Faculty Bibliography

The cutaneous ulcer in a patient with a history of international travel poses a vexing diagnostic dilemma for the clinician. While Streptococcus and Staphylococcus are common causes of cutaneous ecthyma, the necrotizing ulcer can have a vast differential diagnosis including ulcerating zoonoses.

Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors.

A 64-year-old man presented with a three-year history of an enlarging, pruritic, linear, verrucous plaque on his left lower extremity. Histopathologic examination was consistent with a verrucous epidermal nevus, which is a benign epidermal hamartoma, most commonly observed in the pediatric population. Verrucous epidermal nevi are often refractory to treatment and have high rates of recurrences, causing them to be therapeutic challenges. We review the treatment modalities reported to be effective in verrucous epidermal nevi.

Nonmelanoma skin cancers (NMSCs) represent the most common cancer in the United States, accounting for more than 2 million cases per year. Despite the magnitude of health burden on the US population, there remain many questions regarding the epidemiology, health outcomes, and treatments of NMSCs. This article highlights these areas of clinical and research need. The article focuses on the recent epidemiologic trends as well as health outcomes of NMSCs in the United States. In addition, current national guidelines, available treatments and care pathways, and clinical trials are discussed.

OBJECTIVES: To compare online video and pamphlet education at improving patient comprehension and adherence to sunscreen use, and to assess patient satisfaction with the two educational approaches. METHODS: In a randomized controlled trial, 94 participants received either online, video-based education or pamphlet-based education that described the importance and proper use of sunscreen. Sun protective knowledge and sunscreen application behaviors were assessed at baseline and 12 weeks after group-specific intervention. RESULTS: Participants in both groups had similar levels of baseline sunscreen knowledge. Post-study analysis revealed significantly greater improvement in the knowledge scores from video group members compared to the pamphlet group (p=0.003). More importantly, video group participants reported greater sunscreen adherence (p<0.001). Finally, the video group rated their education vehicle more useful and appealing than the pamphlet group (p<0.001), and video group participants referred to the video more frequently (p=0.018). CONCLUSION: Video-based learning is a more effective educational tool for teaching sun protective knowledge and encouraging sunscreen use than written materials. PRACTICE IMPLICATIONS: More effective patient educational methods to encourage sun protection activities, such as regular sunscreen use, have the potential to increase awareness and foster positive, preventative health behaviors against skin cancers.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus that causes significant disease and psychosocial burden in patients. Patient education has the potential to improve clinical outcomes and patient knowledge of this condition. OBJECTIVES: We sought to assess the effectiveness of online video education at improving AD knowledge and disease severity compared with a written pamphlet, and to determine the usefulness and appeal of the two educational delivery vehicles. METHODS: In a randomized controlled trial, 80 participants were randomized to receive either online video-based patient education or written pamphlet education about AD and its management. We assessed AD disease severity using the patient-oriented eczema measure (POEM) scale. AD knowledge was assessed with standardized questionnaires at baseline and after the 12-week intervention. RESULTS: All participants had similar baseline knowledge and AD severity at the beginning of the study. On study completion, improvements in AD knowledge assessed by questionnaire were significantly greater in the video group than the pamphlet group (3.05 vs 1.85, P = .011). Online video-based education resulted in greater improvement in clinical outcome, as measured by POEM, compared with pamphlet-based education (POEM score reduction of 3.30 vs 1.03, P = .0043). Finally, although the usefulness of both interventions was rated equally (P = .77), the online video was significantly more appealing than the pamphlet (P = .0086). LIMITATIONS: This study is limited to AD in adults. CONCLUSION: Online video for patient education is an effective and appealing tool for improving clinical outcomes in adult patients with AD.

Prostate cancer, the leading incidence of cancer in American males, is a disease in which treatment of nonlocalized tumors remains largely unsuccessful. These cancers lose expression of an arginine synthesis enzyme, argininosuccinate synthetase (ASS), and are susceptible to arginine deprivation by arginine deiminase (ADI). We show CWR22Rv1 prostate cancer cells are susceptible to ADI in a caspase-independent manner in vitro and in a xenograft model in vivo. We demonstrate that single amino acid deprivation by ADI is able to trigger autophagy. Inhibition of autophagy by chloroquine and siRNA enhances and accelerates ADI-induced cell death, suggesting that autophagy is a protective response to ADI, at least in the early phases. In addition, the co-administration of docetaxel, a caspase-dependent chemotherapy, with ADI inhibits tumor growth in vivo. Thus, targeting multiple cell death pathways, either through autophagy modulation or non-canonical apoptosis, may find expanded use as adjuvant chemotherapies, providing additional avenues for cancer treatment.

Arginine deprivation as an anticancer therapy has historically been met with limited success. The development of pegylated arginine deiminase (ADI-PEG20) has renewed interest in arginine deprivation for the treatment of some cancers. The efficacy of ADI-PEG20 is directly correlated with argininosuccinate synthetase (ASS) deficiency. CWR22Rv1 prostate cancer cells do not express ASS, the rate-limiting enzyme in arginine synthesis, and are susceptible to ADI-PEG20 in vitro. Interestingly, apoptosis by 0.3 microg/mL ADI-PEG20 occurs 96 hours posttreatment and is caspase independent. The effect of ADI-PEG20 in vivo reveals reduced tumor activity by micropositron emission tomography as well as reduced tumor growth as a monotherapy and in combination with docetaxel against CWR22Rv1 mouse xenografts. In addition, we show autophagy is induced by single amino acid depletion by ADI-PEG20. Here, autophagy is an early event that is detected within 1 to 4 hours of 0.3 microg/mL ADI-PEG20 treatment and is an initial protective response to ADI-PEG20 in CWR22Rv1 cells. Significantly, the inhibition of autophagy by chloroquine and Beclin1 siRNA knockdown enhances and accelerates ADI-PEG20-induced cell death. PC3 cells, which express reduced ASS, also undergo autophagy and are responsive to autophagy inhibition and ADI-PEG20 treatment. In contrast, LNCaP cells highly express ASS and are therefore resistant to both ADI-PEG20 and autophagic inhibition. These data point to an interrelationship among ASS deficiency, autophagy, and cell death by ADI-PEG20. Finally, a tissue microarray of 88 prostate tumor samples lacked expression of ASS, indicating ADI-PEG20 is a potential novel therapy for the treatment of prostate cancer

Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG-ADI on the in vivo growth of pancreatic xenografts was examined. Eighty-seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by approximately 50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG-ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.