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The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future., info:eu-repo/semantics/published

Background and objectives With disease-modifying treatment strategies on the horizon, stratification of individual patients at the earliest stages of Parkinson's disease (PD) is key-ideally already at clinical disease onset. Blood levels of neurofilament light chain (NfL) provide an easily accessible fluid biomarker that might allow capturing the conversion from prodromal to manifest PD. Methods We assessed longitudinal serum NfL levels in subjects converting from prodromal to manifest sporadic PD (converters), at-risk subjects, and matched controls (72 participants with ≈4 visits), using single-molecule array (Simoa) technique. Results While NfL levels were not increased at the prodromal stage, subjects converting to the manifest motor stage showed a significant intraindividual acceleration of the age-dependent increase of NfL levels. Conclusions The temporal dynamics of intraindividual NfL blood levels might mark the conversion to clinically manifest PD, providing a potential stratification biomarker for individual disease onset in the advent of precision medicine for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

Despite the evidence-based effectiveness of several drugs,1 treatment of hidradenitis suppurativa (HS) is still empirical and challenging. The required discovery of candidate treatment targets, may be accomplished through an integrated approach using combined molecular tools.2 Current transcriptome and proteome studies have identified potential biomarkers for HS both in entire involved skin3 and in involved skin apocrine glands.4 These and other studies may support the identification of novel therapeutic targets for HS. Computational drug repurposing/repositioning screening approaches have been previously engaged to identify existing compounds as potential drugs for dermatologic conditions including a study on moderate-to-severe HS.5.

Colorectal cancer is an important cancer worldwide, whose etiology is not fully understood. Known causes include several genetic factors, overweight/obesity, tobacco smoking, and heavy alcohol drinking. An etiologic role of diet is highly plausible but the evidence for specific factors, with the possible exception of processed meat, is not conclusive. Workers exposed to asbestos have been found at increased risk of colorectal cancer in several studies, but the evidence is not sufficiently strong to conclude in favor of a causal association. No other occupational factors have been linked to colorectal cancer. Liver cancer is a common cancer in many regions of the world and is the second cause of cancer-specific mortality. About 75% of liver cancers are hepatocellular carcinoma (HCC), the second most frequent type being cholangiocarcinoma (CCA). HCC develops in the context of a web of interactions between viral (HBV, HCV), environmental (alcohol, aflatoxin), and metabolic (fatty liver disease, obesity) factors. Genetic predisposition accounts for only a small fraction of the global burden of HCC. The only established occupational cause of liver cancer is vinyl chloride, which causes a rare type of neoplasm, angiosarcoma, and has also been associated with HCC. Detection and diagnosis of HCC is complicated by its occurrence in a background of chronic liver disease characterized by inflammation and cycles of hepatocyte proliferation and destruction. Markers used in clinical practice include serological and molecular markers of viral hepatitis, enzymatic tests for liver function and injury, and a growing list of plasma-based tumor markers, the current gold standard being alpha-fetoprotein (AFP). Recent research has identified molecular changes in transcriptome, microRNAome, epigenome and, significantly, plasma proteome, that pave the way to the development of a new generation of biomarkers for early detection of HCC in different etiological contexts.

Background Apocrine glands have been long considered as the initial targeted skin compartment in hidradenitis suppurativa/acne inversa (HS ). Objective Detection of apocrine gland involvement in HS . Methods Apocrine glands were isolated from skin biopsies of involved and uninvolved skin of HS patients (n = 16, females : males 1 : 1) by laser capture microscopy and studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non‐lesional skin obtained from female and male HS patients using the Agilent array platform. Results SULF 1 was the only gene, whose expression levels were found upregulated in apocrine glands of HS lesions of the entire group. Further dysregulated genes associated with vascular functions (FGF 1, IL 17D and S100A9 ) were detected. Genes, which are characteristic for glandular epithelia, confirmed the glandular origin of the studied tissue. The gene upregulation profile of female apocrine glands included several genes (MRO , DYRK 3, SDK 2, GLB 1L, CATSPERB and PRPS 2 ), which are specifically transcribed during testis differentiation and/or regulated by androgens. Genes related to lipid metabolism (AGPAT 3, GAL , ELOVL 3, THRSP , DGAT 2L3, OLAH , THRSP , FADS 1, NR 2F2, FADS 2, PTGDS and HAO 2 ) were mostly downregulated in the apocrine glands of male patients. The levels of RECK and PCSK 5 , which are upstream genes of metalloproteinase‐9 and ‐1, and of S100A9 , which encodes calgranulin B, were commonly increased in the apocrine glands of female and male patients, respectively, and in our previous whole skin study. Conclusion Our findings indicate that apocrine glands are bystanders in HS . Inflammatory signalling is not prominent but a gender‐specific response was detected, which is mostly associated with androgen‐responsive genes in females and alterations of lipid metabolism in males., Journal of the European Academy of Dermatology & Venereology, 34 (7), ISSN:0926-9959, ISSN:1468-3083

Background The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease‐driving mechanisms and tissue targeting. Objective Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments. Methods Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non‐lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real‐time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS‐involved skin compartments were also recognized by immunohistochemistry. Results Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin‐A, calgranulin‐B and serpin‐B4 were detected in the hair root sheath, koebnerisin and connexin‐32 in stratum granulosum, transcobalamin‐1 in stratum spinosum/hair root sheath, small prolin‐rich protein‐3 in apocrine sweat gland ducts/sebaceous glands‐ducts and matrix metallopeptidase‐9 in resident monocytes. Conclusion Our findings highlight a panel of immune‐related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands., Journal of the European Academy of Dermatology & Venereology, 34 (4), ISSN:0926-9959, ISSN:1468-3083

Background: A more reliable classification of skin inflammation and severity of active disease results from ultrasound sonography and the new hidradenitis suppurativa/acne inversa (HS) classification system IHS4. However, an objective assessment of skin inflammation in a continuous mode is still the ultimate goal. Long-wave medical infrared thermography (MIT) may offer a blood flow and temperature differential assessment in inflammatory conditions. Objective: To evaluate the application of MIT in HS. Methods: Standardized photography of the areas involved or been candidates for HS involvement was performed and MIT pictures were taken simultaneously and superimposed on the photographs of 18 patients (11 female, 7 male, median age 38.75 years [95% confidence interval 28.5 and 51 years], Hurley score I 5.6%, Hurley score II 38.9%, and Hurley score III 55.5%). A modification of the Otsu’s method facilitated the automatic lesion segmentation from the background, depicting the inflammation area. Moreover, MIT was administered in real-time mode during radical HS surgery. Results: A 1°C temperature difference from a corresponding symmetric body region was indicative of inflammation. MIT figures detected a gradual increase of skin temperature from 33.0°C in healthy skin on average to 35.0–36.6°C at the center of inflamma tory lesions in the axilla and to 35.4–36.9°C at the center of inflammation in the groin area. Real-time MIT assessment enabled the definition of the margins and depth of the surgical intervention during the procedure. Conclusion: MIT is a promising tool for the detection of inflammation severity in HS lesions and can be used as a clinical biomarker in evaluation studies of medical and surgical HS treatment.

Background: Plaque-associated gingivitis is a prevalent disease and research in its treatment using herbal agents must be encouraged to verify which would be a useful addition to the current range or chemotherapeutic treatment options. Aims: The aim of this study was to evaluate the clinical effect of a mouth rinse containing 10% Anacardium occidentale (AO) Linn., a typical plant commonly found in the Northeast Region of Brazil, on the reduction of plaque and gingivitis in comparison to a gold-standard chemotherapeutic agent. Materials and Methods: Thirty normosystemic adult volunteers of both genders, who had a minimum of twenty natural teeth, aging between 18 and 32 years, were enrolled in this crossover, controlled, examiner-blind clinical study. They were randomly allocated into three groups: 10% AO Linn. (n = 10); 0.12% chlorhexidine digluconate (CLX, n = 10); or placebo (PB, n = 10). All volunteers were instructed to brush their teeth with a fluoridated dentifrice two times a day (12/12 h) and to rinse for 1 min with one of the mouthwashes (AO, CLX, or PB) 30 min after tooth brushing for 1 month. Plaque index (PLI) and gingival bleeding index (BLI) were recorded on days 0 and 30. Nonparametric Kruskal-Wallis and Wilcoxon tests (α = 0.05) were performed to evaluate statistical differences among groups. Results: There was a significant reduction (P < 0.05) on plaque and gingivitis at day 30 just in CLX ([PLI = 0.47 ± 0.16; -30%]; [BLI = 0.15 ± 0.09; -55.8%]) and AO ([PLI = 0.49 ± 0.21; -31%]; [BLI = 0.13 ± 0.10; -56.6%]) groups, but no statistically significant difference was observed among them (P > 0.05). Conclusion: Mouthwash containing 10% AO was effective as an antiplaque and antigingivitis agent, in a similar manner that 0.12% CLX.

Background: Despite existing guidelines and methods for standardized clinical photography in dermatology and plastic surgery, human skin exhibits exquisite site-specific morphologies and functions, and each body region can exhibit an individual pathologic phenotype. The aim of this work was to develop a standardized, representative and reproducible documentation of the multilocular hidradenitis suppurativa/acne inversa (HS) lesions, a disease mostly occurring in skin folds. Method: Optimal body positions for medical photography of candidate areas for HS involvement were evaluated. Pictures of volunteers were taken, and indicative scientific graphics were designed. Results: Due to the variability of HS lesions and the fact of their localization in skin folds, a standardized, reproducible photographic documentation of HS candidate skin areas (50 cm from the skin surface) is proposed. The photographic series includes: (1) right armpit, (2) left armpit, (3) right groin, (4) left groin, (5) genital area, (6) anal area and anal fold, (7) right buttock, (8) left buttock, (9) chest area, (10) mons pubis, (11) right submammary area (females), (12) left submammary area (females). The protocol is accompanied with indicative scientific graphics for photography-proper positioning of the relevant body parts for documentation of potentially flat skin areas. In addition, former proposals for technical standardization of photography in dermatology, regarding instrumentation, environmental lighting and background colour, have to be respected. Conclusion: Standardized photography of candidate skin areas for HS involvement will allow longitudinal intraindividual and interindividual evaluation of the disease course as well as prospective and retrospective comparative studies.

Background Adjuvant treatment for patients (pts) with endometrial cancer (EC) is decided based on risk assessment of recurrence and distant metastasis. Carcinomas of non-endometrioid (NE) histologies are rare, classified as high-risk and adjuvant treatment is recommended. Methods Retrospective analysis of EC pts diagnosed and treated in two units during 10 years (2009-2018) with a focus on pts with NEEC. After surgery and multidisciplinary discussion, pts had either no further treatment, radiotherapy (RT), chemotherapy (CT) followed by RT or CT. We compared these approaches using survival analysis. Results From a total of 330 pts with EC, 66 pts with surgery for NEEC were analyzed. Median age was 68.5 yrs (43-88). Serous histology was found in 34 (51.5%) pts, clear-cell in 13 (19.7%), in 18 (27.3%) carcinosarcoma and one pt had an undifferentiated tumor. Based on the International Federation of Gynecology and Obstetrics (FIGO) staging system, 32 pts (48.5%) were diagnosed at early stage (IA-II) and 34 (51,5%) at advanced stage (IIIA-IV). After surgery, 16 pts (24.4%) had no further treatment, while 11 (16.7%) received CT, 28 (42.4%) CT + RT and 11 (16.7%) only RT. RT included external beam RT and/or brachytherapy. In the survival analysis, the median DFS was significantly higher in the CT + RT group, 31 months (m), compared to both the RT alone group, 14m and the isolated CT group, 11m. For patients without further treatment DFS was 6m, p = 0.03. The median OS showed similar results: pts submitted to CT + RT had favorable survival (78m) compared to the other groups, RT group (64m), CT group (37m) and the group of pts with no further treatment (47m), p = 0.005. Conclusions The best survival results are for pts treated with CT+RT. Patients treated with RT had better results when compared with pts treated with CT or with pts without further treatment. These results show us that pts treated with CT are those with higher FIGO stages that were not considered for adjuvant RT. The worse survival results for untreated pts reflects deteriorated PS, extensive comorbidities or early progression. Due to aging and lifestyle risk factors, like obesity, EC remains the most prevalent gynecological carcinoma where better selection and implementation of adjuvant treatment modalities are needed. Legal entity responsible for the study Author and co-authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

// Marcia Cristina T. dos Santos 1 , Miguel Arturo Barreto-Sanz 2 , Bruna Renata S. Correia 3 , Rosie Bell 4 , Catherine Widnall 5 , Luis Tosar Perez 6 , Caroline Berteau 5 , Claudia Schulte 7 , Dieter Scheller 8 , Daniela Berg 7, 9 , Walter Maetzler 7, 9 , Pedro A. F. Galante 3 and Andre Nogueira da Costa 1 1 Experimental Medicine and Diagnostics, Global Exploratory Development, UCB Biopharma SPRL, Braine-l'Alleud, Belgium 2 SimplicityBio SA, Monthey, Switzerland 3 Hospital Sirio Libanes, Sao Paulo, Brazil 4 Centre for Misfolding Diseases, University of Cambridge, Cambridge, UK 5 Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK 6 Bioanalytical Sciences, Non Clinical Development, UCB Biopharma SPRL, Belgium 7 Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen and German Center for Neurodegenerative Diseases, Tuebingen, Germany 8 Consultancy Neuropharm, Neukirchener, Neuss, Germany 9 Department of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany Correspondence to: Andre Nogueira da Costa, email: andre.dacosta@ucb.com Keywords: exosomal miRNA; early stage PD diagnosis; CSF; machine learning Received: January 06, 2018 Accepted: February 25, 2018 Published: April 03, 2018 ABSTRACT Parkinson’s Disease is the second most common neurodegenerative disorder, affecting 1–2% of the elderly population. Its diagnosis is still based on the identification of motor symptoms when a considerable number of dopaminergic neurons are already lost. The development of translatable biomarkers for accurate diagnosis at the earliest stages of PD is of extreme interest. Several microRNAs have been associated with PD pathophysiology. Consequently, microRNAs are emerging as potential biomarkers, especially due to their presence in Cerebrospinal Fluid and peripheral circulation. This study employed small RNA sequencing, protein binding ligand assays and machine learning in a cross-sectional cohort comprising 40 early stage PD patients and 40 well-matched controls. We identified a panel comprising 5 microRNAs (Let-7f-5p, miR-27a-3p, miR-125a-5p, miR-151a-3p and miR-423-5p), with 90% sensitivity, 80% specificity and 82% area under the curve (AUC) for the differentiation of the cohorts. Moreover, we combined miRNA profiles with hallmark-proteins of PD and identified a panel (miR-10b-5p, miR-22-3p, miR-151a-3p and α-synuclein) reaching 97% sensitivity, 90% specificity and 96% AUC. We performed a gene ontology analysis for the genes targeted by the microRNAs present in each panel and showed the likely association of the models with pathways involved in PD pathogenesis.

Cerebrospinal fluid (CSF) has often been used as the source of choice for biomarker discovery with the goal to support the diagnosis of neurodegenerative diseases. For this study, we selected 15 CSF protein markers which were identified in previously published clinical investigations and proposed as potential biomarkers for PD diagnosis. We aimed at investigating and confirming their suitability for early stage diagnosis of the disease. The current study was performed in a two-fold confirmatory approach. Firstly, the CSF protein markers were analysed in confirmatory cohort I comprising 80 controls and 80 early clinical PD patients. Through univariate analysis we found significant changes of six potential biomarkers ($α$-syn, DJ-1, A$β$42, S100$β$, p-Tau and t-Tau). In order to increase robustness of the observations for potential patient differentiation, we developed-based on a machine learning approach-an algorithm which enabled identifying a panel of markers which would improve clinical diagnosis. Based on that model, a panel comprised of $α$-syn, S100$β$ and UCHL1 were suggested as promising candidates. Secondly, we aimed at replicating our observations in an independent cohort (confirmatory cohort II) comprising 30 controls and 30 PD patients. The univariate analysis demonstrated A$β$42 as the only reproducible potential biomarker. Taking into account both technical and clinical aspects, these observations suggest that the large majority of the investigated CSF proteins currently proposed as potential biomarkers lack robustness and reproducibility in supporting diagnosis in the early clinical stages of PD.

Impulsive-compulsive disorders in Parkinson’s disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson’s disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson’s disease/dopamine replacement therapy related reward bias.

Impulsive-compulsive disorders (ICD) in patients with Parkinson’s disease (PD) have been described as behavioral or substance addictions including hypersexuality, gambling, or compulsive medication use of the dopamine replacement therapy (DRT). A remaining challenge is to understand the neuroadaptations leading to reward bias in PD patients under DRT. To this end, the appetitive effect of the D2/D3 agonist pramipexole was assessed after chronic exposure to l-dopa in an alpha-synuclein PD rat model. Association of progressive nigral loss and chronic l-dopa was required to observe a pramipexole-induced place preference. This behavioral outcome was inhibited by metabotropic glutamate receptor 5 (mGluR5) antagonism while transcriptional profiling highlighted regulations potentially related to the context of psychostimulant addiction. This study provides evidences strongly suggesting that PD-like lesion and l-dopa therapy were concomitant factors involved in striatal remodeling underlying the pramipexole-induced place preference. Molecular and pharmacological data suggest a key involvement of the glutamatergic pathway in this behavioral outcome.

Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 5% of the elderly population. PD diagnosis is still based on the identification of neuromotor symptoms although nonmotor manifestations emerge years prior to diagnosis. The discovery of biomarkers at the earliest stages of PD is of extreme interest. miRNAs have been considered potential biomarkers for neurodegenerative diseases, but only a limited number have been found to be PD related. This review focuses on the current findings in the field of circulating miRNAs in PD and the challenges surrounding clinical utility and validation. We briefly describe the more established circulating biomarkers in PD and provide a more thorough review of miRNAs differentially expressed in PD. We highlight their potential for being considered as biomarkers for diagnosis while emphasizing the challenges for adequate validation of the findings and how miRNAs can be envisioned in a clinical setting satisfying regulatory bodies.

Aim: The aim of this study was to evaluate the antiplaque effect of Lippia sidoides (LS) by in vivo investigation. Materials and Methods: Ten healthy volunteers participated in a cross-over, double-blind clinical study, using a 3-day partial-mouth plaque accumulation model. The participants abolished any method of mechanical oral hygiene and they were randomly assigned initially to use just the following mouth rinses: Distilled water (negative control group), 0.12% chlorhexidine digluconate (positive control group) or 10% LS (test group). The plaque index was recorded in the six anterior upper teeth at the end of the trial and the one-way ANOVA and Bonferroni tests were used to estimate the difference among groups. Results: The clinical results did show statistically significant difference among three groups (P < 0.05), favoring the positive control group and test group, however, no difference in efficacy was found between them (P > 0.05). Conclusions: The mouth rinses containing 0.12% chlorhexidine digluconate and 10% LS were equally able to inhibit plaque re-growth.

Infection by hepatitis B virus (HBV) and dietary exposure to aflatoxin B1 (AFB1) are the main risk factors for the development of chronic liver disease and hepatocellular carcinoma (HCC). How these factors cooperate is still largely unknown. AFB1 activation leads to DNA adduction and mutagenesis, with a specific mutation at codon 249 in TP53 (p.R249S). So far, only limited studies have addressed the effects of AFB1 on HBV replication. We have analysed the effects of both risk factors on p53 induction during HBV infection in HepaRG, a cell line with hepatocyte-like morphology that metabolizes AFB1 and supports HBV infection. Exposure to AFB1 up to 5 µM induced a downregulation of HBV replication after 48 h, as measured by a decrease in viral antigens in the culture medium (HBsAg, HBeAg and large envelope protein) and in intracellular levels of HBV transcripts, DNA and HBsAg. Conversely, HBV infection did not significantly modify AFB1-DNA adduct formation or repair as assessed by immunodot-blot assay, and the induction of p53 in response to AFB1 was similar in infected and non-infected HepaRG cells. Overall, our results suggest that AFB1 exposure decreases HBV replication, whereas DNA damage by AFB1 and subsequent p53 induction is not affected by the presence of the virus. Thus, in HepaRG cell line, AFB1 and HBV do not cooperate to increase DNA damage by AFB1. Further studies on the effects of both factors in a context of chronicity are needed to better understand synergistic effects.

OBJECTIVES: The antiplaque and antigingivitis effect of Lippia Sidoides (LS) was evaluated in this in vivo investigation. MATERIAL AND METHODS: Twenty-three subjects participated in a cross-over, double-blind clinical study, using 21-day partial-mouth experimental model of gingivitis. A toothshield was constructed for each volunteer, avoiding the brushing of the 4 experimental posterior teeth in the lower left quadrant. The subjects were randomly assigned initially to use either the placebo gel (control group) or the test gel, containing 10% LS (test group). RESULTS: The clinical results showed statistically significant differences for plaque index (PLI) (p

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for early diagnosis and prognosis. In this study, we applied targeted massively parallel semiconductor sequencing to assess methylation on a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) in plasma circulating cell-free DNA (cfDNA) and to evaluate the potential of these genes as HCC biomarkers in two different series, one from France (42 HCC cases and 42 controls) and one from Thailand (42 HCC cases, 26 chronic liver disease cases and 42 controls). We also analyzed a set of HCC and adjacent tissues and liver cell lines to further compare with ‘The Cancer Genome Atlas’ (TCGA) data. The methylation in cfDNA was detected for FBLN1, PSMA7, PXDN and VIM, with differences in methylation patterns between cases and controls for FBLN1 and VIM. The average methylation level across analyzed CpG-sites was associated with higher odds of HCC for VIM (1.48 [1.02, 2.16] for French cases and 2.18 [1.28, 3.72] for Thai cases), and lower odds of HCC for FBLN1 (0.89 [0.76, 1.03] for French cases and 0.75 [0.63, 0.88] for Thai cases). In conclusion, our study provides evidence that changes in VIM and FBLN1 methylation levels in cfDNA are associated with HCC and could represent useful plasma-based biomarkers. Also, the potential to investigate methylation patterns in cfDNA could bring new strategies for HCC detection and monitoring high-risk groups and response to treatment.

Priapism is defined as prolonged and persistent penile erection, unassociated with sexual interest or stimulation and increase the development of erectile dysfunction(ED), and is a complication associated with sickle cell disease (SCD). Moreover, prevalence of ED associated with priapism increases progressively with aging, but, understanding of stages involved is still poorly investigated. Thus, we evaluate the muscle reactivity of isolated corpus cavernosum (CC) of SCD old mice. The animals were divided in control (CT; 3 month), control old (CTO; 1.2 year) and SCD old (SSO; 1.2 year) groups. Concentration-response curves to acethylcholine (ACh), sodium nitroprusside (SNP) and phenylephrine (PE) were obtained in CC mice. Nitrergic and neurogenic responses induced by electrical-field stimulation (EFS) were also obtained in all groups. The potency (pEC50) to ACh did not change in all group, but, the maximal response (Emax) was decrease in SSO (Emax: 20 ± 9%, P

Colorectal cancer is an important cancer worldwide, whose etiology is not fully understood. Known causes include several genetic factors, overweight/obesity, tobacco smoking, and heavy alcohol drinking. An etiologic role of diet is highly plausible, but the evidence for specific factors, with the possible exception of processed meat, is not conclusive. Workers exposed to asbestos have been found at increased risk of colorectal cancer in several studies, but the evidence is not sufficiently strong to conclude in favor of a causal association. No other occupational factors have been linked to colorectal cancer. Liver cancer is a common cancer in many regions of the world and is the second cause of cancer-specific mortality. About 75 % of livercancers are hepatocellular carcinoma (HCC), the second most frequent type being cholangiocarcinoma (CCA). HCC develops in the context of a web of interactions between viral (HBV, HCV), environmental (alcohol, aflatoxin), and metabolic (fatty liver disease, obesity) factors. Genetic predisposition accounts for only a small fraction of the global burden of HCC. The only established occupational cause of liver cancer is vinyl chloride, which causes a rare type of neoplasm, angiosarcoma, and has also been associated with HCC. Detection and diagnosis of HCC are complicated by its occurrence in a background of chronic liver disease characterized by inflammation and cycles of hepatocyte proliferation and destruction. Markers used in clinical practice include serological and molecular markers of viral hepatitis, enzymatic tests for liver function and injury, and a growing list of plasma-based tumor markers, the current gold standard being alpha-fetoprotein (AFP). Recent research has identified molecular changes in transcriptome, microRNAome, epigenome, and, significantly, plasma proteome that pave the way to the development of a new generation of biomarkers for early detection of HCC in different etiologic contexts. © Springer-Verlag London 2014.

Understanding and reducing attrition rate remains a key challenge in drug development. Preclinical and clinical safety issues still represent about 40% of drug discontinuation, of which cardiac and liver toxicities are the leading reasons. Reducing attrition rate can be achieved by various means, starting with a comprehensive evaluation of the potential safety issues associated to the primary target followed by an evaluation of undesirable secondary targets. To address these risks, a risk mitigation plan should be built at very early development stages, using a panel of in silico, in vitro, and in vivo models. While most pharmaceutical companies have developed robust safety strategies to de-risk genotoxicity and cardiotoxicity issues, partly driven by regulatory requirements; safety issues affecting other organs or systems, such as the central nervous system, liver, kidney, or gastro-intestinal system are less commonly addressed during early drug development. This paper proposes some de-risking strategies that can be applied to these target organ systems, including the use of novel biomarkers that can be easily integrated in both preclinical and clinical studies. Experiments to understand the mechanisms’ underlying toxicity are also important. Two examples are provided to demonstrate how such mechanistic studies can impact drug development. Novel trends in investigative safety are reviewed, such as computational modeling, mitochondrial toxicity assessment, and imaging technologies. Ultimately, understanding the predictive value of non-clinical safety testing and its translatability to humans will enable to optimize assays in order to address the key objectives of the drug discovery process, i.e., hazard identification, risk assessment, and mitigation.

Background: Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods: Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results: Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions: The validated changes of expression in these proteins have the potential for development into highperformance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cutoffs and combinations for evaluation of performance.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for diagnosis and prognosis. HCC carcinogenesis is a multi-step process that usually arises in background chronic metabolic, inflammatory and/or infectious liver disease and it exhibits a wide range of epigenetic alterations that could potentially be used as biomarkers. In this study, we applied the targeted massively parallel semiconductor sequencing to assess in plasma circulating cell-free DNA (cfDNA) the methylation of a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) and to evaluate the potential of these genes as novel HCC biomarkers in two different series, one from France and one from Thailand. Methylation in cfDNA was detected for FBLN1, PSMA7, PXDN and VIM, with substantial differences in methylation patterns between cases and controls for FBLN1 and VIM. Further, the average methylation level across analyzed CpG-sites was associated with higher odds of HCC for VIM (1.48 [1.02, 2.16] for French cases, and 2.18 [1.28, 3.72] for Thai cases), and lower odds of HCC for FBLN1 (0.89 [0.76, 1.03] for French cases and 0.75 [0.63, 0.88] for Thai cases). We also analyzed a set of HCC and adjacent tissues as well as The Cancer Genome Atlas’ (TCGA) data to further investigate the origin of methylation pattern in cfDNA and noted that the analysis of VIM could be improved based on the methylation pattern detected in TCGA data. Overall, our study provides evidence that changes in methylation levels of cfDNA could be used as potential cancer biomarkers and that VIM and FBLN1 methylation in cfDNA are associated with HCC and may represent useful plasma-based biomarkers for improved detection and patient surveillance. Citation Format: Reetta Holmila, Athena Sklias, David C. Muller, Davide Degli Esposti, Paule Guilloreau, James Mckay, Suleeporn Sangrajrang, Petcharin Srivatanakul, Pierre Hainaut, Philippe Merle, Andre Nogueira da Costa, Zdenko Herceg. Targeted deep sequencing of plasma circulating cell-free DNA shows VIM and FBLN1 methylation as potential biomarkers for hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4468.

The genetic and epigenetic material originating from tumour that can be found in body fluids of individuals with cancer harbours tumour-specific alterations and represents an attractive target for biomarker discovery. Epigenetic changes (DNA methylation, histone modifications and non-coding RNAs) are present ubiquitously in virtually all types of human malignancies and may appear in early cancer development, and thus they provide particularly attractive markers with broad applications in diagnostics. In addition, because changes in the epigenome may constitute a signature of specific exposure to certain risk factors, they have the potential to serve as highly specific biomarkers for risk assessment. While reliable detection of cancer-specific epigenetic changes has proven to be technically challenging, a substantial progress has been made in developing the methodologies that allow an efficient and sensitive detection of epigenomic changes using the material originating from body fluids. In this review we discuss the application of epigenomics as a tool for biomarker research, with the focus on the analysis of DNA methylation in biofluids.

Villar, Stephanie Ortiz-Cuaran, Sandra Abedi-Ardekani, Behnoush Gouas, Doriane Nogueira da Costa, Andre Plymoth, Amelie Khuhaprema, Thiravud Kalalak, Anant Sangrajrang, Suleeporn Friesen, Marlin D Groopman, John D Hainaut, Pierre eng Research Support, Non-U.S. Gov't 2012/06/08 06:00 PLoS One. 2012;7(6):e37707. doi: 10.1371/journal.pone.0037707. Epub 2012 Jun 4.; International audience; Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G ―> T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (>/= 67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA >/= 150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA >/= 150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.

Aim The aim of this in vivo study was to evaluate the antiplaque and antigingivitis effect of Copaifera sp (Cp). Methods and Materials Twenty-three subjects participated in a randomized controlled clinical trial using a 21-day, partial-mouth experimental model of gingivitis. A custom tooth shield was fabricated for each subject to prevent the brushing of the four experimental posterior teeth in the lower-left quadrant. The subjects were randomly assigned to either the control group (using a placebo gel) or the test group (using the test gel containing 10% Cp). Results The clinical results showed statistically significant differences for plaque (PLI), bleeding (BI), and gingival (GI) indexes at days 0 and 21 in both groups (p0.05). Conclusions The test gel containing 10% Cp did not prevent plaque formation and development of gingivitis. Clinical Significance Several medicinal herbs are used empirically by persons in the treatment and prevention of oral conditions. Research in this area must be encouraged to determine which herbal agents would be a useful addition to the current range of chemotherapeutic periodontal treatment options. Citation Pereira SLS, Barros CS, Salgado THY, Filho VPP, Costa FN. Limited Benefit of Copaifera Oil on Gingivitis Progression in Humans. J Contemp Dent Pract [Internet]. 2010 Jan; 11(1):057-064. Available from: http://www.thejcdp. com/journal/view/volume11-issue1-pereira.

Measurements of photosynthetically active radiation (PAR) and global solar irradiance (Rs) were made at a LBA (The Large Scale Biosphere‐Atmosphere Experiment in Amazonia) experimental site, at Fazenda Nossa Senhora (10°45′ S; 62°21′ W), in Rondonia, in the years of 2004 and 2005, with the objective of estimating the seasonal variation of the ratio between the photosynthetically active radiation and the global solar irradiance. The relationship between PAR and Rs were made by using linear regressions equations with data from year 2004 and tested with data from the year 2005. The seasonal variation of the ratio PAR/Rs ranged from 0.43 (September) to 0.48 (January). The linear regression equations between PAR and Rs obtained were: a) On an hourly basis: PAR = 0.747+0.478*Rs, (R2 = 0.99; wet season) and PAR = −4.578+0.452*Rs (R2 = 0.99; dry season); b) On a daily basis: PAR = 4.956+0.466*Rs (R2 = 0.99; wet season) and PAR = −6.762+0.457*Rs (R2 = 0.96; dry season).