Inhibition of UV-Induced Stress Signaling and Inflammatory Responses in SKH-1 Mouse Skin by Topical Small-Molecule PD-L1 Blockade.

The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar UV light-induced skin damage. In this study, we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small-molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using immunohistochemical and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cutaneous squamous cell carcinoma. Topical application of the small-molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced activator protein-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounter transcriptomic analysis confirmed downregulation of cutaneous innate immunity- and inflammation-related responses, together with upregulation of immune response pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.

The Drinking Water and Swimming Pool Disinfectant Trichloroisocyanuric Acid Causes Chlorination Stress Enhancing Solar UV-Induced Inflammatory Gene Expression in AP-1 Transgenic SKH-1 Luciferase Reporter Mouse Skin.

Freshwater sanitation and disinfection using a variety of chemical entities as chlorination agents is an essential public health intervention ensuring water safety for populations at a global scale. Recently, we have published our observation that the small molecule oxidant, innate immune factor and chlorination agent HOCl antagonize inflammation and photocarcinogenesis in murine skin exposed topically to environmentally relevant concentrations of HOCl. Chlorinated isocyanuric acid derivatives (including the chloramines trichloroisocyanuric acid [TCIC] and dichloroisocyanuric acid [DCIC]) are used worldwide as alternate chlorination agents serving as HOCl precursor and stabilizer compounds ensuring sustained release in aqueous environments including public water systems, recreational pools and residential hot tubs. Here, for the first time, we have examined the cutaneous TCIC-induced transcriptional stress response (in both an organotypic epidermal model and in AP-1 luciferase reporter SKH-1 mouse skin), also examining molecular consequences of subsequent treatment with solar ultraviolet (UV) radiation. Taken together, our findings indicate that cutaneous delivery of TCIC significantly enhances UV-induced inflammation (as profiled at the gene expression level), suggesting a heretofore unrecognized potential to exacerbate UV-induced functional and structural cutaneous changes. These observations deserve further molecular investigations in the context of TCIC-based freshwater disinfection with health implications for populations worldwide.

Review: PD-L1 as an emerging target in the treatment and prevention of keratinocytic skin cancer.

Recent advances in the understanding and targeting of immune checkpoints have led to great progress in immune therapies against many forms of cancer. While many types of immune checkpoints are currently targeted in the clinic, this review will focus on recent research implicating the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis as an emerging focus for the treatment of keratinocytic tumors. PD-L1 is of particular interest in nonmelanoma skin cancer (NMSC), as it is not only upregulated in these tumors but is stimulated by environmental ultraviolet exposure. This response may also make PD-L1 an excellent target for photochemoprevention using topically applied small molecule inhibitors. Here, we summarize recent investigations on PD-L1 expression and clinically relevant immune checkpoint inhibitor treatment in cutaneous squamous cell carcinoma, basal cell carcinoma, and head and neck squamous cell carcinoma, as well as small molecule agents targeting PD-L1 that may be useful for clinical development aiming at treatment or prevention of NMSC.

Design, Physicochemical Characterization, and In Vitro Permeation of Innovative Resatorvid Topical Formulations for Targeted Skin Drug Delivery.

Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 (TLR4) antagonist, resatorvid (TAK-242), is a novel prototype chemo preventive agent that suppresses the production of inflammation mediators induced by UV exposure. This study aimed to design and develop TAK-242 into topical formulations using FDA-approved excipients, including DermaBaseTM, PENcreamTM, polyethylene glycol (PEG)-400, propylene glycol (PG), carbomer gel, hyaluronic acid (HA) gel, and Pluronic® F-127 poloxamer triblock copolymer gel for the prevention of skin cancer. The physicochemical properties of raw TAK-242, which influence the compatibility and solubility in the selected base materials, were confirmed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Raman spectroscopy, and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopic analysis. The permeation behavior of TAK-242 from the prepared formulations was determined using Strat-M® transdermal diffusion membranes, and 3D cultured primary human-derived epidermal keratinocytes (EpiDermTM). Despite TAK-242's high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms.

Influence of information provided prior to switching from Humira to biosimilar adalimumab on UK patients' satisfaction: a cross-sectional survey by patient organisations.

OBJECTIVES: To investigate the perceptions and experiences of people with specific immune-mediated inflammatory diseases during the process of switching from Humira to biosimilar adalimumab. DESIGN: Cross-sectional survey. SETTING: An anonymised, self-administered, web-based survey. PARTICIPANTS: The participants were drawn from members and non-members of either the National Rheumatoid Arthritis Society, the National Axial Spondyloarthritis Society, Crohn's and Colitis UK, or Psoriasis Association. Birdshot Uveitis Society and Olivia's Vision also signposted to the survey links. RESULTS: A total of 899 people living with various immune mediated inflammatory diseases participated in this survey. Thirty-four per cent of respondents reported poor overall satisfaction with their biosimilar adalimumab after the switch, associated with complaints related to the switching process including lack of shared decision making, scarcity of information provided by or signposted to by the department instigating the switch as well as lack of training with the new injection device. Where training with the new device had been provided, there were significantly reduced reports of pain when injecting the new biosimilar (OR 0.20, 95% CI 0.07 to 0.55), side effects (OR 0.17, 95% CI 0.06 to 0.47) and difficulty in using the new injection device (OR 0.25, 95% CI 0.15 to 0.41). Self-reported side effects were reduced by (OR 0.13, 95% CI 0.05 to 0.38) when written information was provided by healthcare professionals and by (OR 0.15, 95% CI 0.05 to 0.42) with provision of verbal information. Difficulty in using the new injection device was also reduced by provision of satisfactory information such as written documents (OR 0.38, 95% CI 0.23 to 0.63) or by verbal communication with healthcare professionals (OR 0.45, 95% CI 0.27 to 0.73). Finally, provision of satisfactory written or verbal information was associated with a reduction in any negative perception regarding symptom control with the new biosimilar by (OR 0.05, 95% CI 0.004 to 0.57) and by (OR 0.15, 95% CI 0.03 to 0.84), respectively. CONCLUSIONS: Patient reported experiences of the process of switching from originator to biosimilar emphasise the importance of clear communication, training and information in order to optimise perception and maximise achievable outcomes with the new treatment.

Topical hypochlorous acid (HOCl) blocks inflammatory gene expression and tumorigenic progression in UV-exposed SKH-1 high risk mouse skin.

Hypochlorous acid (HOCl) is the active oxidizing principle underlying drinking water disinfection, also delivered by numerous skin disinfectants and released by standard swimming pool chemicals used on a global scale, a topic of particular relevance in the context of the ongoing COVID-19 pandemic. However, the cutaneous consequences of human exposure to HOCl remain largely unknown, posing a major public health concern. Here, for the first time, we have profiled the HOCl-induced stress response in reconstructed human epidermis and SKH-1 hairless mouse skin. In addition, we have investigated the molecular consequences of solar simulated ultraviolet (UV) radiation and HOCl combinations, a procedure mimicking co-exposure experienced for example by recreational swimmers exposed to both HOCl (pool disinfectant) and UV (solar radiation). First, gene expression elicited by acute topical HOCl exposure was profiled in organotypic human reconstructed epidermis. Next, co-exposure studies (combining topical HOCl and UV) performed in SKH-1 hairless mouse skin revealed that the HOCl-induced cutaneous stress response blocks redox and inflammatory gene expression elicited by subsequent acute UV exposure (Nos2, Ptgs2, Hmox1, Srxn1), a finding consistent with emerging clinical evidence in support of a therapeutic role of topical HOCl formulations for the suppression of inflammatory skin conditions (e.g. atopic dermatitis, psoriasis). Likewise, in AP-1 transgenic SKH-1 luciferase-reporter mice, topical HOCl suppressed UV-induced inflammatory signaling assessed by bioluminescent imaging and gene expression analysis. In the SKH-1 high-risk mouse model of UV-induced human keratinocytic skin cancer, topical HOCl blocked tumorigenic progression and inflammatory gene expression (Ptgs2, Il19, Tlr4), confirmed by immunohistochemical analysis including 3-chloro-tyrosine-epitopes. These data illuminate the molecular consequences of HOCl-exposure in cutaneous organotypic and murine models assessing inflammatory gene expression and modulation of UV-induced carcinogenesis. If translatable to human skin these observations provide novel insights on molecular consequences of chlorination stress relevant to environmental exposure and therapeutic intervention.

Increased PD-L1 Expression in Human Skin Acutely and Chronically Exposed to UV Irradiation.

Overexpression of PD-L1 (CD274) on tumor cells may represent a hallmark of immune evasion, and overexpression has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). While PD-L1/PD-1 activity in the skin has been primarily described in inflammatory models, our goal was to examine PD-L1 expression in human keratinocytes exposed to UV irradiation. We assessed PD-L1 expression in human sun-protected (SP) and sun-damaged (SD) skin, actinic keratosis (AK), and cSCC using IHC and protein microarray. Both methods found low baseline levels of PD-L1 in SP and SD skin and significantly increased expression in cSCC. Next, we examined PD-L1 expression in acute models of UV exposure. In human SP skin exposed to 2-3 MED of UV (n = 20), epidermal PD-L1 was induced in 70% of subjects after 24 h (P = 0.0001). SKH-1 mice exposed to acute UV also showed significant epidermal PD-L1 induction at 16, 24 and 48 h. A time- and dose-dependent induction of PD-L1 was confirmed in cultured human keratinocytes after UV, which was markedly reduced in the presence of MEK/ERK, JNK or STAT3 inhibitors. These findings suggest that UV induces upregulation of PD-L1 through established, pharmacologically targetable stress-signaling pathways in keratinocytes.

Translational Advances in Cancer Prevention Agent Development (TACPAD) Virtual Workshop on Immunomodulatory Agents: Report.

The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) convened the "Translational Advances in Cancer Prevention Agent Development (TACPAD) Workshop on Immunomodulatory Agents" as a virtual 2-day workshop on September 13 to 14, 2021. The main goals of this workshop were to foster the exchange of ideas and potentially new collaborative interactions among leading cancer immunoprevention researchers from basic and clinical research and highlight new and emerging trends in immunoprevention. The workshop included an overview of the mechanistic classes of immunomodulatory agents and three sessions covering the gamut from preclinical to clinical studies. The workshop convened individuals working in immunology and cancer prevention to discuss trends in discovery and development of immunomodulatory agents individually and in combination with other chemopreventive agents or vaccines.

Integrative transcriptomic analysis for linking acute stress responses to squamous cell carcinoma development.

Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer and commonly arises in chronically UV-exposed skin or chronic wounds. Since UV exposure and chronic wounds are the two most prominent environmental factors that lead to cuSCC initiation, we undertook this study to test whether more acute molecular responses to UV and wounding overlapped with molecular signatures of cuSCC. We reasoned that transcriptional signatures in common between acutely UV-exposed skin, wounded skin, and cuSCC tumors, might enable us to identify important pathways contributing to cuSCC. We performed transcriptomic analysis on acutely UV-exposed human skin and integrated those findings with datasets from wounded skin and our transcriptomic data on cuSCC using functional pair analysis, GSEA, and pathway analysis. Integrated analyses revealed significant overlap between these three datasets, thus highlighting deep molecular similarities these biological processes, and we identified Oncostatin M (OSM) as a potential common upstream driver. Expression of OSM and its downstream targets correlated with poorer overall survival in head and neck SCC patients. In vitro, OSM promoted invasiveness of keratinocytes and cuSCC cells and suppressed apoptosis of irradiated keratinocytes. Together, these results support the concept of using an integrated, biologically-informed approach to identify potential promoters of tumorigenesis.

Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn.

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.

TLR4 in skin cancer: From molecular mechanisms to clinical interventions.

The health and economic burden imposed by skin cancer is substantial, creating an urgent need for the development of improved molecular strategies for its prevention and treatment. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin carcinogenesis, and TLR4-dependent inflammatory dysregulation is an emerging key mechanism underlying detrimental effects of acute and chronic UV exposure. Direct and indirect TLR4 activation, upstream of inflammatory signaling, is elicited by a variety of stimuli, including pathogen-associated molecular patterns (such as lipopolysaccharide) and damage-associated molecular patterns (such as HMGB1) that are formed upon exposure to environmental stressors, such as solar UV. TLR4 involvement has now been implicated in major types of skin malignancies, including nonmelanoma skin cancer, melanoma and Merkel cell carcinoma. Targeted molecular interventions that positively or negatively modulate TLR4 signaling have shown promise in translational, preclinical, and clinical investigations that may benefit skin cancer patients in the near future.

Targeting PRPK and TOPK for skin cancer prevention and therapy.

Solar ultraviolet (sUV) irradiation is a major environmental carcinogen that can cause inflammation and skin cancer. The costs and morbidity associated with skin cancer are increasing, and therefore identifying molecules that can help prevent skin carcinogenesis is important. In this study, we identified the p53-related protein kinase (PRPK) as a novel oncogenic protein that is phosphorylated by the T-LAK cell-originated protein kinase (TOPK). Knockdown of TOPK inhibited PRPK phosphorylation and conferred resistance to solar-simulated light (SSL)-induced skin carcinogenesis in mouse models. In the clinic, acute SSL irradiation significantly increased epidermal thickness as well as total protein and phosphorylation levels of TOPK and PRPK in human skin tissues. We identified two PRPK inhibitors, FDA-approved rocuronium bromide (Zemuron®) or betamethasone 17-valerate (Betaderm®) that could attenuate TOPK-dependent PRPK signaling. Importantly, topical application of either rocuronium bromide or betamethasone decreased SSL-induced epidermal hyperplasia, neovascularization, and cutaneous squamous cell carcinoma (cSCC) development in SKH1 (Crl: SKH1-Hrhr) hairless mice by inhibiting PRPK activation, and also reduced expression of the proliferation and oncogenesis markers, COX-2, cyclin D1, and MMP-9. This study is the first to demonstrate that targeting PRPK could be useful against sUV-induced cSCC development.

Services for spondyloarthritis: a survey of patients and rheumatologists.

Objectives: There have been significant advances in axial spondyloarthritis (axSpA), with implications for service delivery. We evaluated the state of axSpA rheumatology services and how people with axSpA perceive their care. Methods: An online patient survey was emailed to all members of the National Ankylosing Spondylitis Society and advertised widely via social media. Separately, a Web-based questionnaire about axSpA services was sent to rheumatologists at all 172 acute hospital trusts in the UK. Results: From the National Ankylosing Spondylitis Society survey, data for 1979 surveys (56% males) were available for analysis. The majority of respondents had longstanding disease and identified their diagnosis as AS, with only 44% aware of the term axSpA. Eighty-two per cent of respondents were currently attending a rheumatologist, with 43% on biologic agents. Satisfaction scores for rheumatology care were high. Respondents' concerns included access during disease flares and adverse effects of analgesics. From the rheumatology survey, the concept and terminology of axSpA was widely accepted by respondents (88%). The majority of centres had at least one rheumatologist with a specialist interest in axSpA (62%), dedicated axSpA clinics (58%) or a multidisciplinary team for axSpA (64%). BASDAI (99%), BASFI (74%) and BASMI (65%) were routinely performed. All centres had access to MRI scans, but scanning protocols varied and were often sub-optimal. Conclusion: Although overall satisfaction with rheumatology care was high, the results indicate significant unmet patient needs and discrepancies in service provision. This information will inform the development of quality standards for axSpA in order to improve quality and deliver equitable care for all patients.

Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice.

An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV-induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-κB signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. ©2018 AACRSee related editorial by Sfanos, p. 251.

TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis.

BACKGROUND: Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention. METHODS: A structured search of bibliographic databases for peer-reviewed research literature revealed 139 articles including our own that are presented and critically evaluated in this TLR4-directed review. OBJECTIVE: To understand the molecular role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation. The specific focus of this review is on recent published evidence suggesting that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention. RESULTS: Cumulative experimental evidence indicates that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-κB and AP-1 stress signaling observable in vitro and in vivo. TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified as a novel class of molecular therapeutics. TLR4 antagonists are in various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling that may also contribute to skin photodamage and photocarcinogenesis in human populations. CONCLUSION: Future research should explore the skin photoprotective and photochemopreventive efficacy of topical TLR4 antagonism if employed in conjunction with other molecular strategies including sunscreens.

Protein activation mapping of human sun-protected epidermis after an acute dose of erythemic solar simulated light.

Ultraviolet radiation is an important etiologic factor in skin cancer and a better understanding of how solar stimulated light (SSL) affects signal transduction pathways in human skin which is needed in further understanding activated networks that could be targeted for skin cancer prevention. We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful technology that allows for broad-scale and quantitative measurement of the activation/phosphorylation state of hundreds of key signaling proteins and protein pathways in sun-protected skin after an acute dose of two minimal erythema dose (MED) of SSL. RPPA analysis was used to map the altered cell signaling networks resulting from acute doses of solar simulated radiation (SSL). To that end, we exposed sun-protected skin in volunteers to acute doses of two MED of SSL and collected biopsies pre-SSL and post-SSL irradiation. Frozen biopsies were subjected to laser capture microdissection (LCM) and then assessed by RPPA. The activation/phosphorylation or total levels of 128 key signaling proteins and drug targets were selected for statistical analysis. Coordinate network-based analysis was performed on specific signaling pathways that included the PI3k/Akt/mTOR and Ras/Raf/MEK/ERK pathways. Overall, we found early and sustained activation of the PI3K-AKT-mTOR and MAPK pathways. Cell death and apoptosis-related proteins were activated at 5 and 24 h. Ultimately, expression profile patterns of phosphorylated proteins in the epidermal growth factor receptor (EGFR), AKT, mTOR, and other relevant pathways may be used to determine pharmacodynamic activity of new and selective topical chemoprevention agents administered in a test area exposed to SSL to determine drug-induced attenuation or reversal of skin carcinogenesis pathways.

The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation.

Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2-ve or unfractionated MSCs. In a sheep cartilage-repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis-derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells 2017;35:2280-2291.

ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK.

Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843-54. ©2017 AACR.

A comparison of three methods to generate a conceptual understanding of a disease based on the patients' perspective.

BACKGROUND: The Food and Drug Administration patient-reported outcome (PRO) guidance provides standards for PRO development, but these standards bring scientific and logistical challenges which can result in a lengthy and expensive instrument development process. Thus, more pragmatic methods are needed alongside traditional approaches. METHODS: Partnering with the National Ankylosing Spondylitis (AS) Society, we compared three methods for eliciting patient experiences: 1) concept elicitation (CE) interviews with 12 individuals with AS, 2) "group concept mapping" (GCM) with 16 individuals with AS, 3) a social media review (SMR) of AS online chatrooms. Three conceptual models were developed and compared to explore data breadth/depth, as well as the practicalities and patient-centeredness. RESULTS: Overlap in concepts was observed between conceptual models; 35% of symptoms were identified by all methods. The SMR approach identified the most concepts (n = 23), followed by CE interviews (n = 18), and GCM (n = 15). Eight symptoms were uniquely identified using GCM and SMR. Eliciting in-depth data was challenging for SMR as detail was not always provided. Insight into the relationships between symptoms was obtained as a "concept map" in GCM, via effective probing within interviews, and through the subject's descriptions in SMR. Practical investment varied; CE interviews were the most resource intensive, whereas SMR was the least. Individuals in GCM and CE interviews reported high engagement. CONCLUSIONS: Primary CE interviews achieved the greatest depth in conceptual understanding of patient experience; however, novel methods (GCM, SMR) provide complementary approaches for identifying measurement concepts. Each method has strengths and weaknesses and should be selected based on specific research objectives.