Linked Article: Lee et al. Br J Dermatol 2019; 180: 1030-1038.

Psoriasis is a chronic, recurrent, heterogeneous, cutaneous inflammatory skin disease for which there is no cure. It affects approximately 7.5 million people in the United States. Currently, several biologic agents that target different molecules implicated in the pathogenic processes of psoriasis are being assessed in diverse clinical studies. However, relapse usually occurs within weeks or months, meaning there is currently no cure for psoriasis. Therefore, recent studies have discovered diverse new potential treatments for psoriasis: inhibitors of bacteria such as Staphylococcus aureus, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and neuropilin 1 (NRP1). A promising approach that has recently been described involves modifying antimicrobial peptides to develop new cutaneous anti-bacterial agents that target inflammatory skin disease induced by Staphylococcus. Increased expression of TRAIL and its death receptors DR4 and DR5 has been implicated in the pathogenesis of plaque psoriasis. In addition, TRAIL has the ability to inhibit angiogenesis by inducing endothelial cell death and by negative regulation of VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. Since NRP1 regulates angiogenesis induced by multiple signals, including VEGF, ECM and semaphorins, and also initiates proliferation of keratinocytes through NF-κB signaling pathway in involved psoriatic skin, targeting NRP1 pathways may offer numerous windows for intervention in psoriasis. In this review, we will focus on the current knowledge about the emerging role of synthetic antimicrobial peptides, TRAIL and NRP1 blocking peptides in the pathogenesis and treatment of psoriasis.

BACKGROUND:Multiple trials have attempted to demonstrate the effective induction of cell death in TRAIL-resistant cancer cells, including using a combined treatment of recombinant TRAIL and various proteasome inhibitors. These studies have yielded limited success, as the mechanism of cell death is currently unidentified. Understanding this mechanism's driving forces may facilitate the induction of cell death in TRAIL-resistant cancer cells.METHODS:Three kinds of recombinant soluble TRAIL proteins were treated into TRAIL-resistant cells and TRAIL-susceptible cells, with or without bortezomib, to compare their respective abilities to induce cell death. Recombinant TRAIL was treated with bortezomib to investigate whether this combination treatment could induce tumor regression in a mouse syngeneic tumor model. To understand the mechanism of combined treatment-induced cell death, cells were analyzed by flow cytometry and the effects of various cell death inhibitors on cell death rates were examined.RESULTS:ILz:rhTRAIL, a recombinant human TRAIL containing isoleucine zipper hexamerization domain, showed the highest cell death inducing ability both in single treatment and in combination treatment with bortezomib. In both TRAIL-resistant and TRAIL-susceptible cells treated with the combination treatment, an increase in cell death rates was dependent upon both the dose of TRAIL and its intrinsic properties. When a syngeneic mouse tumor model was treated with the combination of ILz:rhTRAIL and bortezomib, significant tumor regression was seen as a result of the effective induction of cancer cell death. The combination treatment-induced cell death was both inhibited by TRAIL blocking antibody and caspase-dependent. However, it was not inhibited by various ER stress inhibitors and autophagy inhibitors.CONCLUSIONS:The combination treatment with ILz:rhTRAIL and bortezomib was able to induce cell death in both TRAIL-susceptible and TRAIL-resistant cancer cells through the intracellular TRAIL signaling pathway. The efficiency of cell death was dependent on the properties of TRAIL under the environment provided by bortezomib. The combination treatment-induced cell death was not regulated by bortezomib-induced ER stress response or by autophagy.

Over recent years, several new molecular and immunogenic therapeutic approaches to melanoma treatment have been approved and implemented in clinical practice. Mechanisms of resistance to these new therapies have become a major problem. Mutation-specific pharmacotherapy can result in simultaneous emergence of resistant clones at many separate body sites despite an initially positive therapeutic response. Additionally, treatments aimed at inducing apoptosis are subject to resistance due to escape through other known mechanisms of regulated cell death (RCD). In this review, we discuss the complexity in pharmacological manipulation of melanoma with c-Kit, BRAF, MEK, and/or mTOR mutant cell lines. This study also addresses melanoma evasion of cell death through modalities of RCD such as apoptosis, autophagy, and necroptosis. This study also examines new combination therapies which have been approved to target both cell cycle dysregulation and cell death pathways. Lastly, we recognize the importance of immunomodulation though manipulation of the body's natural killing mechanisms with CTLA4, PD1, and CSF1 inhibition. As we begin to recognize tumor cell activation of alternate pathways, evasion of programmed cell death, and manipulation of the tumor microenvironment, it is increasingly important to grasp the complexity of personalized therapy in melanoma treatment.

Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib. These kinase inhibitors have the potential to work in tandem with MEK, PI3K/AKT, and mTOR to inhibit the activity of melanoma inducing BRAF mutations. This review summarizes the effects of the new therapeutic agents against melanoma and the underlying biology of these BRAF inhibitors.

BACKGROUND:Surgical site infection (SSI) remains a common, costly, and morbid health care-associated infection. Early detection can improve outcomes, yet previous risk models consider only baseline risk factors (BF) not incorporating a proximate and timely data source-the wound itself. We hypothesize that incorporation of daily wound assessment improves the accuracy of SSI identification compared with traditional BF alone.STUDY DESIGN:A prospective cohort of 1,000 post open abdominal surgery patients at an academic teaching hospital were examined daily for serial features (SF), for example, wound characteristics and vital signs, in addition to standard BF, for example, wound class. Using supervised machine learning, we trained 3 Naïve Bayes classifiers (BF, SF, and BF+SF) using patient data from 1 to 5 days before diagnosis to classify SSI on the following day. For comparison, we also created a simplified SF model that used logistic regression. Control patients without SSI were matched on 5 similar consecutive postoperative days to avoid confounding by length of stay. Accuracy, sensitivity/specificity, and area under the receiver operating characteristic curve were calculated on a training and hold-out testing set.RESULTS:Of 851 patients, 19.4% had inpatient SSIs. Univariate analysis showed differences in C-reactive protein, surgery duration, and contamination, but no differences in American Society of Anesthesiologists scores, diabetes, or emergency surgery. The BF, SF, and BF+SF classifiers had area under the receiver operating characteristic curves of 0.67, 0.76, and 0.76, respectively. The best-performing classifier (SF) had optimal sensitivity of 0.80, specificity of 0.64, positive predictive value of 0.35, and negative predictive value of 0.93. Features most associated with subsequent SSI diagnosis were granulation degree, exudate amount, nasogastric tube presence, and heart rate.CONCLUSIONS:Serial features provided moderate positive predictive value and high negative predictive value for early identification of SSI. Addition of baseline risk factors did not improve identification. Features of evolving wound infection are discernable before the day of diagnosis, based primarily on visual inspection.

Vitamin D receptor (VDR) as a ligand-dependent transcription factor forms a heterodimer with retinoid X receptor (RXR) to activate vitamin D response elements-associated various cellular genes during hair growth. Lithocholic acid (LCA) is known to be a naturally produced VDR ligand to induce VDR-RXR conformation. Previous studies demonstrated that the absence of VDR and RXRα ultimately resulted in alopecia development in mouse. However, since the role of LCA is not clear in hair cycling, we examined the functional mechanism of LCA in human dermal papilla cells (hDPCs). Treatment of hDPC cells with LCA significantly increased cellular proliferation together with the enhanced expression of VDR, RXRα, alkaline phosphatase, β-catenin, and dephospho-β-catenin in a dose-dependent manner as well as the acceleration of hair shaft elongation. To elucidate the possibility that the abnormality of hair cycling may be associated with ablation of VDR, we examined the expression of cell cycle control proteins in VDR knockout hDPC cells. The expression of cyclin D1 was decreased in VDR siRNA-transfected hDPC cells. In contrast, p21WAF1/CIP1 was upregulated by VDR knockout in hDPC cells. In this study, we showed the decreased expression of VDR, RXRα, and cyclin D1 as well as the enhanced expression of p21WAF1/CIP1 and the hair follicle cell death in tissue from patches of human alopecia. LCA treatment activated the expression of Bcl-2 and cyclin D1 and inhibited the expression of Bax and p21WAF1/CIP1 in hDPC cells. Furthermore, LCA significantly prevented the cell growth and alkaline phosphatase expression in hDPC cells induced by hair degeneration mediators such as IFN-γ or TNF-α. Therefore, our results suggest that lithocholic acid may play a critical role in hair regeneration through VDR activation in alopecia.

Staphylococcus aureus and S. aureus biofilms are associated with a number of cutaneous disorders. In this study, we examined the role of Helicobacter pylori-derived synthetic peptide ISFGW-P-A3NT3 against various strains of S. aureus. ISFGW-P-A3NT3 is a previously reported a-helical antimicrobial peptide, which has potent bactericidal effects against S. aureus. The minimum bactericidal concentration (MBC) of ISFGW-P-A3NT3 against S. aureus is less than 1.56 μM. ISFGW-P-A3NT3 shows no cytotoxicity in vitro against normal human keratinocytes (HKs) at bactericidal concentrations. Treatment with ISFGW-P-A3NT3 efficiently eliminates intracellular S. aureus in infected HKs in vitro. ISFGW-P-A3NT3 also suppresses the expression of IL-8 and TNF-α induced by S. aureus infection in HK cells. Moreover, ISFGW-P-A3NT3 efficiently eradicates S. aureus biofilms in vitro. We next examined the bactericidal effect of ISFGW-P-A3NT3 against S. aureus in vivo using a mouse model, in which we inoculated S. aureus onto abraded mouse flank skin. Addition of ISFGW-P-A3NT3 leads to smaller lesions at the site of infection with less necrosis. Moreover, ISFGW-P-A3NT3 significantly reduces the quantity of S. aureus on the skin lesions. Therefore, our results suggest that ISFGW-P-A3NT3 may represent a new potential therapeutic approach to skin disorders triggered by S. aureus.

BACKGROUND: Postoperative surgical site infections (SSI) are common and costly. Most occur post discharge, and can result in potentially preventable readmission or unnecessary urgent evaluation. Mobile health approaches incorporating patient-generated wound photos are being implemented in an attempt to optimize triage and management. We assessed how adding wound photos to existing data sources modifies provider decision making. STUDY DESIGN: We used a web-based simulation survey using a convenience sample of providers with expertise in surgical infections. Participants viewed a range of scenarios, including surgical history, physical exam, and description of wound appearance. All participants reported SSI diagnosis, diagnostic confidence, and management recommendations (main outcomes) first without, and then with, accompanying wound photos. At each step, participants ranked the most important features contributing to their decision. RESULTS: Eighty-three participants completed a median of 5 scenarios (interquartile range 4 to 7). Most participants were physicians in academic surgical specialties (n = 70 [84%]). The addition of photos improved overall diagnostic accuracy from 67% to 76% (p < 0.001), and increased specificity from 77% to 92% (p < 0.001), but did not significantly increase sensitivity (55% to 65%; p = 0.16). Photos increased mean confidence in diagnosis from 5.9 of 10 to 7.4 of 10 (p < 0.001). Overtreatment recommendations decreased from 48% to 16% (p < 0.001), and undertreatment did not change (28% to 23%; p = 0.20) with the addition of photos. CONCLUSIONS: The addition of wound photos to existing data as available via chart review and telephone consultation with patients significantly improved diagnostic accuracy and confidence, and prevented proposed overtreatment in scenarios without SSI. Post-discharge mobile health technologies have the potential to facilitate patient-centered care, decrease costs, and improve clinical outcomes. ((C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE The proposed Meaningful Use Stage 3 recommendations require healthcare providers to accept patient-generated health data (PGHD) by 2017. Yet, we know little about the tensions that arise in supporting the needs of both patients and providers in this context. We sought to examine these tensions when designing a novel, patient-centered technology - mobile Post-Operative Wound Evaluator (mPOWEr) - that uses PGHD for post-discharge surgical wound monitoring. MATERIALS AND METHODS As part of the iterative design process of mPOWEr, we conducted semistructured interviews and think-aloud sessions using mockups with surgical patients and providers. We asked participants how mPOWEr could enhance the current post-discharge process for surgical patients, then used grounded theory to develop themes related to conflicts and agreements between patients and providers. RESULTS We identified four areas of agreement: providing contextual metadata, accessible and actionable data presentation, building on existing sociotechnical systems, and process transparency. We identified six areas of conflict, with patients preferring: more flexibility in data input, frequent data transfer, text-based communication, patient input in provider response prioritization, timely and reliable provider responses, and definitive diagnoses. DISCUSSION We present design implications and potential solutions to the identified conflicts for each theme, illustrated using our work on mPOWEr. Our experience highlights the importance of bringing a variety of stakeholders, including patients, into the design process for PGHD applications. CONCLUSION We have identified critical barriers to integrating PGHD into clinical care and describe design implications to help address these barriers. Our work informs future efforts to ensure the smooth integration of essential PGHD into clinical practice.

Alpha-melanocyte stimulating hormone (α-MSH) is a highly conserved 13-aa neuropeptide derived from pro-opiomelanocortin by post-translational processing, which has been reported to exhibit potent anti-inflammatory activity and a wide range of immunosuppressive activities in the skin. However, the regulatory effect of α-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of α-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs). α-MSH pretreatment down-regulated the Staphylococcus aureus LTA-induced expression of both TLR2 and IL-8 as well as NF-κB nuclear translocation in HK cells. The inhibitory effect of α-MSH was blocked by agouti signaling protein (ASP), an α-MSH receptor-1 antagonist. To investigate the mechanism of this response in more detail, siRNA of IRAK-M, a negative regulator of TLR signaling, was utilized in these studies. The α-MSH suppressive effect on IL-8 production and NF-κB transactivation was inhibited by IRAK-M siRNA transfection in HK cells. These results indicate that α-MSH is capable of suppressing keratinocyte TLR2-mediated inflammatory responses induced by S. aureus-LTA, thus demonstrating another novel immunomodulatory activity of α-MSH in normal human keratinocytes.

The cutaneous inflammation associated with acne vulgaris is caused by the anaerobic bacterium Propionibacterium acnes through activation of the innate immune system in the skin. Current standard treatments for acne have limitations that include adverse effects and poor efficacy in many patients, making development of a more effective therapy highly desirable. In the present study, we demonstrate the protective effects of a novel customized α-helical cationic peptide, P5, against P. acnes-induced inflammatory responses in vitro and in vivo. Application of P5 significantly reduced expression of two inflammatory cytokines IL-8 and TNF-α in P. acnes-treated primary human keratinocytes, where P5 appeared to act in part by binding to bacterial lipoteichoic acid, thereby suppressing TLR2-to-NF-κB signaling. In addition, in a mouse model of acne vulgaris, P5 exerted both anti-inflammatory and antimicrobial effects against P. acnes, but exerted no cytotoxic effects against skin cells. These results demonstrate that P5, and perhaps other cationic antimicrobial peptides, offer the unique ability to reduce numbers P. acnes cells in the skin and to inhibit the inflammation they trigger. This suggests these peptides could potentially be used to effectively treat acne without adversely affecting the skin.

This study compared patient-reported claudication-related quality of life and function with physician classification of disease severity, with the goal of developing a more patient-centered assessment tool. Consecutive patients with leg pain and diagnosis of isolated infrainguinal disease were evaluated from 2011 to 2013 with the Vascular Quality of Life Questionnaire (VascuQoL) and Walking Impairment Questionnaire (WIQ). Patient scores were divided in tertiles, and concordance was performed to clinician-reported Rutherford assessment (mild, moderate, or severe). Of 323 patients enrolled, 225 participants (males, 70.7%) completed all three measures (VascuQoL, WIQ, and Rutherford) and were included in the analysis (mean ± standard deviation age, 70.7 ± 9.7 years.) Mean VascuQoL score was 4.72 ± 1.2 of 7 (1, lowest; 7, highest). Mean WIQ distance score was 34.7 ± 29.9 of 100 (lower score indicates lower function). The tertile ranges for the VascuQoL were low (1.4-4.1), moderate (4.2-5.4), and high (5.4-6.9). The tertiles for the WIQ were low (0-13.7), moderate (13.9-44.5), and high (44.6-100). The correlation between the WIQ or VascuQoL score and the Rutherford index were low (ρ = −0.34; P < .001 and ρ = −0.38; P < .001, respectively; Table). In patients reporting low QoL, physicians classified claudication as severe in 54%, moderate in 33%, and as mild in 13%. In patients reporting high QoL, 59% were classified as mild, 23% as moderate, and 18% as severe. Similarly, in patients reporting low walking function, 55% were classified as severe, 29% as moderate, and 16% as mild. In patients reporting high function, 21% were classified as severe, 26% as moderate, and 53% as mild. Lastly, the mean ankle-brachial indices for the Rutherford categories were 0.68, 0.68, and 0.62 for mild, moderate, and severe claudication, respectively (P = .12). The ankle-brachial index to Rutherford association was low (ρ = 0.2217; P = .002). There is significant discordance between quality of life and functional impairment due to claudication as reported by patients and as assessed by clinicians. Physicians overestimate effect of mild claudication and underestimate effect of severe claudication in 50% to 60% of patients. In this era of patient-centered health care, a tool that accounts for patient perception of disease severity is warranted.TableNumber and percentage of patients from each survey category by physician assigned claudication severityVascuQoL categoryRutherford classificationLow QoL (n = 84), No. (%)Moderate QoL (n = 76), No. (%)High QoL (n = 61), No. (%)Mild11 (13)27 (36)36 (59)Moderate28 (33)18 (24)14 (23)Severe45 (54)31 (41)11 (18)WIQ distance categoryRutherford classificationLow function (n = 82), No. (%)Moderate function (n = 71), No. (%)High function (n = 66), No. (%)Mild13 (16)26 (37)35 (53)Moderate24 (29)19 (27)17 (26)Severe45 (55)26 (37)14 (21) Open table in a new tab

BACKGROUND:An effective treatment strategy for acne vulgaris is the reduction of Propionibacterium acnes in the skin. The Helicobacter pylori-derived synthetic antimicrobial peptide HPA3NT3 is a customized α-helical cationic peptide with antibacterial and anti-inflammatory activity.OBJECTIVES:To examine the role of HPA3NT3 as a treatment against P. acnes-induced skin inflammation.METHODS:Morphological alteration of individual P. acnes cells by HPA3NT3 was visualized by scanning electron microscopy. Modulation by HPA3NT3 of a number of P. acnes-induced innate immune responses was analysed in vitro using cultured normal human keratinocytes (HKs), and in vivo using the ICR mouse, a well-established model for P. acnes-induced skin inflammation.RESULTS:The minimum inhibitory concentration of HPA3NT3 against P. acnes was low (0·4 μmol L(-1)). HPA3NT3 showed no cytotoxicity to HK cells at the concentrations used in our in vitro and in vivo studies. Treatment with HPA3NT3 in vitro induced morphological disruptions in P. acnes cells suggestive of a bactericidal effect. HPA3NT3 significantly decreased P. acnes-induced interleukin-8 expression and intracellular calcium mobilization in HK cells by inhibiting P. acnes-activated Toll-like receptor 2-mediated nuclear factor-κB signalling pathways. Intradermal injection of HPA3NT3 in vivo effectively decreased viable P. acnes, as well as erythema, swelling and inflammatory-cell infiltration in ICR mouse ears inoculated with P. acnes.CONCLUSIONS:Our data suggest that HPA3NT3 has potential as a therapeutic agent for acne vulgaris due to its antimicrobial effects on P. acnes and its ability to block P. acnes-induced inflammation.

An effective treatment strategy for acne vulgaris is the reduction of Propionibacterium acnes in the skin. The Helicobacter pylori‐derived synthetic antimicrobial peptide HPA3NT3 is a customized α‐helical cationic peptide with antibacterial and anti‐inflammatory activity. To examine the role of HPA3NT3 as a treatment against P. acnes‐induced skin inflammation. Morphological alteration of individual P. acnes cells by HPA3NT3 was visualized by scanning electron microscopy. Modulation by HPA3NT3 of a number of P. acnes‐induced innate immune responses was analysed in vitro using cultured normal human keratinocytes (HKs), and in vivo using the ICR mouse, a well‐established model for P. acnes‐induced skin inflammation. The minimum inhibitory concentration of HPA3NT3 against P. acnes was low (0·4 μmol L−1). HPA3NT3 showed no cytotoxicity to HK cells at the concentrations used in our in vitro and in vivo studies. Treatment with HPA3NT3 in vitro induced morphological disruptions in P. acnes cells suggestive of a bactericidal effect. HPA3NT3 significantly decreased P. acnes‐induced interleukin‐8 expression and intracellular calcium mobilization in HK cells by inhibiting P. acnes‐activated Toll‐like receptor 2‐mediated nuclear factor‐κB signalling pathways. Intradermal injection of HPA3NT3 in vivo effectively decreased viable P. acnes, as well as erythema, swelling and inflammatory‐cell infiltration in ICR mouse ears inoculated with P. acnes. Our data suggest that HPA3NT3 has potential as a therapeutic agent for acne vulgaris due to its antimicrobial effects on P. acnes and its ability to block P. acnes‐induced inflammation.

BACKGROUND:Post-discharge surgical site infections (SSI) are a major source of morbidity, expense and anxiety for patients. However, patient perceptions about barriers experienced while seeking care for post-discharge SSI have not been assessed in depth. We explored patient experience of SSI and openness to a mobile health (mHealth) wound monitoring "app" as a novel solution to address this problem. METHODS:Mixed method design with semi-structured interviews and surveys. Participants were patients who had post-discharge surgical wound complications after undergoing operations with high risk of SSI, including open colorectal or ventral hernia repair surgery. The study was conducted at two affiliated teaching hospitals, including an academic medical center and a level 1 trauma center. RESULTS:From interviews with 13 patients, we identified 3 major challenges that impact patients' ability to manage post-discharge surgical wound complications, including required knowledge for wound monitoring from discharge teaching, self-efficacy for wound monitoring at home, and accessible communication with their providers about wound concerns. Patients found an mHealth wound monitoring application highly acceptable and articulated its potential to provide more frequent, thorough, and convenient follow-up that could reduce post-discharge anxiety compared to the current practice. Major concerns with mHealth wound monitoring were lack of timely response from providers and inaccessibility due to either lack of an appropriate device or usability challenges. CONCLUSIONS:Our findings reveal gaps and frustrations with post-discharge care after surgery which could negatively impact clinical outcomes and quality of life. To address these issues, we are developing mPOWEr, a patient-centered mHealth wound monitoring application for patients and providers to collaboratively bridge the care transition between hospital and home.