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Prostate cancer (PCa) is the most common malignancy in men and represents the second leading cause of cancer deaths in Western countries. PCa is initially androgen-dependent, however, this tumor inevitably progresses as castration-resistant prostate cancer (CRPC), which represents the most aggressive phase of the pathology. In this work, in two CRPC cell lines (DU145 and PC3), we studied the in vitro inhibitory properties of the tryptophan-derived endogenous metabolite kynurenic acid (KYNA) and of the lactam form of 3–2′-pyrrilonidinyl-kynurenic acid (3-PKA-L), alkaloids usually present in combination in chestnut honey. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell colony formation assay, and Western blot analysis of the major mediator proteins involved in apoptotic processes. In all experiments, KYNA was scarcely or not active while 3-PKA-L showed anticancer activity in the high concentration range (0.01 mM – 1 mM) from 24 to 72 h. The results obtained showed that cell death was induced by extrinsic apoptotic pathway, by cell morphological changes and reduction of cell colonies number. These novel results represent the first promising step to the accurate description of 3-PKA-L cytotoxic effect, not observed with KYNA, paving the way to the search of new anticancer agents, as well as to the better understanding of the physiopathological role of this interesting natural product.

Background:Up to 30% of Psoriasis (PsO) patients are prone to develop Psoriatic Arthritis (PsA). Agreement on how to identify PsO patients at risk of developing PsA is still lacking (1).Objectives:To identify predictors of PsA development in PsO patients through a systematic literature review (SLR) and meta-analyses (MA).Methods:MEDLINE, EMBASE and COCHRANE databases were searched (up to February 22nd, 2020). The PICO framework (population = PsO patients; intervention = clinical, environmental, imaging and genetic features; comparator = not applicable; outcome = PsA development) was used to design searches and define the eligibility of studies for inclusion. The MA focuses on 3 major features as possible predictors: i) PsO skin and nail involvement; ii) musculoskeletal (MSK) complaints; iii) inflammation and structural damage detected by imaging (Table 1). The sample estimates of the relative risk were pooled only when the studies were homogeneous in terms of cohort of patients, follow-up, study design and metrics.Results:4698 articles were screened for eligibility, 110 underwent a full reading and 29 were finally included. Figure 1 shows the study flow-chart for article selection. Though pooling was judge not appropriate, 5/7 prospective studies significantly support a predictive value of PsA development in patients with severe PsO (n=174635). While the predictive value of nail involvement is not well defined (n=2202), the pooled estimate from two cohort studies (n=474) supports nail pitting as predictor of PsA (RR=2.14 [1.32; 3.46]). Moving to the MSK complaints, the risk of developing PsA is about two times greater in PsO with than without arthralgia (pooled RR: 2.15 [1.16, 3.99]) within 2 years. Lastly, PsO patients with inflammation or structural damage detected by imaging are nearly four times more likely to develop PsA within 1-2 years (pooled RR from 4 cohort studies (n=247): 3.72 [2.12; 6.51]) (Table 1). The incidence rate of PsA varies from 1.34 to 5.9/100 p-ys in PsO and from 10.9 to 12.5/100 p-ys in PsOAr.Table 1.Studies reporting the major features as possible predictors of PsA development.PsO skin – severityPsO nail involvementPsO nail lesionsVariablesRelative Risk [95%CI]Follow-upWilson, 2009PsO nail involvementHRadjusted: 2.24 [1.26; 3.98]13.1±8.8 ysFaustini, 2015PASI score + PsO nail involvement/σ= -0.18[-0.84; 0.48] RR: 0.95 [0.37; 2.47]1.2±0.2 ysEder, 2016PASI score PsO nail involvement Type of PsO nail lesionsHR (>20vsHRunadjusted: 1.36 [0.76; 2.45] HRunadjusted: 2.21 [1.24; 3.92]4.1±2.1 ysEder, 2017PASI score + Type of PsO nail lesionsHRunadjusted: 1.05 [1.01; 1.09] HRunadjusted: 1.98 [0.83; 4.74]3.8±2.1 ysLewinson, 2017PsO severity defined from medicationsHRadjusted (moderate/severe vs mild): 5.02 [4.18; 6.04]5.1 ysEgeberg, 2018PsO severity defined from medicationsRR (severe vs mild): 1.31 [1.18; 1.46]18 ysElnady, 2019PASI score + PsO nail Involvement/σ= 0.79[-0.37; 1.95] RR: 1.43 [0.38; 5.31]2 ysGreen, 2020PsO severity defined from medicationRR (severe vs mild): 2.79 [2.49; 3.13]5.8 ysMSK-complaintsVariablesIncident-PsA casesFollow-upFaustini, 2015ArthralgiaRR: 1.98 [0.75; 5.19]1.2±0.2 ysEder, 2017ArthralgiaHRadjusted: 2.59 [1.15; 5.88]3.8±2.1 ysZabotti, 2019ArthralgiaRR: 4.44 [0.54; 36.72]1.6±0.5 ysSimon D, 2020ArthralgiaRR: 2.04 [0.86; 4.86]2.4±1.5 ysSub-clinical inflammation or structural damage detected by imagingVariablesIncident-PsA casesFollow-upFaustini, 2015MRIRR: 2.10 [0.75; 5.90]1.2±0.2 ysElnady, 2019MSK-USRR: 5.38 [1.17; 24.63]2 ysZabotti, 2019MSK-USRR: 6.86 [0.83; 56.63]1.6±0.5 ysSimon D, 2020HR-pQCTRR: 4.32 [1.96; 9.55]2.3±1.4 ysConclusion:Arthralgia and inflammation and/or structural damage detected by imaging are predictive features, likely prodromal, of PsA development. PsO severity and nail pitting are clinical manifestations related to PsA development.Figure 1.References:[1]Zabotti A, et al. Curr Rheumatol Rep. 2020 May 16;22(6):24. doi: 10.1007/s11926-020-00891-x.Disclosure of Interests:Alen Zabotti Speakers bureau: UCB, Novartis, Janssen, Paid instructor for: Amgen, Consultant of: Janssen, Orazio De Lucia Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Garifallia Sakellariou Consultant of: AbbVie, Novartis, Alberto Batticciotto Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Gilberto Cincinelli: None declared, Ivan Giovannini: None declared, Luca Idolazzi Speakers bureau: Eli Lilly, UCB, Celgene, MSD, Abbvie, Novartis, Paid instructor for: UCB, Gabriella Maioli Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Ilaria Tinazzi Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Daniel Aletaha Speakers bureau: not relevant for this type of study, Consultant of: not relevant for this type of study, Grant/research support from: not relevant for this type of study, Salvatore De Vita Consultant of: GSK, Roche, Grant/research support from: Not relevant for this type of study, Antonio Marchesoni Speakers bureau: not relevant for this type of study, Consultant of: not relevant for this type of study, Grant/research support from: not relevant for this type of study, Josef S. Smolen Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Annamaria Iagnocco Speakers bureau: not relevant for this type of study, Paid instructor for: not relevant for this type of study, Consultant of: not relevant for this type of study, Grant/research support from: not relevant for this type of study, Dennis McGonagle Speakers bureau: ABBVIE, CELGENE, PFIZER, MSD, NOVARTIS, JANSSEN, UCB, GILEAD, BMS, LILLY, Grant/research support from: ABBVIE, CELGENE, PFIZER, MSD, NOVARTIS, JANSSEN, UCB, GILEAD, BMS, LILLY, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Gilead, Lilly, Pfizer, Roche, UCB, Sanofi, Fresenius Kabi, Samsung bioepis, MSD, Consultant of: Galapagos, Gilead, Lilly, Janssen, MSD

COVID-19 pandemic in its early months has deeply influenced rheumatic patients’ follow-up in terms of treatment adherence, disease control achieved with treat-to-target and tight-control strategies. Nationwide mitigation strategies such as confinement, travel restrictions and inadequate access to routine visits catalysed the rapid switch to remote rheumatologic consultations as an attempt to partially compensate for the decline of in-person outpatient visits. This observational retrospective study was conducted to establish if the hybrid of in-person and telephone tight-control approach activated by our rheumatology unit in Milan (Italy) during the first lockdown (LD) period has been effective in maintaining remission in patients with rheumatoid arthritis (RA) treated with targeted therapies and to identify potential factors associated with its maintenance. Data were extracted from a longitudinal observational registry (Eethics Committee 138_1999) including consecutive adult patients with RA treated with biologic or targeted synthetic drugs. During the first pandemic wave, before the visit, rheumatologists provided virtual care handled by telephone to assess the clinical status and to guarantee the absence of current contraindications to therapy. After tele counselling, based on the care required, patients …

Summary Tofacitinib is an oral small molecule targeting the intracellular Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] and T [interferon (IFN)-γ, IL-17 or TNF-α] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.

Background Agreement on how to identify psoriasis (PsO) patients at risk of developing psoriatic arthritis (PsA) is lacking. Objective To identify predictors, risk factors and incidence rate (IR) of PsA development in PsO patients through a systematic literature review (SLR) and meta-analyses (MA). Methods MEDLINE, Embase, and Cochrane databases were searched. Cohort studies were used to assess the predictors, while case–control studies for PsA risk factor determination. Results We screened 4698 articles for eligibility, and 110 underwent a full reading and 26 were finally included. Among skin and nail phenotypes, PsO severity and nail pitting were selected as predictors of PsA development. Furthermore, PsO patients with arthralgia (pooled RR 2.15 [1.16; 3.99]) and/or with imaging-MSK inflammation (pooled RR 3.72 [2.12; 6.51]) were at high risk of PsA. Higher categories of BMI and a family history of PsA were other predictors. In outpatient-based cohort studies, the IR of PsA per 100 patient-years varied from 1.34 to 17.4. Limitations Despite the strength of the overall results, the heterogeneity and the number of the cohort studies could be considered a limitation. Conclusions This study provides a tentative profile of the PsO patient at risk of PsA and will help the design of PsA prevention trials. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00378-w.

Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72–77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice.

Background:Rheumatic patients’ follow-up in terms of treatment adherence, disease control achieved with treat-to-target (T2T) and tight-control strategy have been deeply influenced by nationwide mitigation strategies such as quarantine, travel restrictions, and inadequate access to routine visits, laboratory and imaging investigations. These restrictions could be potentially detrimental for patients’ care, but to what extent these measures affected the T2T and tight-control approach in rheumatoid arthritis (RA) is unknown.Objectives:This study investigated whether the adoption of telephone virtual care imposed by COVID-19 pandemic has been effective in maintaining remission in RA treated with targeted therapies and to identify factors associated with its maintenance.Methods:This observational retrospective real-life study was conducted from November 2019 through September 2020. Clinical Disease Activity Index (CDAI) of RA patients treated with targeted therapies was analysed retrospectively before, during and after the national lockdown (LD). During LD period, rheumatologists provided virtual care by telephone to assess the clinical status to guarantee the absence of current contraindications to therapy. Then, patients could choose whether to receive home drug delivery or to maintain their face-to-face consultations. Logistic mixed effects regression models were fitted, with CDAI remission as response variable. A multivariate analysis and a parsimonious model were finally obtained by stepwise selection procedure using AIC.Results:Data were extracted from a longitudinal observational registry, and at baseline, 502 RA patients were eligible for this study. 52 patients failed to complete their follow-up, 450 patients were included in the final analysis. During LD, 359 patients chose in-person visit, 91 patients home drug delivery and virtual visit. Our cohort did not show a statistically significant decrease in the number of patients fulfilling CDAI remission criteria all along the three periods. Among the 450 patients evaluated, the CDAI remission rate was 40.22% (N=181) and 43.78% (N=197) during pre-LD and post-LD, respectively. As for the 359 patients who choose in-person visits during LD, 43.18% (N=155) were in remission according to CDAI. The final model (step-wise selection) applied to the multivariate analysis of factors that potentially could interfere with disease control in patients with CDAI remission showed that the probability to maintain remission was associated with Caucasian ethnicity, male gender and absence of fibromyalgia (Table 1 below).Table 1.Adjusted OR (95% CI)p-valuePeriod (LD vs Pre-LD)1.24 (0.83 - 1.85)0.292Period (Post-LD vs Pre-LD)1.22 (0.84 - 1.77)0.299Gender (male vs female)2.26 (1.15 - 4.61)0.020Disease duration (≥10 years vs 0.65 (0.36 - 1.15)0.141Ethnicity (Hispanic/Asian vs Caucasian)0.32 (0.12 - 0.83)0.021Fibromyalgia (yes vs no)0.30 (0.11 - 0.82)0.021Conclusion:Telephone-based tight control strategy ensured satisfactory management of RA treated with targeted therapies during the first wave of COVID-19 pandemic. All along the three periods, we observed that the probability to be in CDAI remission was significantly associated with Caucasian ethnicity, male gender, and absence of fibromyalgia. This temporary approach has been a feasible compensation for face-to-face visits, thus reassuring for future months before the end of pandemic.Disclosure of Interests:Francesca Ingegnoli: None declared, Gilberto Cincinelli: None declared, Angela Flavia Luppino: None declared, Ennio Favalli Speakers bureau: AbbVie, Sanofi-Genzyme, Lilly, UCB, Pfizer, Novartis, Janssen, Paid instructor for: Roche, MSD, Consultant of: Lilly, Galapagos, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Gilead, Lilly, Pfizer, Roche, UCB, Sanofi, Fresenius Kabi, Samsung bioepis, MSD, Consultant of: Galapagos, Gilead, Lilly,Janssen, MSD.

The epidemiology of autoimmune diseases is characterized by a significant sex dimorphism, with the majority of disorders being more prevalent in women. In a parallel fashion, the immune system shows sex-dependent differences in number and functions of both its innate and its adaptive arms, with women capable to mount a more vigorous response compared to men. This enhanced reactivity may contribute to the stronger defense against infectious agents and to the reasons for which, on the other hand, women are more prone to develop autoimmune diseases. Several factors have been studied and implied to play a role for such an imbalance, most notably sex chromosomes, sex hormones, and gut microbiota differences between sexes. Experimental studies on rodents demonstrate that sex chromosome abnormalities, alterations of gut microbiota composition, and fluctuations of sex hormone concentrations decrease the susceptibility to autoimmunity in female probes or increase it in the male counterparts. Nevertheless, it would be reductive to consider sex only as a risk factor; based on clinical experience, autoimmune disease onset and course differ between men and women in terms of disease progression and severity. Eventually, research has focused on sex as a determinant of antirheumatic treatment response with promising evidence for a further personalized management of patients with autoimmune diseases.

Introduction. Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation, subchondral damage, and bone remodelling, affecting most commonly weight-bearing joints, such as the knee and hip. The loss of cartilage leads to joint space narrowing, pain, and loss of function which could ultimately require total joint replacement. The Wnt/β catenin pathway is involved in the pathophysiology of OA and has been proposed as a therapeutic target. Endogenous and pharmacological inhibitors of this pathway were recently investigated within innovative therapies including the use of platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Methods. A review of the literature was performed on the PubMed database based on the following inclusion criteria: article written in English language in the last 20 years and dealing with (1) the role of Wnt-β catenin pathway in the pathogenesis of osteoarthritis and (2) pharmacologic or biologic strategies modulating the Wnt-β catenin pathway in the OA setting. Results. Evidences support that Wnt signalling pathway is likely linked to OA progression and severity. Its inhibition through natural antagonists and new synthetic or biological drugs shares the potential to improve the clinical condition of the patients by affecting the pathological activity of Wnt/β-catenin signalling. Conclusions. While further research is needed to better understand the mechanisms regulating the molecular interaction between OA regenerative therapies and Wnt, it seems that biologic therapies for OA exert modulation on Wnt/β catenin pathway that might be relevant in achieving the beneficial clinical effect of those therapeutic strategies.

Atypical retinoids (AR) or retinoid-related molecules (RRMs) represent a promising class of antitumor compounds. Among AR, E-3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)acrylic acid (adarotene), has been extensively investigated. In the present work we report the results of our efforts to develop new adarotene-related atypical retinoids endowed also with POLA1 inhibitory activity. The effects of the synthesized compounds on cell growth were determined on a panel of human and hematological cancer cell lines. The most promising compounds showed antitumor activity against several tumor histotypes and increased cytotoxic activity against an adarotene-resistant cell line, compared to the parent molecule. The antitumor activity of a selected compound was evaluated on HT-29 human colon carcinoma and human mesothelioma (MM487) xenografts. Particularly significant was the in vivo activity of the compound as a single agent compared to adarotene and cisplatin, against pleural mesothelioma MM487. No reduction of mice body weight was observed, thus suggesting a higher tolerability with respect to the parent compound adarotene.

The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.

Background:Uveitis is the main extraarticular complication of juvenile idiopathic arthritis (JIA) with still a significant impact on JIA morbidity, despite continuous improvement in systemic treatment. Although antinuclear antibody positivity and early onset of JIA have been associated with a high risk of uveitis onset, so far no clinical features have been widely recognized as predictive factors for JIA-associated uveitis (JIA-U) response to treatment.Objectives:To investigate clinical features associated with response to systemic treatment in a long-term cohort of patients with JIA-UMethods:Clinical records of patients with JIA-U were retrospectively reviewed with regard to clinical features, therapeutic choices and outcome. Clinical and laboratory variables were compared by means of Mann-Whitney U test or chi-square/Fisher exact test, as appropriate.Results:Data from 164 JIA-U patients were analysed (81.7% female), with a median follow up of 12.1 years (7.1-17.3). Median age at JIA and uveitis onset was 2.6 (1.6-4.8) and 4.8 (2.9 – 7.0) years, respectively. Monotherapy with a conventional disease-modifying antirheumatic drug (DMARD) was used in 25.0% of patients, while 111 patients (67.7%) received at least one biologic DMARD (bDMARDs). Compared to patients responsive to DMARDs, children requiring a bDMARDs for uveitis had a lower median age at both JIA (2.4 vs 4.3 years, p 0.0234) and uveitis onset (4.1 vs 6.2 years, p 0.0023). Despite no differences in ocular damage at onset and median disease duration, patients not responsive to conventional DMARDs showed a higher frequency of ocular damage at the last visit (66.2% vs 33.3%, p 0.011). Children requiring more than one bDMARD for uveitis presented a more frequent polyarticular course (87.0% vs 20.2%, p 0.0022), a longer disease duration (median follow-up: 14.2 vs 10.4 years, p 0.0397) and a higher frequency of visual loss (best corrected visual acuity < 4/10: 23.3% vs 6.3%, p 0.0069).Conclusion:JIA-U patients with a lack of response to conventional DMARDs were significantly younger both at JIA and uveitis onset. Severe JIA-U requiring more than one bDMARDs was associated with polyarticular JIA course and longer disease duration. Children resistant to conventional treatment need prompt recognition and additional strategies to improve long-term outcome.References:[1]Heiligenhaus et al. Predictive factors and biomarkers for the 2-year outcome of uveitis in juvenile idiopathic arthritis. Rheumatology 2019.Disclosure of Interests:None declared

Background:Despite significant improvement in the RA management, up to twenty percent of patients with rheumatoid arthritis (RA) have a difficult-to-treat (D2T) disease. The COVID-19 related mitigation policies, for instance quarantine, and consequent difficult access to in-person visits, laboratory and imaging investigations, adversely affected the follow up of rheumatic patients. Although pandemic-imposed limitations could have negatively influenced disease management particularly in D2T patients, to what degree these restrictions affected the treat-to target (T2T) and tight-control strategy in this subgroup of RA patients has not been investigated yet.Objectives:To evaluate whether the switch to telehealth imposed by COVID-19 pandemic was effective in the management of D2T RA patients treated with targeted therapies.Methods:This observational retrospective real-life study was conducted from November 2019 through September 2020. Among RA patients treated with targeted therapies, RA D2T patients according to EULAR definition (1) were identified. Clinical Disease Activity Index (CDAI) of these patients was analysed retrospectively before, during and after lockdown (LD). During LD period, patients could choose whether to receive home drug delivery or to maintain their face-to-face consultations, and in the former rheumatologists provided virtual care. To evaluate the effect of LD on the percentage of patients in remission, logistic mixed effects regression models were fitted, with CDAI remission as response variable.Results:Data were extracted from a longitudinal observational registry, and at baseline, 52 patients treated with targeted therapies were classified as D2T RA. Among them, during pre-LD, LD, and post-LD 11.54% (N=6), 53.49% (N=23), and 46.15% (N=24) had CDAI remission/low disease activity, while 46 (88.46%), 20 (46.51%) and 28 (53.85%) had CDAI moderate/high. All the patients completed the follow-up. Median values of CDAI during pre-LD, LD, and post-LD were 14.5 [IQR 12-21], 9 [IQR 5.5-16], and 11 [IQR 6-19.2] respectively (see Figure 1 below).Conclusion:Telephone-based tight control strategy ensured satisfactory management of D2T RA treated with targeted therapies. This temporary approach has been a feasible compensation for the decline of face-to-face visits also in this challenging group of RA patients, thus reassuring for future months before the end of pandemic.References:[1]Nagy G, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80(1):31-35.Disclosure of Interests:Francesca Ingegnoli: None declared, Angela Flavia Luppino: None declared, Gilberto Cincinelli: None declared, Ennio Favalli Speakers bureau: AbbVie, Sanofi-Genzyme, Lilly, UCB, Pfizer, Novartis, Janssen, Paid instructor for: Roche, MSD, Consultant of: Lilly, Galapagos, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Gilead, Lilly, Pfizer, Roche, UCB, Sanofi, Fresenius Kabi, Samsung bioepis, MSD, Consultant of: Galapagos, Gilead, Lilly,Janssen, MSD.

A novel series of 4-oxo-N-(4-hydroxyphenyl) retinamide (4-oxo-4-HPR) derivatives were synthesized with the aim of increasing the poor solubility of the parent compound in biological fluids, while maintaining the cytotoxic activity and the dual mechanism of action. The most promising compound 13a showed antiproliferative/apoptotic activity. The analysis of its mechanism of action revealed that it retained the particular characteristic of 4-oxo-4-HPR which is able to induce cell cycle arrest during the mitotic phase, coupled with the formation of aberrant mitotic spindles.

Polybrominated diphenyl ethers (PBDEs) are persistent environmental substances that were commonly used as fire retardants in a wide number of commercial products. Their low reactivity, high hydrophobicity and bioaccumulative properties cause their ubiquity in the air, water, food and lead to extensive exposure of world population to these compounds. The severe health problems caused by PBDEs lead them to be banned from the market. In March 2014 the European Commission issued a recommendation in which member states are requested to monitor brominated flame retardants in food, in order to evaluate human and wildlife exposure. Here, we described the development of an electrochemical magnetic particle enzyme-linked immunoassay to analyze PBDEs in food samples. The immunological reaction is based on a competitive scheme, using an alkaline phosphatase labeled congener as tracer. The anti-PBDE antibody modified magnetic particles are captured on the surface of carbon disposable array of sensors. The reaction extent is finally electrochemically measured by differential pulse voltammetry, upon the addition of substrate. Under the optimized conditions, a limit of detection of 0.18 ng/mL with a limit of quantification of 0.30 ng/mL and a quantification range of 0.30–6.9 ng/mL, (RSD%=12) is obtained. Results of food samples obtained from the newly developed electrochemical immunoassay are also reported.

Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors.

Non-Small Cell Lung Cancer (NSCLC) remains an aggressive and fatal disease with low responsiveness to chemotherapy, frequent drug resistance development and metastatic behavior. Platinum-based therapy is the standard of care for NSCLC with limited benefits. Since epigenetic alterations have been implicated in the aggressive behavior of lung cancer, the purpose of the present study was to examine the capability of the pan-histone deacetylase inhibitor SAHA and of ST3595, a novel hydroxamate-based compound, to interfere with the proliferative and invasive potential of NSCLC cells. We used two NSCLC cell lines (H460 and A549) and the cisplatin-resistant variants (H460/Pt and A549/Pt), to mimic a frequent clinical condition. The resistant models exhibited increased invasive properties as compared to parental cells, features associated with a wide modulation of the level of angiogenesis- and invasion-related factors in the cell conditioned media. The levels of urokinase-type plasminogen activator, IL-8, and macrophage migration inhibitory factor were increased in the conditioned media from both H460/Pt and A549/Pt cells. SAHA and ST3595 induced a strong inhibition of cell invasive properties, which was more marked after ST3595 exposure. Both HDAC inhibitors up-regulated the metastasis suppressor KiSS1 at the mRNA level. Forced expression of KiSS1 significantly decreased the invasive capability of drug-resistant cells. ST3595 displayed an anti-metastatic effect in tumors associated with decreased of phosphorylation of Src. Our data indicate that HDAC inhibitors are effective in NSCLC cell systems. The ability of ST3595 to counteract the invasive potential of resistant cells through mechanisms involving KiSS1 is an interesting novel finding.

In the last few decades, Indoor Air Quality (IAQ) has received increasing attention from the international scientific community, political institutions, and environmental governances for improving the comfort, health, and wellbeing of building occupants.[...]

Microplastics (MPs) are emerging pollutants, which are considered ubiquitous in aquatic ecosystems. The effects of MPs on aquatic biota are still poorly understood, and consequently, there is a need to understand the impacts that MPs may pose to organisms. In the present study, Tubifex tubifex, a freshwater oligochaete commonly used as a bioindicator of the aquatic environment, was exposed to fluorescent polyethylene microspheres (up to 10 µm in size) to test whether the oxidative stress status was affected. The mortality rate of T. tubifex, as well as the activities of the oxidative stress status biomarker enzymes glutathione reductase and peroxidase, were assessed. In terms of oxidative stress, no significant differences between the exposure organisms and the corresponding controls were detected. Even though the data suggest that polyethylene MPs and the selected concentrations did not pose a critical risk to T. tubifex, the previously reported tolerance of T. tubifex to environmental pollution should be taken into account and thus MPs as aquatic pollutants could still represent a threat to more sensitive oligochetes.

A versatile synthetic route to new 4-quinolone-based polycyclic systems is described. TFA-catalyzed intramolecular reaction of N-unsubstituted quinolone-2-carboxylic acid amides gives structurally diverse compounds, depending on the length of the chain. Acid treatment of β-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas TFA treatment of δ- and e-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction.

Background The aim of this randomized clinical trial was to evaluate the efficacy of Apically Positioned Flap with Fibre Retention Osseous Resective Surgery (FibReORS) or Osseous Resective Surgery (ORS) to treat periodontal pockets associated with infrabony defect ≤3 mm at posterior natural teeth. Material and methods Thirty patients with chronic periodontitis showing persistent periodontal pockets after cause-related therapy were enrolled; 15 patients were randomly assigned to FibReORS (test group) and 15 to ORS (control group). Measurements were performed by a blind and calibrated examiner. Outcome measures included intra-operative and post-operative morbidity and root sensitivity, 1-year probing depth (PD), gingival recession (Rec) and radiographic bone changes. Results No differences in clinical and bone defect parameters were observed at baseline. Marginal bone resection was reduced by 0.9–1.6 mm in the FibReORS group. ORS was associated with patient perception of greater surgical hardship (p = 0.0264), higher 1-week pain experience (p = 0.0001) and greater dental hypersensitivity (p = 0.0002). After 1 year, shallow, maintainable PD with no difference between the two procedures (p = 0.3707) was obtained. FibReORS was associated with less final Rec (p

Levoglucosan was present in all samples and its concentrations showed a pronounced annual cycle with maximum levels in the cold season. The annual percentage of ratios of levoglucosan to OC ranged from 0.04 to 9.75% evidencing a major contribution of biomass burning to the aerosol OC during the winter. In the urban-background site, OC was strongly correlated with EC in winter, suggesting that the major fraction of OC was generated as primary particles along with EC. A background levoglucosan component showed that biomass burning was continuously taking place in all the investigated sites. The biomass burning contribution to the Tuscany aerosol was made up of a background component and an additional component during winter probably due to wood burning for domestic heating.

The ability of histone deacetylase inhibitors to modulate the expression of genes relevant for growth or apoptotis regulation supports their interest in combination treatments of resistant tumors. We explored the effect of the combination of the histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in ovarian carcinoma cell lines, including the IGROV-1 cell line and two p53 mutant platinum-resistant sublines (IGROV-1/OHP and IGROV-1/Pt1). We found a synergistic interaction between the two drugs, more evident in the p53-mutant resistant sublines, which was associated with increa sed apoptosis. The treatment with ST2782 resulted in early induction of Bax as well as in cleavage of caspase 3 and poly (ADP-ribose) polymerase only in the resistant cell lines. The inhibition of p53-transcriptional transactivation by pifithrin alpha in IGROV-1 cells enhanced the synergism. Conversely, knockdown of endogenous wild-type p53 in IGROV-1 cells determined synergism reduction. These opposite effects support the relevance of the transactivation-deficient mutant p53 as a synergism determinant. Moreover, in vivo studies indicated that tumor growth inhibition tended to be more evident in mice receiving the drug combination than in those treated with bortezomib alone. Overall, our study supports the potential effectiveness of the combination in platinum drug-resistant ovarian cancer carrying mutant p53.

Background The aim of this randomized clinical trial (RCT) was to evaluate the adjunctive benefit of Connective Tissue Graft (CTG) to Coronally Advanced Flap (CAF) for the treatment of gingival recession associated with inter-dental clinical attachment loss equal or smaller to the buccal attachment loss (RT2). Material and Methods A total of 29 patients with one recession were enrolled; 15 patients were randomly assigned to CAF+CTG while 14 to CAF alone. Measurements were performed by a blind and calibrated examiner. Outcome measures included complete root coverage (CRC), recession reduction (RecRed), Root coverage Esthetic Score (RES), intra-operative and post-operative morbidity, and root sensitivity. Results After 6 months, CAF+CTG resulted in better outcomes in terms of CRC (adjusted OR = 15.51, p = 0.0325) than CAF alone. CRC was observed in >80% of the cases treated with CAF+CTG when the baseline amount of inter-dental CAL was ≤3 mm. No difference was detected in term of RecRed. CAF+CTG was associated with longer surgical-time (p

Individual sugars, organic acids, total polyphenols, vitamin C and antiradical activity (as measured by DPPH method) were quantified in cultivated Fragaria vesca berries, comparing different varieties (Regina delle Valli, Alpine, Sara and Valitutto) and different environments with regard to altitude. Cultivar effect mainly influenced the concentration of total polyphenols and antiradical activity which are strongly correlated (R2 = 0.91; P = 0.001); conversely, altitude seemed to exert an influence in sugar and organic acid composition. The comparison of the general quality of the most diffused cultivar of F. vesca (Regina delle Valli and Alpine) evidenced that both cultivars have the same nutritional properties, whereas Regina delle Valli is better than Alpine from the point of view of total polyphenolic content (716 vs 471 mg catechin/100 g fresh weight) and radical scavenging activity (301 vs 219 ml DPPH solution/100 g fresh weight), thus resulting more attractive from the health protecting attributes point of view. F. vesca berries showed also a concentration of sugars, citric acid, malic acid and total polyphenols much higher than those reported in literature for Fragaria x ananassa.

Cairo F, Nieri M, Cincinelli S, Mervelt J, Pagliaro U. The interproximal clinical attachment level to classify gingival recessions and predict root coverage outcomes: an explorative and reliability study. J Clin Periodontol 2011; doi: 10.1111/j.1600-051X.2011.01732.x. Abstract Background: The aims of this study were (i) to test the reliability of a new classification system of gingival recessions using the level of interproximal clinical attachment as an identification criterion and (ii) to explore the predictive value of the resulting classification system on the final root coverage outcomes. Material and methods: Patients showing at least one buccal gingival recession were recruited by one operator. Three recession types (RT) were identified. While class RT1 included gingival recession with no loss of interproximal attachment, class RT2 recession was associated with interproximal attachment loss less than or equal to the buccal site and class RT3 showed higher interproximal attachment loss than the buccal site. The classification was tested by two examiners blinded to the data collected by the other examiner. Intra-rater and inter-rater agreement was assessed. Furthermore, the 6-month root coverage outcomes of consecutively treated gingival recessions were retrospectively evaluated in order to explore the predictive value of the proposed classification on the final recession reduction (Rec Red). Results: The new classification system of gingival recessions was tested in a total of 116 gingival recessions (mean 3.2±1.2 mm) in 25 patients. The intra-class correlation coefficient (ICC) for inter-rater agreement was 0.86, showing an almost perfect agreement between the examiners. The RT classification was predictive of the final Rec Red (p

A high activity α-carbonic anhydrase (CA, EC 4.2.1.1) has been purified from various tissues of the Antarctic seal Leptonychotes weddellii. The new enzyme, denominated lwCA, has a catalytic activity for the physiologic CO(2) hydration to bicarbonate reaction, similar to that of the high activity human isoform hCA II, with a k(cat) of 1.1×10(6) s(-1), and a k(cat)/K(m) of 1.4×10(8) M(-1) s(-1). The enzyme was highly inhibited by cyanate, thiocyanate, cyanide, bicarbonate, carbonate, as well as sulfamide, sulfamate, phenylboronic/phenylarsonic acids (K(I)s in the range of 46-100 μM). Many clinically used sulfonamides, such as acetazolamide, methazolamide, dorzolamide, brinzolamide and benzolamide were low nanomolar inhibitors, with K(I)s in the range of 5.7-67 nM. Dichlorophenamide, zonisamide, saccharin and hydrochlorothiazide were weaker inhibitors, with K(I)s in the range of 513-5390 nM. The inhibition profile with anions and sulfonamides of the seal enzyme was rather different from those of the human isoforms hCA I and II. The high sensitivity to bicarbonate inhibition of lwCA, unlike that of the human enzymes, may reflect an evolutionary adaptation to the deep water, high CO(2) partial pressure and hypoxic conditions in which Weddell seals spend much of their life.

The anti-proliferative and pro-apoptotic effects of Retinoid-Related Molecules (RRMs) are described as independent from Retinoids' receptors-mediated transcriptional activity. Prototypes of this class are CD437 and its more potent analogue ST1926, which have a strong antitumor activity by targeting DNA polymerase 1 alpha (POLA1) (Han et al. Nat Chem Biol. 2016; Abdel-Samad et al. AJCR, in press). With aim to identify new RRMs with an improved pharmacological profile, we synthetized and screened a library of RRMs for their antitumor properties and inhibitory activity on POLA1. From this screening, four molecules, MIR002, MIR020, MIR072 and MIR075, were selected. All exert a potent anti-proliferative effect, with G1/S arrest and apoptosis, in more than 50 cancer cell lines derived from human hematological and solid tumors. From a mechanistic point of view, these RRMs modulate, at different extent, POLA1 activity and/or expression. Notably, NSCLC cells harboring POLA1-L764F mutation (H460-R9A), are resistant to both CD437 and ST1926 (IC50>50 higher than the one of wild type H460 cells), while they are sensitive to MIR002, showing for this RRM-derivative an improved/different pharmacological profile with respect to CD437 and ST1926. Hints on the possibility of these new RRMs to be orally absorbed were obtained using cancer cells overexpressing or not P-glycoprotein (Pgp), known as the major player limiting the oral absorption of several chemotherapeutic agents. Results from these experiments revealed that the Tested compounds are not Pgp substrate thus suggesting the possibility for their absorption via oral route MIR002 in vivo activity was assessed in tumors from Malignant Mesothelioma derived cells (MM487), and lung cancer cells (H460 and H460-R9A). In all the evaluated models, MIR002 induced a strong Tumor Growth Inhibition either alone or in combination with cisplatin (TGI>61% and TGI>80-100%, respectively). The treatment of orthotopic models of malignant mesothelioma (MM487) with MIR072 in combination with Cisplatin, resulted in a impressive synergic antitumor activity if compared to Cisplatin monotherapy (TGI 95% vs 55%). Tests on orthotopic transplants of hepatocellular carcinoma cells (HepG2), showed that MIR020 has significant antitumor effects (TGI 72%). Finally, the activity of MIR075 was evaluated on glioblastoma luciferase-expressing cells (U-87MG) intracranically injected. Also this compound displayed a significant tumor growth inhibition (TGI 72%), as measured by IVIS imaging system. Taken together, the results from in vitro and in vivo experiments indicate that this new class of RRMs, including MIR002, MIR072, MIR020, and MIR075, modulate POLA1 functions and activate pro-apoptotic pathways. The large spectrum of antitumor activity, together with the high tolerability observed, opens the possibility for their clinical investigation in different population of cancer patients. Citation Format: Claudio Pisano, Lucio Merlini, Sergio Penco, Raffaella Cincinelli, Nadine Darwiche, Mario B. Guglielmi, Ilaria La Porta, Giacomo Signorino, Gabriele De Rubis, Fabiana Colelli, Francesco Cardile, Alessandra Fucci, Egildo L. D'Andrea, Sabrina Dallavalle. Preclinical antitumor activity of novel DNA polymerase 1 (POLA1) inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4848.

An α-carbonic anhydrase (CA, EC 4.2.1.1) has been purified from the Antarctic hemoglobinless fish Chionodraco hamatus (icefish). The new enzyme, denominated ChaCA, has a good catalytic activity for the physiologic CO2 hydration to bicarbonate reaction, similar to that of the low activity human isoform hCA I, with a kcat of 5.3×10(5) s(-1), and a kcat/Km of 3.7×10(7) M(-1) s(-1). The enzyme was inhibited in the submillimolar range by most inorganic anions (cyanate, thiocyanate, cyanide, bicarbonate, halides), whereas sulfamide, sulfamate, phenylboronic/phenylarsonic acids were micromolar inhibitors, with KIs in the range of 9-77 μM. Many clinically used drugs, such as acetazolamide, methazolamide, dorzolamide, brinzolamide, topiramate and benzolamide were low nanomolar inhibitors, with KIs in the range of 39.1-77.6 nM. As the physiology of CO2/bicarbonate transport or the Root effect in this Antarctic fish are poorly understood at this moment, such inhibition data may give a more detailed insight in the role that CAs play in these phenomena, by the use of inhibitors described here as physiologic tools.

Human milk samples were collected from 67 mothers in 2014 at a Primary Care Centre in Murcia (Spain) and analyzed for perfluorinated carboxylic acids (PFCAs). Concentrations measured for perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorododecanoic acid (PFDoDA) ranged from

The aim of this study was to evaluate the effect of traffic related polycyclic aromatic hydrocarbons (PAHs) on blood parameters of subjects, including traffic police officers (TP), drivers (DR) and control subjects (CN) with presumably different levels of exposure. We quantified the urinary 1-hydroxypyrene (1-OHPyr), α-naphthol and β-naphthol (α- and β-naph) as biomarkers of exposure to PAHs in relation with biomarkers of effect (Hb, MCV, PCV, PLT, RBCs), biomarkers of inflammation/infection (CRP, WBCs), oxidative stress (SOD) and oxidative DNA damage i.e. 8-hydroxy-2-deoxyguanosine (8-OHdG). Results showed that mean 1-OHPyr, α-naph and β-naph concentrations were significantly higher in TPs (0.98, 1.55, and 1.9µmolmol-Cr(-1), respectively, p

A versatile synthetic route to new 4-quinolone-based polycyclic systems is described. TFA-catalyzed intramolecular reaction of N-unsubstituted quinolone-2-carboxylic acid amides gives structurally diverse compounds, depending on the length of the chain. Acid treatment of β-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas TFA treatment of δ- and e-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction.

Atypical retinoids (AR) represent a class of proapoptotic agents with promising potential in the treatment of neoplastic diseases. In the present work 4'-hydroxybiphenyl-4-ylacrylic acids were studied as a novel series of AR. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocytic leukemia cell line (NB4) and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of a bulky lipophilic group at position 3' (adamantan-1-yl being the best) and the E configuration of the acrylic moiety appear essential for activity below 1 muM. No substitution on the rings or on the double bond improved the activity. A qualitative correlation between the log P and molecular volume of the 3'-substituent and the antiproliferative activity was found. From the study of a few selected compounds, it appears that the presence of the carboxylic group is an essential requirement for apoptogenic properties but not for antiproliferative activity, this being maintained in amide derivatives. On the other hand, compounds able to induce apoptosis produced a detectable level of genotoxic damage. This observation supports the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this class. Among the compounds investigated, E-3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)acrylic acid (2) was chosen for further investigation.

Adarotene belongs to the so-called class of atypical retinoids. The presence of the phenolic hydroxyl group on Adarotene structure allows a rapid O-glucuronidation as a major mechanism of elimination of the drug, favoring a fast excretion of its glucuronide metabolite in the urines. A series of ether, carbamate and ester derivatives was synthesized. All of them were studied and evaluated for their stability at different pH. The cytotoxic activity in vitro on NCI-H460 non-small cell lung carcinoma and A2780 ovarian tumor cell lines was also tested. A potential back-up of Adarotene has been selected to be evaluated in tumor models. (C) 2012 Elsevier Ltd. All rights reserved.

Background and Purpose. Excessive sweating, known as hyperhidrosis, involves the eccrine sweat glands of the axillae, soles, palms, and/or forehead. The use of iontophoresis to reduce or eliminate excessive sweating has been described since 1952. The purpose of this case report is to describe the use of tap water galvanism (TWG) using direct current (DC) with a patient who had postsurgical hyperhidrosis. Case Description. The patient was a 36-year-old male electrician with traumatic phalangeal amputation and postsurgical development of hyperhidrosis. Tap water galvanism was administered using a DC generator, 2 to 3 times per week for 10 treatments. The patient's hands were individually submerged in 2 containers of tap water with the electrodes immersed directly into the containers. Each hand was treated with 30 minutes of TWG at 12 mA. Hyperhidrosis was measured by a 5-second imprint and subsequent tracing of the left hand placed on dry paper toweling. Outcomes. The patient's hyperhidrosis decreased from the full left palmar pad, with a surface area of 10.3×12.0 cm, to a reduced area of wetness that covered a 2.2-×2.7-cm area. The patient returned to work as an electrician without needing absorbent gloves, which had prevented him from performing electrical work. Discussion. Following use of TWG, the patient's palmar hyperhidrosis returned to normhidrosis.

Atmospheric aerosols were collected during the period from May 2000 through January 2001 at 13 different sites in and around the Baciacavallo sewage treatment plant in Prato (Italy). The urban area surrounding the plant contains significant textile industrial activity and a main arterial road. Aerosol-associated n -alkane, polycyclic aromatic hydrocarbon (PAH), nonylphenol (NP) and nonylphenolethoxylate (NPnEO) ( n =1–3) concentrations were measured in order to evaluate contributions from the sewage treatment plant, naturally produced aerosols, transportation and industrial activities to the air quality in the vicinity of the sewage treatment plant. Aerosol-associated n -alkane concentrations ranged from 36.7 to 205 ng/m 3 and their possible origin was determined by the presence of typical petroleum characteristics such as the unresolved complex mixture and an odd/even carbon ratio (Carbon Preference Index). PAH concentrations ranged from 0.855 to 24.2 ng/m 3 , in accordance with those generally found for urban aerosols in Europe. NP and NPnEO ( n =1–3), as well as fine aerosol particulate matter (PM 10 ) were significantly correlated with relative wind direction with increased levels observed in the ambient atmosphere when the relative wind direction was from the Baciacavallo sewage treatment plant. This study confirms the use of NP and NPnEO ( n =1–3) as markers of sewage treatment emissions and the importance of the contribution of aerosols produced by sewage treatment plant aeration tanks to the local atmospheric composition.

The aim of this study was to evaluate and compare the exposure of household women and professional male workers to combustion emission in the indoor and semi-outdoor environments, respectively, by using biochemical parameters and the biomarkers of exposure to polycyclic aromatic hydrocarbon (PAH). Female (WR n = 60) and male "cooks" (WC n = 60) exposed to the combustion emission of fuel wood and coal in rural/suburban areas of Pakistan were recruited in this study and compared to non-exposed female (CF) and male (CM) groups (n = 32 and 34, respectively). Urinary biomarkers of PAH exposure including 1-hyroxypyrene (1-OHPyr), α-naphthol, and β-naphthol were analyzed together with the biomarkers of effect, including the serum c-reactive proteins (CRP), white blood cells (WBCs), hemoglobin (Hb), red blood cells (RBC), and platelet (PLT) count. In addition, blood superoxide dismutase (SOD) and urinary level of 8-hydroxydeoxyguanosine (8-OHdG) were evaluated to determine the oxidative stress and DNA damage, respectively. A questionnaire was used to document demographic-, health-, and exposure-related information. The results showed that urinary β-naphthol was almost 44% higher in WR subjects than WC (median 7.69 vs. 3.39 μmol/mol-Cr, respectively; p = 0.01) and respective controls (CF). Higher urinary 8-OHdG were observed in WR (71.1 ng/mg-Cr) than WC (56.37 ng/mg-Cr) (p 0.001), and lower life status and higher degree of headache were observed in WR than WC. In WCs, however, a low Hb and high WBC (8.29 × 10(3) μL(-1), ranging between 6.1 and 10.6 × 10(3) μL(-1)) were observed in comparison with CM. The study shows that WC subjects used larger amount of fuel and were subjected to prolonged exposure. It was concluded that the role of ventilation is fundamental and WR were more exposed to PAHs despite the fact that WC spent more time in cooking (due to occupational requirement) than WR.

This study presents the analyses of urinary biomarkers (1-OHPyr, α- and β-naphthols) of polycyclic aromatic hydrocarbons (PAHs) exposure and biomarkers of effect (i.e. blood parameters) in petroleum-refinery workers (RFs) and auto-repair workers (MCs). Exposed subjects had higher concentrations of white blood cell (WBC) count than control subjects (CN) subjects (5.31 × 103 μL−1 in exposed vs. 5.15 × 103 μL−1 in CN subjects), while the biomarker of oxidative DNA damage (8-OHdG) was significantly higher in MCs. The exposure among these two cohorts could be influenced by the ambience of the workplaces; in fact, MCs’ shops are relatively damp and enclosed workplaces in comparison with the indoor environment of refineries. PAHs in the dust samples from mechanical workshops probably originated from mixed sources (traffic exhaust and petroleum spills), while the incremental lifetime cancer risk (ILCR) for MCs showed moderate-to-low cancer risk from exposure to dust-bound PAHs. The study shows that increasing PAH exposure can be traced in MC workstations and needs to be investigated for the safety of public health.

A recent work from Han et al. disclosed DNA polymerase 1 alpha (POLA1) as the key target for the anti-cancer effects of CD437, a molecule belonging to the class of Retinoid Related Molecules (RRMs). Before this evidence, this family of compounds, of which CD437 and ST1926 represent the prototypes, has been characterized for its antiproliferative, antitumor and pro-apoptotic activity. With aim to identify a new RRM with an improved pharmacological profile, we recently selected MIR002 as a novel compound endowed with a potent antitumor activity and a peculiar pharmacological profile. In vitro treatment with MIR002 leads to a G1/S arrest and exerts a potent anti-tumor/proapoptotic activity in a wide range of cancer cell lines, including H460-R9A cells, which are cross resistant to ST1926 and CD437 (IC50>70 fold of H460-R9A vs H460). Moreover, in H460-R9A cells, we identified the L764F mutation in POLA1, already described as a mutation conferring resistance to CD437. We also demonstrated that POLA1 is the molecular target of both MIR002 and ST1926 and that, interestingly, the expression of the L764F mutant, although associated with the resistance to RRM’s, only marginally reduces the cytotoxic effects of MIR002. In order to investigate the activity of MIR002 against tumor growth, we examined a panel of in vivo xenograft tumor models, including those originating from human Non-Small Cell Lung Cancer (NSCLC) and Malignant Pleural Mesothelioma (MPM). In these models, using a q2dx5x3w schedule in doses ranging from 50 to 70 mg/Kg administered orally, we observed a strong tumor growth inhibition (TGI>70%). Interestingly, the combination of MIR002 with Cisplatin (4mg/Kg; qd7x3w; i.v.) in MPM models showed a synergistic antitumor efficacy, reaching a TGI>90%, and cured animals. Interestingly, we previously identified POLA1 as a key pro-proliferative player in 9 primary MPM samples. The ex-vivo analyses indicated that POLA1 expression was strongly modulated upon MIR002 treatment. Furthermore, in the same models, we also observed that the expression/secretion of multiple circulating factors is affected by MIR002 and we identified some of them as potential biomarkers of tumor responsiveness to MIR002. Taken together, our results identify MIR002 as a novel anti-cancer compound and suggest POLA1 as a target for new antitumor strategies to be investigated in Clinical Trials. Citation Format: Claudio Pisano, Lucio Merlini, Sergio Penco, Raffaella Cincinelli, Nadine Darwiche, Mario B. Guglielmi, Antonietta Esposito, Ilaria La Porta, Giacomo Signorino, Gabriele De Rubis, Fabiana Colelli, Francesco Cardile, Alessandra Fucci, Egildo L. D'Andrea, Sabrina Dallavalle. MIR002: a new POLA1 inhibitor endowed with a large spectrum of antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4195. doi:10.1158/1538-7445.AM2017-4195

Aims of this study were to provide firsthand data on the incidence of trace metals in human seminal plasma and find possible correlations between levels of toxic metals and semen quality of Pakistani population. Human semen samples were collected from male partners of couples undergoing infertility assessment at the National Institute of Health Islamabad (Pakistan). We investigated seventy-five seminal plasma samples, which were further categorized into three groups (normozoospermia, oligozoospermia and azoospermia) according to WHO guidelines. The concentration of 17 different toxic metals in human seminal plasma was determined simultaneously by using Inductively coupled plasma mass spectrometry (ICP-MS). Out of 17 trace metals, Cd and Ni showed significant difference (p

In this study we investigated the clinico-chemical parameters and the level of exposure of brick kiln workers to polycyclic aromatic hydrocarbons (PAHs) in Punjab (Pakistan). The brick kiln workers and a non-occupationally exposed group were recruited for comparative analysis of urinary biomarkers of PAH exposure (i.e. 1-hydroxypyrene (1-OHPyr), α-naphthol and β-naphthol) and blood level of superoxide dismutase (SOD), as a biomarker of oxidative stress and other hematologic parameters. Questionnaires were used to document information on socio-demographic characteristics of all the subjects. The analysis of urinary biomarkers showed higher median concentrations of 1-OHPyr, and α- and β-naphthols in brick kiln workers (1.53, 3.65 and 1.53 μmol/mol-Cr, respectively) than non-occupationally exposed group (0.62, 0.64 and 0.66 μmol/mol-Cr, respectively). The 1-OHPyr in brick kiln workers was above the occupational exposure level. Among the clinical parameters of brick kiln workers, hemoglobin (Hb) and red blood cells (RBCs) were very low and closely associate with 1-OHPyr and β-naphthol. Additionally, the white blood cells (WBCs) and superoxide dismutase (SOD) were also elevated in brick kiln workers, which suggested inflammatory symptoms and high oxidative stress. The results show that regardless of possibly being affected by the poor nutrition, the anemic state and hematological changes observed in brick kiln workers may be associated with their exposure to smoke present in the environment of brick kilns.

Air samples were collected both at an urban and an industrial area of Florence (Italy) in order to evaluate the occurrence, profiles, seasonal variation and gas/particle partitioning of polybrominated diphenyl ethers (PBDEs). The mean total (gas + particle phase) PBDE concentrations were 42.8 ± 7.8 and 89.0 ± 21.1 pg/m^3 in the urban and industrial sites, respectively. In all samples, BDE-209 was the most abundant congener, followed by BDE-47 and BDE-153 in the industrial site, and by BDE-99 in the urban site. The Σ6PBDE (sum of BDE-28, -47, -99, -100, 153, -154) concentrations in the urban (12.1-27.9 pg/m^3) and industrialised (21.4-44.3 pg/m^3) sites were comparable to, or slightly lower than measured at other sites. The partition coefficient of PBDEs between the gas and particle phases (Kp) was well correlated with the subcooled liquid vapor pressure (P°L) for all samples. The measured particulate sorption of PBDEs was compared to the predictions from Junge-Pankow (J/P) model and KOA absorption model. While the Junge-Pankow model tends to overestimate the particulate sorption, the KOA based model seemed to fit the PBDE data.

7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals.

The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds.

International audience; Background: Aims of this study were i) to test the reliability of a new classification system of gingival recessions using the level of interproximal clinical attachment as identification criterion ii) to explore the predictive value of the resulting classification system on the final root coverage outcomes. Material and methods: Patients showing at least one buccal gingival recession were recruited by one operator. Three recession types (RT) were identified. The classification was tested by two examiners blinded to the data collected by the other examiner. Intra-rater and inter-rater agreement was assessed. Furthermore, the 6-month root coverage outcomes of consecutively treated gingival recessions were retrospectively evaluated to explore predictive value of the proposed classification on the final outcomes. Results: The new classification system of gingival recessions was tested in 116 gingival recessions (mean 3.2  1.2mm) in 25 patients. The Intra-class Correlation Coefficient (ICC) for inter-rater agreement was 0.86 showing an almost perfect agreement between examiners. The RT classification was predictive of the final recession reduction (p

Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21(WAF1/Cip1) by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination.