T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva (TM)): Mechanisms of action

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis. Copyright (C) 2004 S. Karger AG, Basel

Is overweight and obesity in 9–10-year-old children in Liverpool

Objectives: To determine whether weight problems in children (overweight, obesity and overweight or obesity) were related to deprivation indices when attributed only according to electoral ward of the school attended. To determine whether children with weight problems were more likely to be found in some wards rather than others, and to compare the distribution for boys and girls. Design: Retrospective, cross-sectional, observational study. Setting: One hundred and six primary schools from all parts of Liverpool city. Subjects: Five cohorts of 9–10-year-old children between 1998 and 2003. Main outcome measures: Body mass index (BMI) for each child to estimate proportions overweight, obese and overweight or obese according to international criteria. Results: Between January 1998 and March 2003, the heights and weights of 7902 boys and 7514 girls were measured and BMI calculated. The prevalence of boys and girls categorised as overweight or obese was very high (1620, 20.6% and 1909, 25.7%, respectively). Prevalence was not related to deprivation and varied between wards only for the girls; some wards had very different prevalence rates for boys and girls (Picton: 59 boys, 23.4%; 106 girls, 36.6%). The most deprived ward did not have a remarkable prevalence of overweight or obesity (Speke: 32 boys, 15.3%; 40 girls, 19.8%). Conclusions: Obesity is a major problem and requires urgent action but targeting intervention on the basis of administrative areas may be very wasteful. Different factors seem to lead to obesity in boys and girls, and attention should be paid to the role of the physical environment

A bibliometric study of the top 100 most-cited randomized controlled trials, systematic reviews and meta-analyses published in endodontic journals

Aim To identify and analyse the main features of the top 100 most‐cited randomized controlled trials, systematic reviews and meta‐analyses published in endodontic journals from 1961 to 2018. Methodology The Clarivate Analytics’ Web of Science ‘All Databases’ was used to search and analyse the 100 most frequently cited randomized controlled trials, systematic reviews and meta‐analyses having ‘randomized’, ‘randomised’, ‘randomized controlled’, ‘randomised controlled’, ‘randomized controlled trial’, ‘randomized controlled trials’, ‘clinical trial’, ‘systematic’, ‘systematic review’, ‘meta‐analysis’, and ‘meta‐analyses’ in the title section. The ‘International Endodontic Journal’, ‘Journal of Endodontics’, ‘Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology’, ‘Australian Endodontic Journal’, ‘Endodontics & Dental Traumatology’, ‘Endo‐Endodontic Practice Today’ and ‘European Endodontic Journal’ were included in the publication name section. After ranking the articles in a descending order based on their citation counts, each article was cross‐matched with the citation counts in Elsevier's Scopus and Google Scholar. The articles were analysed, and information on citation counts, citation density, year of publication, contributing authors, institutions and countries, journal of publication, study design, topic of the article and keywords was extracted. Results The citation counts of the 100 most‐cited articles varied from 235 to 20 (Web of Science), 276 to 17 (Scopus) and 696 to 1 (Google Scholar). The year in which the top 100 articles were published was 2010 (n = 13). Among 373 authors, the greatest number of articles was associated with three individuals namely Reader A (n = 5), Beck M (n = 5) and Kvist T (n = 5). Most of the articles originated from the United States (n = 24) with the greatest contribution from Ohio State University (USA) (n = 5). Randomized controlled trials were the most frequent study design (n = 45) followed by systematic reviews (n = 30) with outcome studies of root canal treatment being the major topic (n = 35). The Journal of Endodontics published the largest number of included articles (n = 70) followed by the International Endodontic Journal (n = 27). Among 259 unique keywords, meta‐analysis (n = 23) and systematic review (n = 23) were the most frequently used. Conclusion This study has revealed that year of publication had no obvious impact on citation count. The bibliometric analysis highlighted the quantity and quality of research, and the evolution of scientific advancements made in the field of Endodontology over time. Articles before 1996, that is prior to the CONSORT statement that encouraged authors to include specific terms in the title and keywords, may not have been included in this electronic search

Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model

Background: Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL). Arsenic trioxide (As2O3) has recently been shown to be effective against leukemias, so we studied whether As2O3 induces apoptosis of CTCL cells in vitro. We further investigated if As2O3 is effective in a MF mouse model. Material and methods: Annexin V/7-amino-actinomycin-D stainings were carried out to investigate if As2O3 induced apoptosis of CTCL cell lines. To study the underlying mechanisms, the effects of As2O3 on various transcription factors and apoptosis regulating proteins were analyzed by western blots, electrophoretic mobility shift assays and transcription factor enzyme-linked immunosorbent assays. The ability of As2O3 to induce tumor regression was investigated in a MF mouse model. Results: As2O3-induced apoptosis was paralleled by a reduction of the DNA-binding activities of transcription factors of the NFkB and signal transducer and activator of transcription gene families and reduced expression of the antiapoptotic proteins bcl-1, bcl-xL and mcl-1. Local injections of 200 μM As2O3 into tumors caused complete remissions in five of six mice and one partial remission. Conclusions: As2O3 induced apoptosis of CTCL cells by the down-regulation of transcription factors that stimulate the expression of antiapoptotic genes. Local injection of As2O3 into MF tumor-bearing mice resulted in tumor regressio

Biomarkers in melanoma

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques--DNA and RNA microarrays--have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers--lactate dehydrogenase, S100B and melanoma-inhibiting activity--as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the futur

Biomarkers in melanoma

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques—DNA and RNA microarrays—have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers—lactate dehydrogenase, S100B and melanoma-inhibiting activity—as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma

Purpose: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. Methods: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. Results: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. Conclusion: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone

In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. SIGnIFICAnCE: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens