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Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens.Experimental Design: A pharmacokinetic–pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system.Results: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options.Conclusion: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing. Clin Cancer Res; 20(14); 3742–52. ©2014 AACR.

PDF file - 311KB, Table S1. Results of proliferation assay. Table S2. Estimated PKPD population parameters. Fig. S1. Schematic view of the PK/PD model. Fig S2. Observed PK parameter and model predicted. Fig S3. Visual predictive check.

PDF file - 71K

PDF file - 12K, Antitumor activity of RG7112 against a panel of solid tumor cells.

PDF file - 1272K, Comparison of MDM2 binding properties of RG7112 and nutlin-3a (S1); Overlay of the crystal structures of MDM2 bound to RG7112 and Nutlin-2 (S2); RG7112 is a non-genotoxic p53 activator (S3); Effect of RG7112 on the viability of HCT116 cancer cells and their p53-null clone HCT116R1 (S4); RG7112 blocks the proliferation of mouse NIH-3T3 cells (S5).

PDF file - 136K, Includes HTRF, cell growth/viability, apoptosis assays and biacore, crystal structure and animal studies. Also includes supplemental references.

Most existing Virtual Patients utilize simplistic, predictable, and prescriptive approaches that limit deductive learning and the development of decision-making skills for medical students. We have designed a chat-based virtual patient for performing patient interviews, physical examinations, and investigations to help medical students develop reasoning skills. In this paper, we present results from a two-part study. In the first part, we conducted a usability evaluation with seven medical students and six clinicians. The objectives of the usability evaluation was to determine how VIP’s user interface and its features affect the usability (efficiency, effectiveness and learnability) as well as the general subjective user experience associated with the use of system. Each participant completed a user experience, system usability scale, and a self-prepared survey form. A significant difference was seen between the results of students and tutors. Due to a lack of training data, the chatbot model predicted incorrect responses that led participants to feel frustrated. In the second part of study, we have retrained the chatbot model using the feedback and designed an error correction approach and engaged seven new medical students to test the chatbot intensively — a total of 2169 user interactions were performed with the chatbot. Of that, 77.4% were properly answered by the bot, 10.8 % were out-of-domain concepts, 8.6 % were unknown concepts (Li et al., 2018), 3.3 % were corrected using the error correction approach designed.

During the COVID-19 pandemic, distorted information about the COVID-19 vaccination is widely disseminated through social media. The present study examined the association between perceived information distortion about COVID-19 vaccination on social media, individuals’ functional and critical literacy, and addictive social media use (SMU), as well as the moderating roles of functional and critical literacy in the association between perceived information distortion and addictive SMU among social media users in Hong Kong. A web-based, cross-sectional survey was conducted among 411 Chinese citizens from June to August 2021. Findings showed that after adjusting for significant background variables, including age, gender, marital status, education, occupation, and income, functional literacy was negatively associated with addictive SMU. In addition, significant moderation effects of functional literacy and critical literacy were also observed, such that a positive association between perceived information distortion on social media and addictive SMU was significant among participants with lower functional literacy or higher critical literacy. Findings highlight the importance of improving functional literacy in addictive SMU prevention for social media users. Special attention should also be paid to the potential influence of critical literacy on addictive SMUs.

Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation ensues when the PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are cis-repressed via their 3’-UTR miR-17 binding element. Eliminating this motif (Pkd1Δ17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also autoinhibited via its 3’-UTR miR-17 motif, and Pkd2Δ17-induced Polycystin-2 derepression partly compensates and retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, PKD1Δ17 or PKD2Δ17 alleles revert cyst-pathogenic sequala in patient-derived primary ADPKD cultures. Thus, evading 3’-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.

Despite the proliferation of eHealth interventions, such as web portals, for health information dissemination or the use of mobile apps and wearables for health monitoring, research has shown that underserved groups do not benefit proportionately from these eHealth interventions. This is largely because of usability issues and the lack of attention to the broader structural, physical, and psychosocial barriers to technology adoption and use. The objective of this paper is to draw lessons from a decade of experience in designing different user-centered eHealth interventions (eg, web portals and health apps) to inform future work in leveraging technology to address health disparities. We draw these lessons from a series of interventions from the work we have done over 15 years in the Viswanath laboratory at the Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, focusing on three projects that used web portals and health apps targeted toward underserved groups. The projects were the following: Click to Connect, which was a community-based eHealth intervention that aimed to improve internet skills and health literacy among underserved groups by providing home access to high-speed internet, computer, and internet training classes, as well as a dedicated health web portal with ongoing technical support; PLANET MassCONECT, which was a knowledge translation project that built capacity among community-based organizations in Boston, Lawrence, and Worcester in Massachusetts to adopt evidence-based health promotion programs; and Smartphone App for Public Health, which was a mobile health research that facilitated both participatory (eg, surveys) and passive data (eg, geolocations and web-browsing behaviors) collection for the purpose of understanding tobacco message exposure in individuals' built environment. Through our work, we distilled five key principles for researchers aiming to design eHealth interventions for underserved groups. They are as follows: develop a strategic road map to address communication inequalities (ie, a concrete action plan to identify the barriers faced by underserved groups and customize specific solutions to each of them), engage multiple stakeholders from the beginning for the long haul, design with usability-readability and navigability-in mind, build privacy safeguards into eHealth interventions and communicate privacy-utility tradeoffs in simplicity, and strive for an optimal balance between open science aspirations and protection of underserved groups. Published version

BACKGROUND Examining public perception of tobacco products is critical for effective tobacco policy making and public education outreach. While the link between traditional tobacco products and lung cancer is well established, it is not known how the public perceives the association between electronic cigarettes (e-cigarettes) and lung cancer. In addition, it is unclear how members of the public interact with official messages during cancer campaigns on tobacco consumption and lung cancer. OBJECTIVE In this study, we aimed to analyze e-cigarette and smoking tweets in the context of lung cancer during National Cancer Prevention Month in 2018 and examine how e-cigarette and traditional tobacco product discussions relate to implementation of tobacco control policies across different states in the United States. METHODS We mined tweets that contained the term “lung cancer” on Twitter from February to March 2018. The data set contained 13,946 publicly available tweets that occurred during National Cancer Prevention Month (February 2018), and 10,153 tweets that occurred during March 2018. E-cigarette–related and smoking-related tweets were retrieved, using topic modeling and geospatial analysis. RESULTS Debates on harmfulness (454/915, 49.7%), personal experiences (316/915, 34.5%), and e-cigarette risks (145/915, 15.8%) were the major themes of e-cigarette tweets related to lung cancer. Policy discussions (2251/3870, 58.1%), smoking risks (843/3870, 21.8%), and personal experiences (776/3870, 20.1%) were the major themes of smoking tweets related to lung cancer. Geospatial analysis showed that discussion on e-cigarette risks was positively correlated with the number of state-level smoke-free policies enacted for e-cigarettes. In particular, the number of indoor and on campus smoke-free policies was related to the number of tweets on e-cigarette risks (smoke-free indoor, r49=0.33, P=.02; smoke-free campus, r49=0.32, P=.02). The total number of e-cigarette policies was also positively related to the number of tweets on e-cigarette risks (r49=0.32, P=.02). In contrast, the number of smoking policies was not significantly associated with any of the smoking themes in the lung cancer discourse (P>.13). CONCLUSIONS Though people recognized the importance of traditional tobacco control policies in reducing lung cancer incidences, their views on e-cigarette risks were divided, and discussions on the importance of e-cigarette policy control were missing from public discourse. Findings suggest the need for health organizations to continuously engage the public in discussions on the potential health risks of e-cigarettes and raise awareness of the insidious lobbying efforts from the tobacco industry.

Background Examining public perception of tobacco products is critical for effective tobacco policy making and public education outreach. While the link between traditional tobacco products and lung cancer is well established, it is not known how the public perceives the association between electronic cigarettes (e-cigarettes) and lung cancer. In addition, it is unclear how members of the public interact with official messages during cancer campaigns on tobacco consumption and lung cancer. Objective In this study, we aimed to analyze e-cigarette and smoking tweets in the context of lung cancer during National Cancer Prevention Month in 2018 and examine how e-cigarette and traditional tobacco product discussions relate to implementation of tobacco control policies across different states in the United States. Methods We mined tweets that contained the term “lung cancer” on Twitter from February to March 2018. The data set contained 13,946 publicly available tweets that occurred during National Cancer Prevention Month (February 2018), and 10,153 tweets that occurred during March 2018. E-cigarette–related and smoking-related tweets were retrieved, using topic modeling and geospatial analysis. Results Debates on harmfulness (454/915, 49.7%), personal experiences (316/915, 34.5%), and e-cigarette risks (145/915, 15.8%) were the major themes of e-cigarette tweets related to lung cancer. Policy discussions (2251/3870, 58.1%), smoking risks (843/3870, 21.8%), and personal experiences (776/3870, 20.1%) were the major themes of smoking tweets related to lung cancer. Geospatial analysis showed that discussion on e-cigarette risks was positively correlated with the number of state-level smoke-free policies enacted for e-cigarettes. In particular, the number of indoor and on campus smoke-free policies was related to the number of tweets on e-cigarette risks (smoke-free indoor, r49=0.33, P=.02; smoke-free campus, r49=0.32, P=.02). The total number of e-cigarette policies was also positively related to the number of tweets on e-cigarette risks (r49=0.32, P=.02). In contrast, the number of smoking policies was not significantly associated with any of the smoking themes in the lung cancer discourse (P>.13). Conclusions Though people recognized the importance of traditional tobacco control policies in reducing lung cancer incidences, their views on e-cigarette risks were divided, and discussions on the importance of e-cigarette policy control were missing from public discourse. Findings suggest the need for health organizations to continuously engage the public in discussions on the potential health risks of e-cigarettes and raise awareness of the insidious lobbying efforts from the tobacco industry.

UNSTRUCTURED Despite the proliferation of eHealth interventions, such as web portals, for health information dissemination or the use of mobile apps and wearables for health monitoring, research has shown that underserved groups do not benefit proportionately from these eHealth interventions. This is largely because of usability issues and the lack of attention to the broader structural, physical, and psychosocial barriers to technology adoption and use. The objective of this paper is to draw lessons from a decade of experience in designing different user-centered eHealth interventions (eg, web portals and health apps) to inform future work in leveraging technology to address health disparities. We draw these lessons from a series of interventions from the work we have done over 15 years in the Viswanath laboratory at the Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, focusing on three projects that used web portals and health apps targeted toward underserved groups. The projects were the following: Click to Connect, which was a community-based eHealth intervention that aimed to improve internet skills and health literacy among underserved groups by providing home access to high-speed internet, computer, and internet training classes, as well as a dedicated health web portal with ongoing technical support; PLANET MassCONECT, which was a knowledge translation project that built capacity among community-based organizations in Boston, Lawrence, and Worcester in Massachusetts to adopt evidence-based health promotion programs; and Smartphone App for Public Health, which was a mobile health research that facilitated both participatory (eg, surveys) and passive data (eg, geolocations and web-browsing behaviors) collection for the purpose of understanding tobacco message exposure in individuals’ built environment. Through our work, we distilled five key principles for researchers aiming to design eHealth interventions for underserved groups. They are as follows: develop a strategic road map to address communication inequalities (ie, a concrete action plan to identify the barriers faced by underserved groups and customize specific solutions to each of them), engage multiple stakeholders from the beginning for the long haul, design with usability—readability and navigability—in mind, build privacy safeguards into eHealth interventions and communicate privacy–utility tradeoffs in simplicity, and strive for an optimal balance between open science aspirations and protection of underserved groups.

Purpose – The purpose of this paper is to present an overview of the history of heritage inventories in England and look at the requirements for a future vision of networked, digital heritage inventories to support heritage protection in England as outlined in the Heritage Information Access Strategy (HIAS). The strategy, led by Historic England, the UK Government-funded agency for heritage in England, is proposing a more formalized network where the prime sources of data relating to non-designated heritage assets will be the local authority historic environment records. Design/methodology/approach – This paper looks at the historic development of the inventories from paper-based publications to digital data sets and the proliferation of data. The Monument Inventory Data Standard Heritage will also be discussed in the context of providing a common framework. Findings – The present loose network presents several challenges for the multiple organizations maintaining similar data sets on disparate IT software, namely, the duplication of content, ownership of content and different approaches to recording practice and standards. There is a need for common data standards and controlled vocabularies in order to facilitate data exchange and interoperability across the network. Practical implications – The findings are based on the common experience of heritage inventory providers in England, but are relevant to any country where multiple inventories exist. It is anticipated that the implementation of the HIAS will provide a future-proofed environment for a shared national inventory. Originality/value – This paper presents the HIAS in its historic context. It is hoped that this may be of value to inventory programmes from outside the UK.

The spiral ganglion conveys afferent auditory information predominantly through a single class of type I neurons that receive signals from inner hair cell (IHC) sensory receptors. These auditory primary afferents, like in other systems (Puopolo and Belluzzi, 1998, Gascon and Moqrich, 2010, Leao et al., 2012) possess a marked diversity in their electrophysiological features (Taberner and Liberman, 2005). Consistent with these observations, when the auditory primary afferents were assessed in neuronal explants separated from their peripheral and central targets it was found that individual neurons were markedly heterogeneous in their endogenous electrophysiological features. One aspect of this heterogeneity, obvious throughout the ganglion, was their wide range of excitability as assessed by voltage threshold measurements (Liu and Davis, 2007). Thus, while neurons in the base differed significantly from apical and middle neurons in their voltage thresholds, each region showed distinctly wide ranges of values. To determine whether the resting membrane potentials (RMP) of these neurons correlate with the threshold distribution and to identify the ion channel regulatory elements underlying heterogeneous neuronal excitability in the ganglion, patch-clamp recordings were made from postnatal day (P5-8) murine spiral ganglion neurons in vitro. We found that RMP mirrored the tonotopic threshold distribution, and contributed an additional level of heterogeneity in each cochlear location. Pharmacological experiments further indicated that threshold and RMP was coupled through the Kv1 current, which had a dual impact on both electrophysiological parameters. Whereas, hyperpolarization-activated cationic channels (HCN) decoupled these two processes by primarily affecting RMP without altering threshold level. Thus, beyond mechanical and synaptic specializations, ion channel regulation of intrinsic membrane properties imbues spiral ganglion neurons with different excitability levels, a feature that contributes to primary auditory afferent diversity.

This paper presents a novel framework for evaluating the shape sensitivities of the von Mises stress function using an isoparametric finite-element formulation. The use of the isoparametric formulation allows us to apply the level set method to structures that are confined to irregularly shaped domains and therefore must be modeled using body-fitted, nonuniform finite element meshes. The shape sensitivities of the von Mises stress function are evaluated on this nonuniform mesh and mapped isoparametrically to a uniform Cartesian grid on which the Hamilton-Jacobi equation is solved. The paper also introduces a new approach to the enforcement of volume constraints based on the augmented Lagrangian formulation. The method is demonstrated on a series of two-dimensional problems including an isoparametric variation of the classic L-bracket problem. We show that the isoparametric level set method produces converged, feasible designs whose performance is comparable to SIMP results in terms of their final objective value.

This paper presents an approach for the topology optimization of structures under design-dependent pressure loading. Compared with traditional optimization problems with a fixed load, in a design-dependent load problem, the location, direction, and magnitude of the load change with respect to the design at every iteration. Using the SIMP model, the current method proposes a material boundary identification scheme by iteratively connecting points of equal density, with the use of a predefined void region. This predefined void region allows the structure to be loaded by pressure from outside the domain, as well as by pressure that is completely enclosed within the domain. This is particularly useful when there are multiple pressure vessels that can be interacting, or when symmetry cannot be used to bisect the pressure vessel. Also, by using an iso-density line to define the boundary, no additional artificial parameters that might affect the final solution are needed. An analytical method for deriving the sensitivity of the loads is also presented; this is an alternative to the finite-difference method and it could reduce the number of function calls. Numerical examples are presented to show the advantages and robustness of the proposed method.

This study examines data, information, and knowledge management in the historic environment sector in the context of broader trends in information technology, and information and knowledge management approaches. The opportunity provided by changes in technology over the career of the author are reviewed, with a caution against focusing purely on technology as a solution. A shift is proposed towards a greater emphasis on socially constructed knowledge of good practice, captured by social media or Web 2·0 systems in online communities of practice. This should complement the recorded data and information about the past that has been the traditional focus of data and information management in the sector.

The purpose of this paper is to apply stress constraints to structural topology optimization problems with design-dependent loading. A comparison of mass-constrained compliance minimization solutions and stress-constrained mass minimization solutions is also provided. Although design-dependent loading has been the subject of previous research, only compliance minimization has been studied. Stress-constrained mass minimization problems are solved in this paper, and the results are compared with those of compliance minimization problems for the same geometries and loading. A stress-relaxation technique is used to avoid the singularity in the stress constraints, and these constraints are aggregated in blocks to reduce the total number of constraints in the optimization problem. The results show that these design-dependent loading problems may converge to a local minimum when the stress constraints are enforced. The use of a continuation method where the stress-constraint aggregation parameter is gradually increased typically leads to better convergence; however, this may not always be possible. The results also show that the topologies of compliance-minimization and stress-constrained solutions are usually vastly different, and the sizing optimization of a compliance solution may not lead to an optimum.

The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, severalgroups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. Cancer Res; 70(5); 1970–80

Objectives We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide. Methods Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 times 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory Emax model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM. Key findings The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 1/h, 130 1 and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (Emax) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males. Conclusions The pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.

Efalizumab (anti-CD11a) interferes with LFA-1/ICAM-1 binding and inhibits several key steps in psoriasis pathogenesis. This study characterizes the effects of efalizumab on T-cell activation responses and expression of surface markers on human circulating psoriatic T cells during a therapeutic trial. Our data suggest that efalizumab may induce a unique type of T-cell hyporesponsiveness, directly induced by LFA-1 binding, which is distinct from conventional anergy described in animal models. Direct activation of T cells through different activating receptors (CD2, CD3, CD3/28) is reduced, despite T cells being fully viable. This hyporesponsiveness was spontaneously reversible after withdrawal of the drug, and by IL-2 in vitro. In contrast to the state of anergy, Ca(+2) release is intact during efalizumab binding. Furthermore, lymphocyte function-associated antigen-1 (LFA-1) blockade resulted in an unexpected downregulation of a broad range of surface molecules, including the T-cell receptor complex, co-stimulatory molecules, and integrins unrelated to LFA-1, both in the peripheral circulation and in diseased skin tissue. These observations provide evidence for the mechanism of action of efalizumab. The nature of this T-cell hyporesponsiveness suggests that T-cell responses may be reduced during efalizumab therapy, but are reversible after ceasing efalizumab treatment.

Each new semiconductor technology node brings smaller transistors and wires. Although this makes transistors faster, wires get slower. As FPGA device designers strive to obtain the lowest possible circuit delays from a given technology node, they must take an increasingly interconnect-focused viewpoint in the design process. In particular, for long interconnect wires, signals now require rebuffering somewhere in the middle of the wire. This paper presents a framework for designing and evaluating long, buffered interconnect wires in FPGAs with near-optimal delay performance. Given a target physical wire length, width and spacing, the method determines the number, size, and position of buffers required to obtain the fastest signal velocity for programmable interconnect. A metric introduced during the design is the "path delay profile", or the arrival time of a signal at different points of a long wire. This method is used to design buffering strategies for interconnect based on 0.5mm, 2mm, and 3mm wire lengths in 180nm technology. These interconnect designs are coded into VPR along with an improved timing analyzer which accurately determines the "path delay profile" arrival times. Using VPR, average critical-path delay is reduced by 19% for 0.5mm wires and by up to 46% for 3mm wires over previous designs given in Lemieux et al. (2004)

Performing on-chip antenna measurements at 60 GHz presents new challenges and magnifies legacy challenges. Testing on-chip antennas uses a micro-probe to interface the RF measurement system to the antenna under test (AUT). The small features of the antenna, the micro-probe, and the wavelength are among these challenges. In this paper, we assess these challenges and present techniques to ensure quality measurements.

We assessed expression of IL-20 and its receptors in psoriasis, given the recent implication of IL-20 in epidermal hyperplasia. Psoriatic lesional (LS) skin consistently expressed more IL-20 mRNA than nonlesional (NL) skin. Immunoreactivity to IL-20 protein was greater in LS tissue and mainly localized to infiltrating CD68 + /CD11c + (myeloid-derived) dermal leukocytes. Because this contrasted with earlier reports of a keratinocyte source, we assessed IL-20 mRNA expression in a variety of cells in vitro , and confirmed a myeloid-derived cellular source (monocytes). Plastic adhesion, activation of β 2 integrins, and incubation with tumor necrosis factor- α stimulated expression in these cells. IL-20 receptor (IL-20R) α and IL-20R β mRNA was decreased in LS versus NL skin, which also contrasted with earlier findings. To investigate the relationship between IL-20 and disease activity, we examined psoriasis patients treated with the CD2-targeted agent alefacept. In therapeutic responders, lesional IL-20 mRNA decreased to NL levels, suggesting that CD2 + leukocytes may proximally regulate IL-20. Finally, to assess IL-20 function, we used microarrays to screen IL-20-treated keratinocytes, which demonstrated upregulation of disease-related and IFN- γ -induced genes. Hence, IL-20 may influence inflammation through IFN-like effects. Together, these data indicate that IL-20 may be an important effector cytokine in psoriasis, and that its inhibition may represent a potential therapeutic target.