reported in this journal (Fig 1). At that time, we postulated that the virus inoculated the skin after facial trauma. In addition, sarcoidal plaques appeared to produce an immunocompromised district that favored HPV growth. In the absence of any previously reported cases of verrucous sarcoidosis of the face, the optimal approach for targeting both HPV and the underlying sarcoidal plaques was unknown. The response to a variety of treatments was instructive.