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Nowadays, eating habits and lifestyles are moving towards a diet high in sugars and carbohydrates, which is extremely harmful to both oral integrity and systemic health. The aim of the study was to identify the variations between the bacterial plaque formed in carious lesions, infected root canals and prosthetic components, in comparison with commensal oral microflora. The study was carried out on a group of 21 patients aged between 7 and 84 years, 13 women and 8 men, with various oral diseases, which were diagnosed during the specialized examination. The preparation of the medical record, the signing of the informed consent, the anamnesis and the consultation were carried out in the private dental office where the patients presented for a personalized treatment plan, and the examination of the pathological products and the interpretation of the results obtained in the Microbiology Discipline, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania. The study carried out on the preparations taken from patients with carious lesions reveals the presence of numerous G+ cocci arranged in short chains (23%), frequent G+ cocci in diplo, thin G+ bacilli with rounded ends and G+ cocci in diplo, arranged in small piles (15 %), and values lower than 8% are represented by G+ in diplo cocci, lanceolate, rare G+ in diplo cocci, very rare fusiform bacilli and dentinal fragments. The study carried out on the preparations taken from the endodontic space showed a remarkable percentage of epithelial cells and leukocytes (28%), rare fusiform bacilli, very small fragments of epithelial tissue, thin G+ bacilli with rounded ends, G+ cocci in diplo and in small piles and buns arranged in short chains (5-6%). The study carried out on the preparations taken from the level of prosthetic components, recorded a relatively high number of epithelial cells (19%), G+ cocci arranged in diplo, lanceolate and in small piles (13%), thin G+ bacilli, with rounded ends (10 %), cocci in short chains (10%) and rare polymorphonuclear leukocytes (10%), while at the opposite pole, squamous epithelial cells, fusobacteria and pleomorphic forms (3%) are found.

Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. Toxicity: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315–25. ©2018 AACR.

Purpose:The relevance of the MET/hepatocyte growth factor pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease.Patients and Methods:PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib (60 mg once daily) in women with endometrial cancer with progression after chemotherapy. Coprimary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg, carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort.Results:A total of 102 patients were accrued. Among 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67%, and median PFS was 4.8 months. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56%, and median PFS was 4.0 months. In a separate cohort of 32 patients with uncommon histology endometrial cancer (including carcinosarcoma), response rate was 6% and 12-week PFS was 47%. Six patients were on treatment for >12 months, including two for >30 months. Common cabozantinib-related toxicities (>30% patients) included hypertension, fatigue, diarrhea, nausea, and hand–foot syndrome. Gastrointestinal fistula/perforation occurred in four of 70 (6%) patients with serous/endometrioid cancer and five of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic CTNNB1 mutation [four partial responses (PRs) in 10 patients, median PFS 7.6 months] and concurrent KRAS and PTEN/PIK3CA mutations (three PRs in 12 patients, median PFS 5.9 months).Conclusions:Cabozantinib has activity in serous and endometrioid histology endometrial cancer. These results support further evaluation in genomically characterized patient cohorts.

Figure S1: Frequency of Tregs does not significantly decline post treatment and does not correlate with p53-reactivity or PFS.; Figure S2: Frequency of MDSC does not significantly differ to healthy controls, does not decline post treatment and does not correlate with p53-reactivity or PFS.; Supplementary Table T1: Multi variation analysis* shows an association between progression free survival and frequency of p53-reactive T cells, disease stage and baseline MDSC. Supplementary Table T2: Correlations (Pearson) of variables included in multi variation analysis.

Supplemental Table S1. 48 genes included in the TruSeq Amplicon Cancer Panel (TSACP, Illumina). Panel includes 212 amplicons covering a total genomic region 35.84 kb.

Several 1-azulenyl vinyl crown ethers were synthesized starting from (1-azulenylmethyl) triphenylphosphonium iodide and 4-formylbenzo-crown ethers in the Wittig reaction conditions. The reaction worked in fair conditions and the obtained mixtures of geometric isomers were separated using column chromatography. The isomers were identified using 1H-NMR spectra and the mass spectra were recorded using ESI. The UV-vis spectra showed bathochromic effect in Z isomer compared with the E one.

Like any business process, auditing is a process that can be perfected, technology complementing a set of advanced data processing skills and techniques. The objective of this paper is to research the way how Romanian auditors work and perceive the impact of IT on audit missions. The results of the conducted survey, based on 102 responses, highlight a series of working tools (Data Analytics, Microsoft Excel, Data Automation) which, through the analysis of the Big Data phenomenon, facilitate the audit process. Regarding the software category, Ciel Audit and Revision, Gaudit, CaseWare are among the most frequently used, auditors considering ready to work with emerging technologies. Continuous professional training is ensured by participation in professional training courses, along with severe documentation about new technologies. In Romania, the current level of performing audits based on new technologies is average, for the future a higher level and a higher forecasting and analysis capacity are expected. The auditing profession will be perfected more and more, the current tasks will be gradually replaced by the new technologies, auditors becoming more appreciated by the external environment. Professional skepticism remains the basic quality of the auditor, along with the understanding of the competitive environment. Uncertainty characterizes the amendment of the International Standards on Auditing (ISA). This paper contributes to the literature by bringing to the fore the current technological context for the audit profession, namely the impact perceived by auditors during the fourth industrial revolution.

Mint minden üzleti folyamat, így a könyvvizsgálat is tökéletesíthető, mivel a fejlett adatfeldolgozási készségeket kiegészíti a technológia. A jelen cikkben a román könyvvizsgálók munkamódszereit vizsgáljuk, valamint azt, hogy szerintük milyen hatást gyakorol az informatika a könyvvizsgálói megbízások végrehajtására. A 102 résztvevővel végzett felmérés válaszai között többször előfordultak bizonyos módszerek és eszközök (adatelemzés, Microsoft Excel, adatautomatizálás), amelyek a big data elemzésével megkönnyítik a könyvvizsgálati folyamatot. A használatra kész, feltörekvő technológiák közül a leggyakrabban a Ciel Audit and Revision, a Gaudit és a CaseWare szoftvereket használják a könyvvizsgálók. Az új technológiákról szóló szakmai ismeretek folyamatos bővítését szakmai továbbképzések és átfogó dokumentációk biztosítják. Romániában az új technológiák alapján jelenleg átlagos szinten végeznek könyvvizsgálatokat, a jövőben magasabb szint, magasabb előrejelzési és elemzési kapacitás várható. A könyvvizsgálói szakmát egyre inkább tökéletesítik, a munkafolyamatba fokozatosan beépítik az új technológiákat. A külső környezet is jobban megbecsüli a könyvvizsgálókat, akik alapvetően továbbra is szakmai szkepticizmussal, valamint a versenykörnyezet ismeretével jellemezhetők. Bizonytalanság övezi a Nemzetközi Könyvvizsgálati Standardok (ISA) módosítását. A jelen cikk azáltal gazdagítja a szakirodalmat, hogy a könyvvizsgálói szakma jelenlegi technológiai környezetét helyezi előtérbe, nevezetesen a negyedik ipari forradalom során a könyvvizsgálók által észlelt hatásokat.

The IT impact can be noticed in all activity fields of this world, and the audit is no exception from the evolution of this technological trend. Motivation: Given that professionals are progressively pursuing experimentation in working with new technologies, the development of Artificial Intelligence (AI), Blockchain, RPA, Machine Learning through the Deep Learning subset is a particularly interesting case, on which the researcher argues for debate. The objective of the article is to present the latest episode of the new technologies impact that outline the auditor profession, the methods and tools used. The quantitative, applied and technical research method allows the analysis of the emerging technologies impact, completing a previous specialized paper of the same author. The results of this paper propose the integration of AI, Blockchain, RPA, Deep Learning and predictive analytics in financial audit missions. The projections resulted from discussions with auditing and IT specialists from Big Four companies show how the technologies presented in this paper could be applied on concrete cases, facilitating current tasks. Machine Learning and Deep Learning would allow a development for prescriptive analytics, revolutionizing the data analytics process. Both the analysis of the literature and the conducted interviews admit AI as a business solution that contributes to the data analytics in an intelligent way, providing a foundation for the development of RPA.

The electrochemical behavior of 4-(azulen-1-yl)-2,6-bis((E)-2-(thiophen-2-yl)vinyl) pyrylium perchlorate (L) was studied by cyclic voltammetry, differential pulse voltammetry, and rotating disk electrode voltammetry. The electrochemical polymerization of L was studied. Modified electrodes covered by polyL films were obtained by successive scanning or by controlled potential electrolysis (CPE) at different charges and potentials. The new electrodes obtained by CPE were applied for sensing the following heavy metals ions: Cu(II), Pb(II), Cd(II), Hg(II). The best results have been registered for Pb(II) ion with a detection limit of 10-8 M.

Some considerations regarding the mechanism of arsa-Wittig condensation have been supplemented with the synthesis of compounds substituted with the nitro to phenyl and various alkyl groups to the azulene moiety. For several unknown meta-substituted 1-styrylazulenes Wittig synthesis was used. The obtained products were completely characterized. A look at the behavior of the products in NMR and UV-Vis spectrometry was taken.

In the context of assessing the impact of IT concern on financial audit missions, the purpose of this paper is to investigate how new Big Data technologies shape the auditor profession, the methods and tools used. Motivation: technology has put its mark on all fields of activity and professionals tend, step by step, to experiment within auditing by testing new technologies; taking into account the hypothesis of large-scale adoption of modern technologies offered by IT, Big Data development and Data Analytics (BDA) represent a highly interesting case, on which the author pleads for debating. The two qualitative and fundamental research methods, together with the critical observation that consisted in manual selections of the online publications of the professional bodies in audit and accounting, the specialized literature and discussions with IT and audit Big Four specialists support the analysis of Big Data impact, completing previous specialized papers, given the fact that the need for (extended) documentation in this regard is further pointed out. The results of this investigation propose Data Analytics, Hadoop, NoSQL as Big Data top technologies applicable on financial audit missions, in order to simplify audit procedures, improve the organizational performance and reduce the level of risk.

Research Question: What are the main security threats emphasized by national and international surveys? Motivation: The rapid growth of IT brings worldwide security issues (Takahashi et al., 2010; Benjamin et al., 2015). IT usage brings new challenges (e.g. higher risks of data exposure, sensitive corporate data, phishing, electronic fraud, impersonations, information security issues) (Morrow, 2012; Thielens, 2013; Rinda?u, 2016), cybercrime being a “sophisticated transnational threat operating on an industrial scale” (Hunton, 2012: 203). Idea: This paper intends to underline the great exposure of financial and non-financial information in the new cybersecurity context, indicated by IT impact on security threats and cyberattacks. Data: The author traced the analysis of the most frequent cyber threats, over a period of six years (2013-2018), based on 20 security reports. Tools: The author adopts the qualitative method, applying critical observations on emerging technologies impact. A hand-collecting method is required, for the analysis and comparison of cybersecurity threats reports. Findings: This investigation highlights Targeted attacks/ APTs, malware and ransomware on top security threats that continue to disrupt worldwide and Romanian landscape, along with a major rate of employee errors. The paper enhances on the consequences, main security threats and concludes on security cybercrime prevention (i.e. adequate business model implementation, Cloud security solutions, 24/7 monitoring for continuous protection, continuous IT security training, implemented modules against a variety of security incidents, regular updates). Contribution: By bringing to the fore actual security issues, the author concludes on main security threats and completes previous specialized works on security against cybercrime.

The tetrazole-5-diazonium salt, obtained by diazotizing 5-aminotetrazole in strong acid solution, was coupled with azulenes in the presence of pyridine to produce 5-(azulen-1-yldiazenyl)tetrazoles in good yields. The tetrazole moiety was monoalkylated in 1- and in 2- position using dimethyl sulfate for methylation and benzyl bromide for benzylation. The excess of alkylating agent generated in small amount tetrazole dialkylated salts. The synthesized compounds were characterized and some of their properties have been investigated, such as optical, magnetical and electrical.

We sought to evaluate androgen receptor (AR) and PI3K pathway activity in ovarian cancer cell lines and tissue and determine if either pathway was correlated with growth of ovarian cancers. AR expression and activity were quantified using immunohistochemistry (IHC) and RT-qPCR in six ovarian cancer cell lines and 51 tissue samples. Phospho-mTOR and AKT expression were quantified by IHC as well. Cell growth was assessed in the presence of AR modulating drugs and metformin. We found that despite robust AR expression and activity, no cell line was dependent on androgen for growth. However, metformin inhibited activity in five of the six cell lines. Patient tissues had large variation in AR expression and activity, as well as in expression of phospho-mTOR and AKT, but none of these variables correlated with progression-free survival (PFS). AR expression and activity did not predict the dependence of ovarian cancer cell lines on androgens for growth, and AR expression and activity did not correlate with PFS. This result suggests that AR expression as a criterion for patient selection for clinical trials evaluating molecules targeting AR may not predict response for ovarian cancer patients.

As a continuation of research on 1-vinylazulenes synthesis, on their physico–chemical properties as well as on their use as colorimetric and electrochemical materials for the detection of heavy metals ions, new compounds, 4-(azulen-1-ylmethylene)-2-phenyloxazol-5(4H)-ones, are reported. The exceptional structure of azulene moiety with symmetrical electron distribution only with respect to the x-axis gives some special chemical and physical properties to compounds in which it is inserted. Various azulene-1-carbaldehydes and hippuric acids are condensed with good yields in Erlenmeyer—Plöchl reaction conditions. The obtained 1-vinylzulenes were characterized and their UV-Vis and NMR spectra were briefly discussed.

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75–4.5 mg), B (14 days on, 7 days off; 2.0–3.0 mg), and C (7 days on, 14 days off; 2.0–4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1–4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.

The paper reports on monitoring methylmalonic aciduria (MMA)-specific and non-specific metabolites via NMR urinomics. Five patients have been monitored over periods of time, things involved were diet, medication and occasional episodes of failing to comply with prescribed diets. An extended dataset of targeted metabolites is presented, and correlations with the type of MMA are underlined. A survey of previous NMR studies on MMA is also presented.

Biosimilars are new drugs, highly similar copies of biological medicines, equally effective and safe but at lower prices. The aim of this brief review is to provide the current status of biosimilars approved in the European Union for dermatological use. We used PubMed for literature search up to June 2018. The keyword 'biosimilars' was searched and 1,691 items were found. From the 1,691 studies, we included 34 articles in our review. Biologics, biosimilars and generics are different types of drugs. Biosimilars are complex molecules produced by a difficult manufacturing process, and changes in product quality may affect its safety and efficacy. Now, there are 9 biosimilar medicines approved by European Medicines Agency (EMA) for plaque psoriasis and hidradenitis suppurativa: Amgevita, Solymbic, Cyltezo, Imraldi, Benepali, Erelzi, Flixabi, Inflectra and Remsima, and the number is increasing. In 2005, EMA issued the first guidelines for approval of biosimilars. Next-generation biologics, called 'biobetters', have the same target or mechanism of action as previously approved biologics, but they have structural changes and an improved formulation. The debate over the future of biosimilars is far from being finished. The explosive development of biological therapy and the emergence of biosimilars represent a significant success in the effort to provide advanced healthcare to patients all over the world.

Biosimilars are new drugs, highly similar copies of biological medicines, equally effective and safe but at lower prices. The aim of this brief review is to provide the current status of biosimilars approved in the European Union for dermatological use. We used PubMed for literature search up to June 2018. The keyword ‘biosimilars’ was searched and 1,691 items were found. From the 1,691 studies, we included 34 articles in our review. Biologics, biosimilars and generics are different types of drugs. Biosimilars are complex molecules produced by a difficult manufacturing process, and changes in product quality may affect its safety and efficacy. Now, there are 9 biosimilar medicines approved by European Medicines Agency (EMA) for plaque psoriasis and hidradenitis suppurativa: Amgevita, Solymbic, Cyltezo, Imraldi, Benepali, Erelzi, Flixabi, Inflectra and Remsima, and the number is increasing. In 2005, EMA issued the first guidelines for approval of biosimilars. Next-generation biologics, called ‘biobetters’, have the same target or mechanism of action as previously approved biologics, but they have structural changes and an improved formulation. The debate over the future of biosimilars is far from being finished. The explosive development of biological therapy and the emergence of biosimilars represent a significant success in the effort to provide advanced healthcare to patients all over the world.

Human herpesviruses are widespread human pathogens with a remarkable impact on worldwide public health. Despite intense decades of research, the molecular details in many aspects of their function remain to be fully characterized. To unravel the details of how these viruses operate, a thorough understanding of the relationships between the involved components is key. Here, we present HVint, a novel protein-protein intraviral interaction resource for herpes simplex virus type 1 (HSV-1) integrating data from five external sources. To assess each interaction, we used a scoring scheme that takes into consideration aspects such as the type of detection method and the number of lines of evidence. The coverage of the initial interactome was further increased using evolutionary information, by importing interactions reported for other human herpesviruses. These latter interactions constitute, therefore, computational predictions for potential novel interactions in HSV-1. An independent experimental analysis was performed to confirm a subset of our predicted interactions. This subset covers proteins that contribute to nuclear egress and primary envelopment events, including VP26, pUL31, pUL40, and the recently characterized pUL32 and pUL21. Our findings support a coordinated crosstalk between VP26 and proteins such as pUL31, pUS9, and the CSVC complex, contributing to the development of a model describing the nuclear egress and primary envelopment pathways of newly synthesized HSV-1 capsids. The results are also consistent with recent findings on the involvement of pUL32 in capsid maturation and early tegumentation events. Further, they open the door to new hypotheses on virus-specific regulators of pUS9-dependent transport. To make this repository of interactions readily accessible for the scientific community, we also developed a user-friendly and interactive web interface. Our approach demonstrates the power of computational predictions to assist in the design of targeted experiments for the discovery of novel protein-protein interactions.

The 3+2 cycloaddition reaction of 1-(3-nitrophenacyl)-1,10-phenanthrolinium ylide 4 with activated alkynes gave pyrrolo(1,2-a)(1,10)phenanthrolines 7a-e. The reaction of N-ylide 4 with DMAD, under controlled conditions, gave regioselectively the primary cycloadduct trans-5a which, in the presence of triethylamine, rearranged regio- and stereoselectively to trans-6a. Evidence for the helical chirality of pyrrolophenanthrolines 7b-e was obtained by NMR spectroscopy.

The synthesis, characterization and X-ray crystal structure of 2-(4-chloro-phenyl)-7-methylpyrrolo[1,2-b]pyridazine are reported. The compound crystallizes in the space group P2(1)/c (No.14) with a =3.8568(1), b = 11.0690(3), c = 26.4243(7) A, beta =92.777(1) degrees and Z = 4. Accurate molecular parameters for the novel heterocyclic system were obtained from intensity data collected at 113K. The molecule assumes a planar conformation in the crystal and the packing is based on pi-pi stacking with interplanar spacing 3.400 å, typical of aromatic molecules with potential for displaying useful optical properties.

Epithelial ovarian cancer remains the most lethal gynecologic malignancy despite advances in treatment. The standard management generally involves a combination of surgical tumor debulking and chemotherapy. Over the decades, chemotherapy for ovarian cancer has evolved and currently involves a combination of intravenous platinum and taxane chemotherapy. Over the past decade, three randomized phase III trials have been reported, and all have demonstrated a significant survival advantage for intraperitoneal compared with intravenous chemotherapy. However, there are potential barriers and controversies related to the administration of intraperitoneal chemotherapy in ovarian cancer patients. In this review, we discuss the evolution and current management considerations of chemotherapy for the treatment of epithelial ovarian cancer.