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Abstract Introduction Standard therapy for patients with mild to moderate atopic dermatitis (AD) typically includes topical therapies; however, patients with more extensive AD and/or AD refractory to topical therapy may benefit from systemic treatment. Ruxolitinib cream monotherapy has demonstrated superior antipruritic and anti-inflammatory effects versus vehicle in patients with mild to moderate AD, and long-term disease control with as-needed use. Here, efficacy/safety of 1.5% ruxolitinib cream through 52 weeks was assessed in a subset of patients with moderate and/or more extensive disease. Methods This post hoc analysis of TRuE-AD1/TRuE-AD2 included patients who, at baseline, had Investigator’s Global Assessment (IGA) score of 3, Eczema Area and Severity Index (EASI) ≥ 16, and affected body surface area (BSA) ≥ 10% (higher severity of disease threshold subgroup). Disease control and safety were assessed. Results Of 1249 patients in the overall population, 78 (6.2%) met all higher severity of disease threshold criteria (continuous-use vehicle-controlled period: 1.5% ruxolitinib cream, n = 32; vehicle, n = 13); 28 and 4 of these patients, respectively, continued as-needed 1.5% ruxolitinib cream during the long-term safety (LTS) period. At week 8 (continuous-use), IGA-treatment success (IGA 0/1, with ≥ 2-grade improvement from baseline) was achieved by 19/32 (59.4%) patients applying 1.5% ruxolitinib cream versus no patients applying vehicle. In the LTS period, those achieving clear/almost clear skin increased from 19/28 patients (67.9%; continuous-use: week 8) to 18/23 patients (78.3%; as-needed use: week 52) in patients applying ruxolitinib cream from day 1. Ruxolitinib cream was well tolerated, with few application site reactions, regardless of disease severity threshold. Efficacy and safety results were similar to the overall study population. Conclusion Patients with AD who meet standard disease severity eligibility criteria for systemic therapy may achieve IGA-treatment success with clear/almost clear skin with continuous-use ruxolitinib cream, and maintain long term-disease control with as-needed ruxolitinib cream monotherapy. Trial Registration Number NCT03745638/NCT03745651.

Background First-line treatment with pembrolizumab plus chemotherapy in recurrent and metastatic head and neck squamous cell carcinomas (HNSCC) has improved survival. However, the overall response rate with this standard of care regimen (SOC) remains limited. Interleukin (IL)-12 is a potent cytokine that facilitates the crosstalk between innate and adaptive immunity, making it crucial in the antitumor response. Alum-anchored murine IL-12 (mANK-101) has been demonstrated to elicit robust antitumor responses in diverse syngeneic models, which were correlated with increased immune effector functions and prolonged local retention of IL-12. This study investigates the therapeutic benefit of combining mANK-101 with SOC in the MOC1 and MOC2 murine HNSCC tumor models.Methods MOC1 and MOC2 tumor-bearing C57BL/6 mice were administered with a single intratumoral injection of mANK-101 and weekly intraperitoneal injections of cisplatin and α-programmed death 1 (PD-1) for 3 weeks. For MOC1, flow cytometry and cytokine array were performed to assess the immune effector functions associated with the combinational treatment. Multiplex immunofluorescence was employed to characterize the influence of the treatment on the immune architecture in the tumors. RNA analysis was implemented for in-depth examination of the macrophage and effector populations.Results In the MOC1 and MOC2 models, combination therapy with mANK-101, cisplatin, and α-PD-1 resulted in superior tumor growth inhibition and resulted in the highest rate of tumor-free survival when compared with treatment cohorts that received mANK-101 monotherapy or SOC treatment with α-PD-1 plus cisplatin. Furthermore, the combination therapy protected against tumor re-growth on rechallenge and controlled the growth of distal tumors. The improved therapeutic effect was associated with increased CD8+ T-cell recruitment, increased CD8+ and CD4+ activity, and repolarization of the macrophage population from M2 to M1 at the tumor site. Elevated and prolonged interferon-γ expression is central to the antitumor activity mediated by the combination therapy. In addition, the combination therapy with mANK-101+cisplatin+α-PD-1 induced the formation of tertiary lymphoid structure-like immune aggregates in the peritumoral space.Conclusion The current findings provide a rationale for the combination of alum-tethered IL-12 with cisplatin and α-PD-1 for HNSCC.

AbstractPurpose: Ruxolitinib (selective Janus kinase [JAK] 1 and JAK2 inhibitor) cream demonstrated efficacy and safety in patients with atopic dermatitis (AD) in the phase 3 TRuE-AD studies. In TRuE-AD1/TRuE-AD2 (NCT03745638/NCT03745651), adults and adolescents with mild to moderate AD were randomized to apply twice-daily ruxolitinib cream or vehicle for eight weeks. Here, we evaluated the efficacy and tolerability of ruxolitinib cream by anatomic region, focusing on head/neck (HN) lesions that are typically difficult to manage and disproportionately affect quality of life (QoL).Materials and methods: Eczema Area and Severity Index (EASI) responses in anatomic regions were evaluated in the pooled population (N = 1208) and among patients with baseline HN involvement (n = 663). Itch, Investigator’s Global Assessment (IGA), QoL, and application site tolerability were also assessed.Results: By Week 2 (earliest assessment), ruxolitinib cream application resulted in significant improvements across all EASI anatomic region subscores and AD signs versus vehicle, with further improvements through Week 8. Significantly more patients with HN involvement who applied ruxolitinib cream versus vehicle achieved clinically meaningful improvements in itch, IGA, and QoL. Application site reactions with ruxolitinib cream were infrequent (

Objective The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.Methods and analysis In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti−PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).Results A total of 107 patients received INCB001158 50–150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50–100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti–PD-1/PD-L1–naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.Conclusions INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.Trial registration number NCT02903914.

Tactile maps designed for individuals with blindness can greatly improve their mobility, safety and access to new locations. While 3D-printed maps have already been demonstrated to be a powerful tool for delivering spatial information, they might not always be available. Alternatively, a combination of audio and haptic information can be used to efficiently encode 2D maps. In this paper, we discuss the development and user-testing of a novel audio-haptic map creator application. Maps created using this application can provide people with blindness with a tool for understanding the navigational routes and layouts of spaces before physically visiting the site. Thirteen people with blindness tested various components of the virtual map application, such as audio, haptic feedback and navigation controls. Participants’ data and feedback were collected and analyzed to determine the effectiveness of the virtual maps as it relates to this user group’s readability and usability. The study showed that it was easy to use and that it efficiently delivered information about travel routes and landmarks that the participants could successfully understand.

Background Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis.Methods An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript.Results The panel determined unique clinical trial designs tailored to different stages of cancer development—from premalignant to unresectable/metastatic—that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments.Conclusions The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most.

Objetivo: investigar los factores que influyen en la alfabetización en salud de los pacientes con enfermedad arterial coronaria. Método: estudio transversal, que incluyó 122 pacientes con enfermedades coronarias (60,7% del sexo masculino; 62,07±8,8 años); se evaluó la alfabetización en salud y el conocimiento específico sobre la enfermedad mediante entrevistas con los participantes, utilizando el Short Test of Functional Health Literacy in Adults e Short version of the coronary artery disease education questionnaire. Los datos fueron descritos por medidas de tendencia central y frecuencias. Los factores que influyen en la alfabetización en salud se determinaron mediante un modelo de regresión lineal. El nivel de significación adoptado fue del 5%. El estudio fue aprobado por el Comité de Ética e Investigación. Resultados: la edad y la hipertensión mostraron una relación inversa y significativa con la alfabetización en salud. Por otro lado, un mayor nivel educativo y tener empleo se asociaron con puntajes más altos en el instrumento de alfabetización en salud. El conocimiento específico sobre la enfermedad no influyó en la alfabetización en salud. Las variables del modelo de regresión explicaron el 55,3% de alfabetización inadecuada. Conclusión: en el presente estudio, se concluyó que el conocimiento sobre la enfermedad no influye en la alfabetización en salud, pero los profesionales deben considerar los factores sociodemográficos y clínicos para planificar las intervenciones.

This experiment used a dismantling approach to examine change mechanisms in motivational interviewing (MI). Seventy-two undergraduate participants who scored in the top 35th percentile on trait anger were randomly assigned to: full MI (FMI), spirit-only MI (SOMI), or psychoeducation. They met individually with an experimenter for one 30- to 45-minute session to discuss their anger. In the FMI condition, the relational and technical elements of MI were both used to elicit change talk. In the SOMI condition, the supportive and relational elements of MI were emphasized. In the psychoeducation condition, the focus was placed on teaching the components of anger episodes. Participants were then asked to launch a daily, online, deep breathing exercise during the following week. Results showed that participants in both MI conditions emitted more change talk than those in the psychoeducation condition. Independent session ratings showed that despite the attempted elimination of technical elements in the SOMI condition, the FMI and SOMI conditions did not differ on the experimenter’s acceptance, empathy, direction, autonomy support, and collaboration. Also, results did not support the main effect on program launches. These results indicate it is challenging to separate relational from technical elements in MI and, thus, to identify core mechanisms of change.

Introduction Inflammatory bowel disease (IBD) consisting of Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory conditions affecting the gastrointestinal tract. Infliximab (IFX) is a chimeric anti‐tumor necrosis factor antibody used to treat moderate to severe IBD. Eosinophils are commonly found in chronically inflamed tissues in IBD. Peripheral eosinophilia (PE) was previously implicated as a marker of disease severity at diagnosis. The main aim of this study was to investigate whether in IBD patients on IFX, development of PE is associated with adverse outcomes and poor IFX efficacy. Methods A comprehensive retrospective chart review of IBD patients on IFX (January 2006 to July 2015) treated at a tertiary pediatric IBD center was performed. Data was collected at time specified points over a 24 month period and included demographics, atopy, disease severity, development of PE, human antichimeric antibodies (HACA), infusion reactions, cancer, psoriasis, and loss of clinical response. Results One hundred twenty‐one IBD patients starting IFX (67 male), mean age of 12.4 years (range 4–22 years old), met inclusion criteria. Of them, 36.3% had ≥1 PE episode (CD: 25 male, 11 female; UC: 6 male, 2 female). Mean absolute eosinophil count (AEC) did not change over time. PE was associated with clinically active disease. Among patients who developed PE, adverse outcomes were not significantly different versus those who did not have PE. Conclusions In a cohort of primarily pediatric IBD patients on IFX, PE was associated with clinically active disease; however, PE was not related to increased incidence of adverse outcomes or loss of drug efficacy.

Abstract Background The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). Methods We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. Results Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. Conclusions While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.

Background: Local relapse is a predominant form of recurrence among pediatric patients with Hodgkin lymphoma (PHL). Although PHL radiotherapy doses have been approximately 20 Gy, adults with Hodgkin lymphoma receiving 30 to 36 Gy experience fewer in-field relapses. We investigated the dosimetric effect of such a dose escalation to the organs at risk (OARs). Materials and Methods: Ten patients with PHL treated with proton therapy to 21 Gy involved-site radiation therapy (ISRT21Gy) were replanned to deliver 30 Gy by treating the ISRT to 30 Gy (ISRT30Gy), delivering 21 Gy to the ISRT plus a 9-Gy boost to postchemotherapy residual volume (rISRTboost), and delivering 30 Gy to the residual ISRT target only (rISRT30Gy). Radiation doses to the OARs were compared. Results: The ISRT30Gy escalated the dose to the target by 42% but also to the OARs. The rISRTboost escalated the residual target dose by 42%, and the OAR dose by only 17%to 26%. The rISRT30Gy escalated the residual target dose by 42% but reduced the OAR dose by 25% to 46%. Conclusion: Boosting the postchemotherapy residual target dose to 30Gy can allow for dose escalation with a slight OAR dose increase. Treating the residual disease for the full 30Gy, however, would reduce the OAR dose significantly compared with ISRT21Gy. Studies should evaluate these strategies to improve outcomes and minimize the late effects.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Abstract Background A key concern for people with chronic pain is experiencing increased pain and/or re-injury. Consequently, individuals with chronic pain can develop a maladaptive fear of movement that leads to adverse functional consequences. A primary goal of chronic pain rehabilitation is re-engagement in feared movements through exposure. This is often challenging since safe movement can be uncomfortable. Virtual environments provide a promising opportunity to safely and gradually expose Veterans to movements that are avoided in the real world. The current study will utilize multiple virtual reality (VR) applications (APPs) of varying the intensity levels ranging from passive distraction from pain to active exposure to feared movement. The primary aims of this pilot are to examine VR as an adjunctive nonpharmacological intervention to assist with the adoption and implementation of skills to decrease fear of movement and increase overall functioning among Veterans with chronic pain. Second, to build a hierarchy of VR APPs to assist in gradual exposure to feared movements. Methods This study will be conducted in the Chronic Pain Rehabilitation Program (CPRP) at the James A. Haley Veterans Hospital, a unique inpatient program within the VA system. Participants will include up to 20 Veterans who receive a VR intervention as part of their physical therapy. A rating form containing qualitative and quantitative experiences will be administered following each VR session to assess feasibility and to provide descriptive information for the proposed hierarchy. Effect sizes will be calculated from intake and discharge measures for the primary outcome fear of movement and secondary pain and functional outcomes. Discussion This study will inform the feasibility of a randomized controlled trial examining the clinical utility of using VR to reduce fear of movement and increase function among Veterans with chronic pain. VR has the advantage of being easily implemented both within VA healthcare settings as well as in Veterans’ own residences, where engagement in ongoing self-management approaches is often most challenging. Presumably, VR that is matched to patient needs, progresses in intensity, immerses Veterans in the applications, and is perceived positively by Veterans, will result in positive functional outcomes.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

OBJECTIVE: To evaluate the efficacy of using serum total and ionized magnesium (Mg) concentrations and urine Mg concentrations to identify Mg deficiency in cats. ANIMALS: 6 healthy castrated male cats. [...]

ABSTRACT Objective: to describe the theoretical construction process of nursing process support documents in COVID-19 care scenarios. Methods: an experience report of the joint activity of the Brazilian Nursing Process Research Network (Rede de Pesquisa em Processo de Enfermagem) composed of Higher Education and Health Institution researchers in Brazil. Results: five instruments were organized collectively, involving the elements of nursing practice (nursing diagnoses, outcomes and interventions) in assistance for community; for patients (with suspected or mild, moderate, and critical COVID-19 and residents in Nursing Homes); for nursing workers’ health support, also subsidizing registration and documentation during the COVID-19 pandemic. Final considerations: valuing the phenomena manifested by families/communities, patients and health professionals is essential for early detection, intervention, and prevention of diseases.

The deterioration signs of water quality in the Hau River are apparent. The present study analyzed the surface water quality of the Hau River using multivariate statistical techniques, including principal component analysis (PCA) and Cluster Analysis (CA). Eleven water quality parameters were analyzed at 19 different sites in An Giang and Can Tho Provinces for 12 months from January to December 2019. The findings show high levels of Biological Oxygen Demand (BOD), Total Soluble Solids (TSS), and total coliform, all year round. The PCA revealed that all the water quality parameters influenced the water quality of the Hau River, hence the relevance for water sample scrutiny. The dendrogram of similarity between sampling sites showed a maximum similarity of 95.6%. The Accumulation Factor (AF) trend showed that the concentrations/values of TSS, BOD, and phosphate (PO43−) in the downstream were 1.29, 1.53, and 1.52 times, respectively, greater than the upstream levels. Despite most of the parameters analyzed supporting aquaculture production, caution is needed in the regulation of pollution point sources to undertake sustainable aquaculture production.

Representative samples of offshore workers engaged in the use of totally enclosed lifeboats were recruited in two different regions of Atlantic Canada for this study. Body mass, height and three selected anthropometric dimensions were measured with and without the presence of an immersion suit. Statistical comparisons were made between the two groups and to the main criteria values for body weight and space allocation used international standards for lifeboat capacity rating. There was no difference in the height, body mass and BMI values between the two groups. Both groups were found to be considerably heavier than the IMO Life Saving Code standard of 75 kg. Not surprisingly, the shoulder breadths measurements were always greater than the hip breadth measurements. The seat pan allocation of 430 mm was found to be inadequate for this population and needs to be increased. Finally, the wearing of an immersion suit increases the physical size of each subject by substantial amounts. The magnitude of increase is related to the type of suit and whether there was external compression applied during the measurement. It was recommended that the international standard should be altered by reducing the lifeboat capacity ratings by 20%. [ABSTRACT FROM AUTHOR]

OBJECTIVES: While epidemiological evidence suggests homes with guns are more likely to be the site of a suicide or homicide than homes without guns, the public's perception of these risks remains unknown. This study assesses the prevalence of the belief that homes with guns are safer than homes without guns, and factors associated with this belief. METHODS: Telephone interviews were conducted with a random sample of 4138 registered voters in urban areas in the US. Multinomial logistic regression was used to assess correlates of beliefs about the safety of keeping a gun in the home. RESULTS: Twenty nine per cent of respondents believed keeping a gun in the home makes the home more safe, 40% said less safe, 23% said it depends, and 9% were unsure. The belief that a home is more safe with a gun was associated with being male, young, completing 12 years or fewer of education, having no children living at home, Republican party affiliation, and low levels of trust in the police for protection. Prior exposure to violence and fear of victimization were not associated with the outcome. CONCLUSIONS: Findings may increase understanding about the public's perception of the risk in keeping guns in the home and assist educational efforts to decrease the risk of these injuries. [ABSTRACT FROM AUTHOR]

Objective: To identify and analyze the concept of the powerlessness in individuals with stroke, according to the NANDA-I Taxonomy. Methods. Concept analysis from online access of four databases using the descriptors: impotence; helplessness, learned; Stroke, depression in languages: Portuguese, English and Spanish. Results. The critical attributes of the feeling of powerlessness are: fragility, helplessness, lack of control, and power to chieve the proposed results for recovery and adaptation. Eleven new antecedents were found. It is recommended to reformulate three antecedents present in the taxonomy. Fourteen consequent were found. It is suggested to amend three consequential from the review. Conclusion. With the analysis, a more complete concept of the powerlessness was elaborated allowing clarifying the critical attributes that, in turn, will help the rehabilitating nurse to recognize the signs and symptoms and to strengthen mechanisms of tolerance and resistance to stress. How to cite this article: Silva RA, Martins AKL, Castro NB, Viana AV, Butcher HK, Silva VM. Analysis of the concept of powerlessness in individuals with stroke. Invest. Educ. Enferm. 2017; 35(3):306-319.

RESUMO Objetivo Analisar a acurácia do diagnóstico “Disposição para melhora da Esperança” em pacientes renais crônicos. Método Estudo transversal com 62 pacientes em clínica de hemodiálise entre agosto a novembro de 2015. Utilizou-se a Escala de Esperança de Herth para a construção das definições das características definidoras da North American Nursing Diagnosis Association International. Analisaram-se medidas de sensibilidade, especificidade, valor preditivo, razão de verossimilhança e odds ratio das características definidoras do diagnóstico. Resultados 82,22% apresentaram o diagnóstico. Verificou-se que as características definidoras “Expressa desejo de intensificar a coerência entre expectativas e desejos” e “Expressa o desejo de reforçar a resolução de problemas para alcançar as metas” aumentou em onze e cinco vezes, respectivamente, a chance de possuírem o diagnóstico. Conclusão “Expressa desejo de intensificar a coerência entre expectativas e desejos” e “Expressa o desejo de reforçar a resolução de problemas para alcançar as metas” apresentaram boas medidas de acurácia.

Leflunomide is a novel immunomodulatory drug prescribed for treating rheumatoid arthritis. It inhibits the activity of protein tyrosine kinases and dihydroorotate dehydrogenase, a rate-limiting enzyme in the pyrimidine nucleotide synthesis pathway. Here, we report that A77 1726, the active metabolite of leflunomide, inhibited the phosphorylation of ribosomal protein S6 and two other substrates of S6K1, insulin receptor substrate-1 and carbamoyl phosphate synthetase 2, in an A375 melanoma cell line. A77 1726 increased the phosphorylation of AKT, p70 S6 (S6K1), ERK1/2, and MEK through the feedback activation of the IGF-1 receptor–mediated signaling pathway. In vitro kinase assay revealed that leflunomide and A77 1726 inhibited S6K1 activity with IC50 values of approximately 55 and 80 μM, respectively. Exogenous uridine partially blocked A77 1726–induced inhibition of A375 cell proliferation. S6K1 knockdown led to the inhibition of A375 cell proliferation but did not potentiate the antiproliferative effect of A77 1726. A77 1726 stimulated bromodeoxyuridine incorporation in A375 cells but arrested the cell cycle in the S phase, which was reversed by addition of exogenous uridine or by MAP kinase pathway inhibitors but not by rapamycin and LY294002 (a phosphoinositide 3-kinase inhibitor). These observations suggest that A77 1726 accelerates cell cycle entry into the S phase through MAP kinase activation and that pyrimidine nucleotide depletion halts the completion of the cell cycle. Our study identified a novel molecular target of A77 1726 and showed that the inhibition of S6K1 activity was in part responsible for its antiproliferative activity. Our study also provides a novel mechanistic insight into A77 1726–induced cell cycle arrest in the S phase.