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Introduction: The interleukin-23p19 subunit inhibitor, guselkumab, has demonstrated improvements in clinical and patient-reported outcome (PRO) measures in patients with moderate-to-severe psoriasis. Understanding the relationship among clinical response, PRO measures and baseline characteristics could help clinicians individualize treatment plans. The objective of this analysis was to examine changes in signs, symptoms and quality-of-life (QoL) PRO measures in patients who maintained complete skin clearance through ≥ 3 years in the phase 3 VOYAGE 1 trial. Methods: A descriptive post hoc analysis of data from VOYAGE 1 was conducted to compare baseline characteristics of patients who maintained complete skin clearance (Psoriasis Area and Severity Index [PASI] = 0 for ≥ 156 consecutive weeks) versus patients who did not. Mean scores for individual domains of the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD) were evaluated in patients who maintained complete skin clearance, and baseline characteristics of patients who achieved PRO scores of DLQI = 0/1 and PSSD = 0 were compared with those who did not. Results: Of the 329 patients included in this post hoc analysis, 73 (22.2%) maintained PASI = 0 for ≥ 156 weeks. This group had a numerically lower proportion of patients at baseline with obesity, depression or previous biologic treatment and a higher proportion who had never smoked. Patients who maintained PASI = 0 generally achieved positive DLQI and PSSD outcomes, though some impact of residual disease was observed, largely related to the DLQI "Symptoms and feelings" sub-scale and PSSD components "Dryness," "Redness" and "Itch." Patients reporting continued disease impact (despite sustaining PASI = 0) had greater disease severity at baseline versus those achieving DLQI = 0/1 and PSSD = 0. Conclusion: Clinical measures alone do not capture the full patient experience. While both QoL and clinical symptoms are responsive to highly effective treatment, a subset of patients with complete clinical response is still impacted by their psoriasis. Further investigation into this population is warranted. Trial registration: ClinicalTrials.gov, NCT02207231. [ABSTRACT FROM AUTHOR]

Background: Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. Materials and Methods: This post-hoc analysis of the 5-year VOYAGE 1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥ 156 consecutive weeks (PASI = 0 group) with those that never achieve PASI = 0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4–156. Results: Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥ 156 consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p < 0.05) associated with the PASI = 0 group. Conclusion: A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥ 156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. Trial Registration: NCT02207231. [ABSTRACT FROM AUTHOR]

Our patients had a median time from neoplasm diagnosis to the first dose of biologics of 4.1 years (IQR 4.4), and more than half (52%) were diagnosed with a neoplasm < 5 years before starting the treatment. The second patient received a diagnosis of bladder neoplasm (T1N0M0) after 8 months of treatment with risankizumab. All patients received an IL inhibitor, with risankizumab being the most prescribed drug (11 patients), followed by ixekizumab (6), guselkumab and secukinumab (3 each). [Extracted from the article]

Introduction: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by heterogeneous clinical phenotypes and high symptom burden, especially through itch. Baricitinib (BARI), an oral Janus Kinase 1/2 inhibitor, is approved in Europe, Japan, and other countries, for treatment of adults with moderate-to-severe AD who are candidates for systemic therapy. This post hoc analysis of a Phase 3 topical corticosteroid (TCS) combination therapy trial (BREEZE-AD7) aims to characterize patients who might benefit most from BARI. Method: Classification and regression tree (CART) analysis was used to identify baseline predictors for patients treated with BARI 4-mg, who achieved ≥ 75% improvement in Eczema Area and Severity Index (EASI75), or EASI75 or Itch Numerical Rating Scale (NRS) ≥ 4-point improvement at week 16 (responders), versus non-responders. Subgroup efficacy analyses were performed based on identified predictor variables, combined with Itch NRS < 7/ ≥ 7. Missing data were imputed as non-responder. Results: Baseline body surface area (BSA) was identified by CART as strongest variable predicting response to BARI at week 16, with a cut-off around 40% (BSA ≤ 40%). When combining BSA with itch severity, highest response rates were achieved by BARI patients with BSA ≤ 40%/Itch NRS ≥ 7 at baseline. In this subgroup, 69% and 58% of patients treated with BARI 4-mg achieved EASI75 and Itch NRS ≥ 4-point response at week 16, respectively. While these response rates were 65% and 50% for BARI 4-mg patients with baseline BSA ≤ 40%/Itch NRS < 7, they were 33% and 11% in BSA > 40%/Itch NRS < 7, and 32% and 49% in BSA > 40%/Itch NRS ≥ 7 subgroups, respectively. Conclusion: Using a machine learning approach, patients with moderate-to-severe AD and a BSA affecting 10–40% and Itch NRS ≥ 7 were characterized as likely to benefit most from BARI 4-mg TCS combination therapy. This was confirmed by subgroup analyses, which showed that these patients are most likely to show favorable response rates in improving AD signs and symptoms, specifically itch, after 16 weeks of treatment. [ABSTRACT FROM AUTHOR]

The three other patients never received an anti-Il-17 because of a personal history of I Candida i infections (two patients) and risk factors for inflammatory bowel diseases (one patient). In particular, seven patients (58.33%), experienced loss of efficacy after more than 6 months of treatment with an anti-IL-23, while the other five patients (41.67%) never improved with the first biological drug. [Extracted from the article]

Background: The efficacy and safety of upadacitinib in atopic dermatitis (AD) have been defined in clinical trials, but no real-world data are currently available. We aimed to assess the safety and effectiveness of upadacitinib in a real-world AD patient cohort that mostly included patients who failed the available systemic therapies, including dupilumab. Methods: Prospective cohort study collecting data on upadacitinib-treated AD adult patients completing at least 16 weeks of therapy. Results: Forty-three patients showed rapid and marked response to upadacitinib with significant reduction of all disease severity scores since the first follow-up visit. At week 16, Eczema Area and Severity Index (EASI) 75, EASI 90, and EASI 100 response was observed in 97.5%, 82.1%, and 69.2% of patients, respectively. EASI 90 response reflected the achievement of a clear or almost clear condition (POEM 0-2), self-evaluated by 79.5% of patients. Patients' quality of life improved as suggested by the achievement of DLQI 0/1 by 38.5% of patients at week 4, and by 76.9% at week 16. Conclusion: Elevated effectiveness and favorable safety of upadacitinib were confirmed in patients unresponsive to dupilumab, who were not included in upadacitinib trials. [ABSTRACT FROM AUTHOR]

Purpose: Established that the only approved agents in previously treated metastatic colorectal cancer (CRC) are trifluoridine/tipiracil and regorafenib, we conducted a systematic review of all the published phase 2–3 trials, with the scope to evaluate the benefit of any later-line regimens in refractory metastatic CRC. Methods: Phase 2–3 studies that enrolled patients with stage IV disease receiving salvage therapies for refractory CRC were identified using electronic databases (Pubmed, EMBASE, and Cochrane Library). Clinical outcomes were pooled using a point estimates for the weighted values of median overall survival (OS), progression-free survival (PFS), response rate (ORR), stable disease rate (SD), and 6-month and 1-year OS. Results: Overall, 7556 patients were included from 67 studies (n = 70 arms). Overall, the pooled ORR and SD were 15.4% (95% CI 13–18%) and 36.9% (95% CI 33.5–40.6%). Median PFS, 6-month and 1-year OS, and median OS were 3.2 (95% CI 2.9–3.3) months, 65.4% (95% CI 61.9–68.8%), 36% (95% CI 32.3–39.9%) and 8.8 (95% CI 8.3–9.2) months. Overall survival was different in the monochemotherapy, polychemotherapy, chemotherapy + targeted therapy, and targeted therapy alone arms (7.6, 9.5, 10.3, and 7.9 months, respectively, P for difference = 0.01). Median PFS were respectively 2.3, 3.9, 3.8, and 2.6, respectively (P for difference < 0.01). Conclusions: Overall, combination therapy (polychemotherapy with or without targeted agents) is associated with a higher control of disease and better outcome than approved agents. Treatment, if possible, should be personalized according to the patients' conditions, physician preference and molecular profile of disease. [ABSTRACT FROM AUTHOR]

Several historical towns and sites in Italy and other parts of Southern Europe were built on topographic reliefs, and they host inestimable cultural heritage. In Calabria (southern Italy), the historical town of Gerace is located in a highly seismic area and lies on top of an unstable cliff, constituted by a soft rock slab overlying a thick clay shale formation. A comprehensive study was carried out to reproduce the seismic response of the cliff and analyse potential effects due to severe earthquakes, such as those attributed by historical documents to the Calabrian seismic sequence that occurred in 1783. Much effort was spent on the geotechnical characterisation of the soils; in particular, a subsoil model was obtained by combining data from field and laboratory tests. The seismic response of the cliff due to the first event of the Calabrian sequence was simulated by 1D and 2D non-linear analyses, which enabled an assessment of the influence of topography on the seismic response. The 2D analyses justified the occurrence of large permanent deformations, as reported by the chronicles following the historical seismic sequence. [ABSTRACT FROM AUTHOR]

Since August 2016, Central Italy has been struck by three strong earthquakes (Mw 6.0 Amatrice, Mw 5.9 Visso and Mw 6.5 Norcia). This seismic sequence resulted in ground failure, infrastructural damages and destruction of several villages. This work aims to analyze the site effects on the ground shaking along the valley of the Tronto River across the Acquasanta Terme municipality, where some historical sites were located. These suffered heavy and differentiated damage during the seismic sequence. Following the Amatrice earthquake of August 24, authors managed the deployment and acquisition of seismic stations located in an array along the valley of the Tronto River approximately 25 km from the epicenter. By recording the two stronger earthquakes (i.e., Mw 5.9 Visso and Mw 6.5 Norcia) and 30 aftershocks with varying magnitudes and also ambient vibration, the site effects were preliminarily studied using the horizontal-to-vertical spectral ratio (HVSR). Furthermore, the amplification effects on the ground motion were also evaluated with reference to the earthquakes in terms of the standard spectral ratio (SSR) and the normalized energy content, in both cases using the bottom of the valley where the seismic bedrock outcrops as a reference. The comparison between the spectral accelerations due to the two strong earthquakes and those provided by ground motion prediction equations displayed values that were usually inadequately precautionary for periods lower than 0.35 s. High spectral accelerations were detected in period ranges corresponding to those predominant for masonry structures that are available in the literature. According to the current knowledge about surface geology, the local site effects seem to have significantly influenced ground shaking along the slopes of the valley, thus producing a larger seismic effect on ancient structures with more than two floors. The results can provide useful information for undertaking a possible future microzonation study that would be able to support urban planning and seismic designs in the rebuilding phase. [ABSTRACT FROM AUTHOR]

Introduction: Immune-mediated inflammatory diseases (IMIDs) are chronic autoimmune conditions that share common pathophysiologic mechanisms. The optimal management of patients with IMIDs remains challenging because the coexistence of different conditions requires the intervention of several specialists. The aim of this study was to develop a series of statements defining overarching principles that guide the implementation of a multidisciplinary approach for the management of spondyloarthritis (SpA)-related IMIDs including SpA, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and uveitis.Methods: A Delphi consensus-based approach was used to identify a core set of statements. The process included development of initial questions by a steering committee, an exhaustive search of the literature using complementary approaches to identify potential statements and two Delphi voting rounds for finalization of the statements.Results: Consensus was achieved on the related nature of IMIDs, the existence of a high prevalence of multiple IMIDs in a single patient and the fact that a multidisciplinary approach can result in a more extensive evaluation and comprehensive approach to treatment. The goals of a multidisciplinary team should be to increase diagnosis of concomitant IMIDs, improve the decision-making process, and increase patient satisfaction and adherence. Early referral and diagnosis, early recognition of concomitant IMIDs and optimizing treatment to improve patient quality of life are some of the advantages of using multidisciplinary teams. To be effective, a multidisciplinary team should be equipped with the appropriate tools for diagnosis and follow-up, and at a minimum the multidisciplinary team should include a dermatologist, gastroenterologist and rheumatologist; providing psychologic support via a psychologist and involving an ophthalmologist, general practitioners and nurses in multidisciplinary care is also important.Conclusion: The present Delphi consensus identified a set of overarching principles that may be useful for implementation of a multidisciplinary approach for the management of SpA-related IMIDs.Funding: Aristea and Hippocrates. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome is currently considered an 'autoimmune epithelitis,' as exocrine glands, especially salivary and lacrimal, are progressively destructed by an immune-mediated process associated with specific serum autoantibodies and local lymphocyte infiltrate. Xerostomia remains a key complain in patients with Sjögren's syndrome but should be evaluated also for other causes such as xerogenic medications, followed by radiation and chemotherapy for head and neck cancers, hormone disorders, infections, or other connective tissue diseases. Further, xerophtalmia (also known as dry eye) frequently associated with keratoconjunctivitis sicca cumulatively affects approximately 10-30% of the general population with increasing incidence with age and is more frequently secondary to non-autoimmune diseases. On the other hand, numerous patients with Sjögren's syndrome manifest signs of systemic dryness involving the nose, the trachea, the vagina, and the skin, suggesting that other glands are also affected beyond the exocrine epithelia. Skin involvement in Sjögren's syndrome is relatively common, and various manifestations may be present, in particular xeroderma, eyelid dermatitis, annular erythema, and cutaneous vasculitis. Additional skin non-vasculitic manifestations include livedo reticularis which may occur in the absence of vasculitis, and localized nodular cutaneous amyloidosis possibly representing lymphoproliferative diseases related to Sjögren's syndrome. The treatment of skin and mucosal manifestations in Sjögren's syndrome is similar regardless of the cause, starting from patient education to avoid alcohol and tobacco smoking and to pursue dental hygiene. In conclusion, a strict collaboration between the dermatologist and the rheumatologist is essential in the adequate management of Sjögren's syndrome skin and mucosal manifestations. [ABSTRACT FROM AUTHOR]

The article describes the case of a 67-year-old man with deep dermatophytosis caused by Trichophyton verrucosum. The patient was presented with symptoms such as painful vegetating lesions discharging purulent material on his right forearm. He underwent a biopsy of his forearm and received oral terbinafin and bifonazole cream to treat his disease.

Skin and joint manifestations associated with psoriasis and psoriatic arthritis (PsA) can significantly impact a patient's quality of life. Successful treatment is imperative in order to improve signs and symptoms of the disease, and to alleviate physical or psychological distress. For patients with mild psoriasis with or without PsA, topical agents and targeted phototherapy are appropriate treatments for psoriasis. Systemic therapies, such as methotrexate and phototherapy are recommended options for patients with more severe psoriasis, but their long-term use is hindered by safety concerns. Advancements in understanding the pathogenesis of psoriasis, including the role of T cells and cytokines, have been crucial to the development of biological therapies. These target the immune system and are suitable options for patients with extensive disease. Biological therapies for the treatment of psoriasis include targeted therapies (alefacept) and anti-cytokine therapies (anti-tumour necrosis factor [TNF] therapies [adalimumab, etanercept, infliximab] and a monoclonal antibody against interleukin [IL]-12 and IL-23 [ustekinumab]). Patients with PsA should be treated appropriately in order to improve symptoms and inhibit structural joint damage. Non-steroidal anti-inflammatory drugs or local intra-articular injections of corticosteroids can be used successfully in patients with mild PsA; however, neither treatment prevents the development of structural joint damage. For patients with moderate to severely active PsA, disease-modifying antirheumatic drugs (such as methotrexate), TNF inhibitor treatments (adalimumab, etanercept, infliximab and golimumab) or their combination are considered first-line treatment. This review provides a brief overview of treatment options for psoriasis and PsA, with an emphasis on the efficacy and safety of anti-TNF therapies. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory disorder of the skin and joints. Although rarely life threatening, psoriasis can significantly impair quality of life (QOL) and cause considerable physical and psychological distress. Between 6 and 42% of patients with psoriasis develop psoriatic arthritis, which is characterized by stiffness, pain, swelling and tenderness of the joints. Nail psoriasis is highly prevalent in both plaque-type psoriasis and psoriatic arthritis and is found in approximately 50% of patients with psoriasis and in 80% of patients with psoriatic arthritis. Infliximab, a chimeric human-murine monoclonal antibody directed against tumour necrosis factor α, is approved in the USA and EU for the treatment of plaque psoriasis and psoriatic arthritis at a recommended dosage of 5 mg/kg administered by intravenous infusion at 0,2 and 6 weeks, then every 8 weeks thereafter. The EXPRESS and EXPRESS II trials demonstrated that infliximab is efficacious as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis and also improved health-related QOL. Infliximab is also efficacious in the treatment of psoriatic arthritis, as shown in the IMPACT and IMPACT II studies. Infliximab is generally well tolerated, with a similar adverse event profile in both psoriasis and psoriatic arthritis. The use of infliximab in three case reports is presented. The patients are similar to those normally seen by clinicians, and include a male patient with plaque psoriasis and a history of severe psoriatic arthritis who was corticosteroid dependent and in whom other systemic treatments were not effective or were not able to be used. This patient showed a rapid response to infliximab with no skin lesions or arthritis after 7 weeks' treatment. Infliximab was also safe and effective in the treatment of a female patient with plaque and nail psoriasis and a history of psoriatic arthritis. Importantly, this case report supports the efficacy of infliximab in psoriatic nail disease in the context of severe skin and joint involvement. Case 3 describes a young male patient with moderate plaque-type psoriasis associated with severe nail involvement and early signs of psoriatic arthritis. Treatment with infliximab improved nail psoriasis and appears to be an effective biological treatment for nail psoriasis. Importantly, ultrasound was able to diagnose joint involvement, as seen from the proliferative synovitis in the distal interphalangeal joint and mild enthesitis, despite there being no clinical evidence of psoriatic arthritis. This case report highlights the importance of early screening. If such abnormalities are detected early on in the course of psoriasis, clinicians may be able to predict which patients are more likely to develop psoriatic arthritis, and therefore offer effective and long-term treatment that may reduce the disability and impairment of daily activities that can be associated with psoriatic arthritis. [ABSTRACT FROM AUTHOR]

Background: Since targeted biologic treatments have been introduced for the treatment of plaque-type psoriasis and psoriatic arthritis, switching between different medications has become necessary in selected patients, particularly after treatment failures. Objective: To evaluate the efficacy and safety of etanercept treatment in adult patients with psoriasis after failure to respond to other previous therapies. In particular, the differences in efficacy profiles after switching from traditional (cyclosporine [ciclosporin], methotrexate, retinoids, fumaric acid esters, psoralen plus UVA therapy, corticosteroids) or biologic (infliximab, efalizumab) treatments were analyzed. Methods: The study included 124 patients affected by plaque-type psoriasis who received etanercept administered subcutaneously at a dosage of 50 mg twice weekly for 12 weeks, followed by 25mg twice weekly for an additional 12 weeks, and 110 patients affected by psoriatic arthritis who were treated with etanercept 25 mg twice weekly in a continuous regimen, after a 12-week period of treatment with etanercept 50 mg twice weekly. Results: Efficacy results were consistent in both groups of patients (plaque-type psoriasis and psoriatic arthritis), as expressed by the percentage of patients who achieved Psoriasis Area and Severity Index (PASI) 50 and PASI 75 scores. Among psoriatic arthritis patients, the mean pain Visual Analog Scale (VAS) score showed a substantial reduction during the treatment course, from 67.2 at week 0 to 15.8 at week 24. After 24 weeks, among patients with plaque-type psoriasis who had not previously received biologic therapies, 89.9% of patients achieved PASI 50 and 75.3% achieved PASI 75, while among patients who had received biologic therapies, 69.6% of patients achieved PASI 50 and 65.2% achieved PASI 75. In addition, 92.3% of patients with psoriatic arthritis who had not previously received biologic therapies achieved PASI 50 and 73.8% achieved PASI 75, while among patients who had received biologic therapies, 45.8% of patients achieved PASI 50 and 29.2% achieved PASI 75. Conclusions: Our study demonstrated that etanercept was more effective in those patients who had not previously received other biologic therapies than in those who had. The results of the present study indicate that etanercept may represent a valid, effective, and well tolerated therapeutic alternative even after failure to respond to traditional and other biologic therapies. [ABSTRACT FROM AUTHOR]

The discovery of two new p53 homologs, p73 and p63, has defined a family of transcription factors heavily involved in the control of growth suppression, apoptosis, differentiation and development. While p53-deficient mice undergo spontaneous tumors, p73 and p63 knockout mice exhibit severe developmental defects. We demonstrate here that p73 gene is an in vivo transcriptional target of the muscle regulatory factors MyoD, myogenin, Myf5 and Myf6. Ectopic expression of the transcriptional repressor δEF1/ZEB/zfhx1a counteracts MyoD/Myf5- or MyoD/Myf6-mediated transcriptional activation of p73. A distinct pattern of in vivo recruitment of muscle regulatory factors and δEF1 on p73 regulatory regions was found between proliferating and differentiating muscle cells. We also found that δEF1 plays a role in the transcriptional regulation of p53 family members during keratinocytic differentiation. Mouse embryo fibroblasts derived from δEF1-deficient mice exhibit unbalanced expression of ΔNp63, TAp73 and ΔNp73 but not of TAp63 and p53. The analysis of tissues derived from δEF1+/− mice exhibit a selective enrichment of ΔNp63 in skin.Oncogene (2005) 24, 7273–7280. doi:10.1038/sj.onc.1208891; published online 4 July 2005 [ABSTRACT FROM AUTHOR]

The p53 protein plays a pivotal role in determining the quality of the response to DNA damage through its transcriptional activity. Upon DNA damage, p53 is activated by post-translational modifications, binds its cognate sequences on the promoters of its target genes and stimulates transcription. In proliferating keratinocytes, the activity of p53 is blunted by its inhibitor ΔNp63α. Here, we describe a novel mechanism through which ΔNp63 functions in order to prevent the survival and propagation of ultraviolet (UV)-damaged keratinocytes. We found that UVB stimulation induces the rapid phosphorylation of ΔNp63, which precedes ΔNp63 transcriptional downregulation and protein degradation, which is mediated by the p38 MAPK. Phosphorylated ΔNp63 has a lower affinity for p53REs and detaches from cell cycle arrest and apoptotic promoters, thus allowing the rapid activation of p53-dependent transcriptional apoptotic program.Oncogene (2005) 24, 6970–6975. doi:10.1038/sj.onc.1208835; published online 20 June 2005 [ABSTRACT FROM AUTHOR]

The discovery of the p73 and p63 genes, homologous to p53 tumor suppressor has uncovered a family of transcription factors and widened the scenario of cell cycle control and apoptosis. We have identified a putative p53-responsive element in the human adenosine deaminase (ADA) gene, an important enzyme involved in nucleotide metabolism, the deficit of which causes the inhibition of DNA synthesis and repair. Here, we demonstrate that the ectopic expression of p73 isoforms leads to the ADA gene upregulation, showing for the first time a correlation between p73 and ADA. We found that p73 promotes ADA gene expression following a dNTP unbalance generated by ADA enzyme deficiency and 2'deoxyadenosine accumulation. The abrogation of p73 transcriptional activity by the specific dominant-negative p73DD abolishes ADA induction. By contrast, the ADA gene does not appear to be a functional p53 target in the physiological conditions we tested. On the whole, our results contribute to the emerging picture that p73 could play a different role from p53 in normal growth and development by inducing alternative target genes, which are not shared by p53.Oncogene (2003) 22, 8738-8748. doi:10.1038/sj.onc.1206967 [ABSTRACT FROM AUTHOR]

E2F1, a member of the E2F family of transcription factors, in addition to its established proliferative effect[SUP1], has also been implicated in the induction of apoptosis through p53-dependent and p53-independent pathways[SUP2]. Several genes involved in the activation or execution of the apoptotic programme have recently been shown to be upregulated at the transcriptional level by E2F1 overexpression, including the genes encoding INK4a/ARF, Apaf-1, caspase 7 and p73 (refs 3-5). E2F1 is stabilized in response to DNA damage[SUP6,7] but it has not been established how this translates into the activation of specific subsets of E2F target genes. Here, we applied a chromatin immunoprecipitation approach to show that, in response to DNA damage, E2F1 is directed from cell cycle progression to apoptotic E2F target genes. We identify p73 as an important E2F1 apoptotic target gene in DNA damage response and we show that acetylation is required for E2F1 recruitment on the P1p73 promoter and for its transcriptional activation. [ABSTRACT FROM AUTHOR]

Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage–activated signaling network. [ABSTRACT FROM AUTHOR]

Shows that, in response to a non apoptotic DNA damage induced by low doses of doxorubicin, p53 binds in vivo, as detected by a p53-specific chromatin immunoprecipitation assay, and activates the P2-p73 promoter. Effect of unchecked DNA damage on S phase and mitosis; Factors that influence the choice between cell cycle arrest and apoptosis; Role of DNp73 proteins in the cellular responses to DNA damage.

Presents research which showed that the amount of the p73 protein in a cell is increased by the cancer chemotherapeutic agent cisplatin. How such agents function; Activation of apoptosis by the gene p53; Induction of p73; p73's half-life; Traits of mutated p73 in mice; Cisplatin-induced cytotoxicity and the roles of p73 and the tyrosine kinase c-Abl.

T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell–derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis. [ABSTRACT FROM AUTHOR]