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1.
Dtsch Arztebl Int ; 118(Forthcoming)2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33531114

RESUMO

BACKGROUND: Familial pancreatic carcinoma (FPC) is a rare hereditary tumor syndrome with a heterogeneous clinical phenotype. The study of FPC also contributes to a better understanding of the more common sporadic pancreatic ductal adenocarcinoma (PDAC). We report on the past 20 years' experience of the German National Case Collection for Familial Pancreatic Carcinoma (FaPaCa) of the German Cancer Aid (Deutsche Krebshilfe). METHODS: From 1999 onward, families in which at least two first-degree relatives had PDAC, and which did not meet the criteria for any other tumor syndrome, have been entered into the FaPaCa registry and analyzed both clinically and with molecular genetic techniques. Persons at risk are offered the opportunity to participate in an early detection program. RESULTS: From June 1999 to June 2019, 227 families (a total of 2579 persons) met the criteria for entry into the FaPaCa registry. PDAC was the sole tumor entity present in 37% of the families (95% confidence interval [31.1; 44.1]); in the remaining 63% [55.9; 68.9], other tumor types were present as well, particularly breast cancer (70 families, 31% [24.9; 37.3]), colon carcinoma (25 families, 11% [7.3; 15.8]) , and melanoma (22 families, 9.7% [6.2; 14.3]). The mode of inheritance of PDAC was autosomal dominant in 72% [65.5; 77.6] of the families. Predisposing germ-line mutations were found in 25 of the 150 (16.7%) families studied, in the following genes: BRCA2 (9 families), CDKN2A (5 families), PALB2 (4 families), BRCA1 (3 families), ATM (2 families), and CHEK2 (2 families). The early detection program revealed high-grade cancer precursor lesions or a PDAC in 5 of the participating 110 persons at risk (4.5%, [1.5; 10.3] during a period of observation of at least five years. CONCLUSION: The care of families with FPC is complex and should be provided in centers with the necessary expertise. Prospective, controlled longitudinal studies are needed to determine whether the screening of persons at risk for PDAC truly lessens mortality and is cost-effective.

2.
J Org Chem ; 85(20): 12823-12842, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-32885654

RESUMO

A series of 5,7,9-substituted 2-azapyrenes were synthesized for the first time. The synthesis relies on Brønsted acid promoted benzannulation of alkyne precursors prepared by palladium-catalyzed cross-coupling reactions. The synthetic strategy is efficient and the scope covers a variety of functional groups. The electrochemical behavior and photophysical properties of the products were investigated by UV-vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations.

3.
Org Biomol Chem ; 18(33): 6531-6536, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32766664

RESUMO

Several thieno[2,3-h]-/[3,2-h]- and [2,3-f]quinolines have been synthesised from 2,3-dihalogenated pyridines or -quinolines by site-selective Pd catalysed cross-coupling reactions and Brønsted acid mediated cycloisomerisations as the final key step. This newly developed synthetic strategy is used in a modular way to synthesize diverse regioisomeric derivatives, tolerates various functional groups, and proceeds with high selectivity, and the desired final products have been isolated in high overall yields.

4.
Comput Biol Chem ; : 107326, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739275

RESUMO

Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors.

5.
Updates Surg ; 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451836

RESUMO

One anastomosis gastric bypass/Mini Gastric Bypass (OAGB/MGB) is an emerging bariatric surgery (BS) technique. We evaluated and compared attitudes of bariatric surgeons and dietitians towards the considerations for choosing BS-type ("Decision-making"), the contributing factors to the rise of OAGB/MGB in Israel ("OAGB/MGB-rise") and notions regarding the occurrence of gastrointestinal (GI) symptoms and nutritional deficiencies following OAGB/MGB. Anonymous online surveys were distributed. The participants were asked to rate by a 10-point Likert scale (0 = not at all; 100 = very much/often) their attitudes towards "Decision-making", "OAGB/MGB-rise" and occurrence of GI symptoms and nutritional deficiencies following OAGB/MGB. For "Decision-making" and "OAGB/MGB-rise", items were considered prioritized where ≥ 50% of the group considered them as 'very-important' (rating ≥ 80). Data on age, sex, years-in-practice and main workplace were also collected. A total of 106 professionals participated in the survey (42 surgeons; 64 dietitians). The respective mean age, years-in-practice and sex were 52.3 ± 8.7 vs. 42.3 ± 9.0 years, 21.0 ± 10.8 vs. 15.5 ± 9.2 years and 85.7% vs. 3.1% males. The inter-observer agreement for prioritized items related to "Decision-making" was fair (Kappa = 0.250; P = 0.257) and both groups prioritized patient's BMI, comorbidities and compliance. The inter-observer agreement for prioritized items related to "OAGB/MGB-rise" was moderate (Kappa = 0.550; P = 0.099) and both groups prioritized ease of performance, shorter operation duration and failure of former restrictive BS. Surgeons reported lower occurrence of nutritional deficiencies and GI symptoms as adverse effects of OAGB/MGB (P ≤ 0.033). The study highlights the views of bariatric surgeons and dietitians concerning factors that underpin the rise of OABG/MGB in Israel and possible rates of GI symptoms and nutritional deficiencies associated with this modality.

6.
Med Chem ; 16(5): 689-702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31203806

RESUMO

BACKGROUND: The ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) terminate nucleotide signaling via the hydrolysis of extracellular nucleoside-5'-triphosphate and nucleoside- 5'-diphosphate, to nucleoside-5'-monophosphate and composed of eight Ca2+/Mg2+ dependent ectonucleotidases (NTPDase1-8). Extracellular nucleotides are involved in a variety of physiological mechanisms. However, they are rapidly inactivated by ectonucleotidases that are involved in the sequential removal of phosphate group from nucleotides with the release of inorganic phosphate and their respective nucleoside. Ectonucleoside triphosphate diphosphohydrolases (NTPDases) represent the key enzymes responsible for nucleotides hydrolysis and their overexpression has been related to certain pathological conditions. Therefore, the inhibitors of NTPDases are of particular importance in order to investigate their potential to treat various diseases e.g., cancer, ischemia and other disorders of the cardiovascular and immune system. METHODS: Keeping in view the importance of NTPDase inhibitors, a series of thiadiazolopyrimidones were evaluated for their potential inhibitory activity towards NTPDases by the malachite green assay. RESULTS: The results suggested that some of the compounds were found as non-selective inhibitors of isozyme of NTPDases, however, most of the compounds act as potent and selective inhibitors. In case of substituted amino derivatives (4c-m), the compounds 4m (IC50 = 1.13 ± 0.09 µM) and 4g (IC50 = 1.72 ± 0.08 µM) were found to be the most potent inhibitors of h-NTPDase1 and 2, respectively. Whereas, compound 4d showed the best inhibitory potential for both h-NTPDase3 (IC50 = 1.25 ± 0.06 µM) and h-NTPDase8 (0.21 ± 0.02 µM). Among 5a-t derivatives, compounds 5e (IC50 = 2.52 ± 0.15 µM), 5p (IC50 = 3.17 ± 0.05 µM), 5n (IC50 = 1.22 ± 0.06 µM) and 5b (IC50 = 0.35 ± 0.001 µM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. Interestingly, the inhibitory concentration values of above-mentioned inhibitors were several folds greater than suramin, a reference control. In order to determine the binding interactions, molecular docking studies of the most potent inhibitors were conducted into the homology models of NTPDases and the putative binding analysis further confirmed that selective and potent compounds bind deep inside the active pocket of the respective enzymes. CONCLUSION: The docking analysis proposed that the inhibitory activity correlates with the hydrogen bonds inside the binding pocket. Thus, these derivatives are of interest and may further be investigated for their importance in medicinal chemistry.

7.
Appl Physiol Nutr Metab ; 45(1): 81-90, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31163115

RESUMO

Cardiovascular complications contribute to higher morbidity and mortality in patients with anorexia nervosa. We aimed to study biomarkers of cardiovascular risk in anorexic, normal-weight, and obese adolescents with focus on complex cardiovascular autonomic regulation and early arteriosclerotic damage. We examined 20 adolescent girls with anorexia nervosa, 20 obese girls, and 20 healthy normal-weight controls. Collected data: body composition analysis, 5 min recordings of R-R intervals and beat-to-beat blood pressure (BP), and arterial stiffness evaluated using cardio-ankle vascular index (CAVI). Evaluated parameters: beat-to-beat heart rate and BP variability, haemodynamic parameters (total peripheral resistance (TPR) cardiac output), CAVI, and anthropometric indices, including novel body roundness index (BRI). Adolescents with anorexia nervosa had increased CAVI associated with lower arterial constriction indexed by low-frequency band of BP variability compared with normal-weight peers (p = 0.03, p = 0.04, respectively) and obese adolescents (p < 0.01, p = 0.01, respectively). After normalization of CAVI and TPR by BRI, the relationship between CAVI and TPR was significant for all groups with the highest slope in the anorexia nervosa group (R2 = 0.724, p < 0.01). This is the first study revealing early arteriosclerotic damage in anorexic girls with increased CAVI. Complex analysis of cardiovascular autonomic regulation, and early arteriosclerotic, hemodynamic, and anthropometric changes in spectrum anorexia nervosa, normal weight, and obesity could help to understand the mechanisms of increased cardiovascular risk in malnutrition. Novelty Girls with anorexia nervosa showed signs of early arteriosclerotic damage indexed by CAVI. Insufficient sympathetic cardiovascular control was found already in adolescents with anorexia nervosa. The effect of body composition on CAVI was best predicted by novel body roundness index.


Assuntos
Anorexia Nervosa , Hemodinâmica/fisiologia , Obesidade Pediátrica , Rigidez Vascular/fisiologia , Adolescente , Anorexia Nervosa/epidemiologia , Anorexia Nervosa/fisiopatologia , Criança , Estudos Transversais , Feminino , Humanos , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/fisiopatologia
8.
Beilstein J Org Chem ; 15: 2830-2839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807218

RESUMO

A two-step palladium-catalyzed procedure based on Suzuki-Miyaura cross coupling, followed by a double Buchwald-Hartwig reaction, allows for the synthesis of pharmaceutically relevant benzo[4,5]furo[3,2-b]indoles in moderate to very good yield. The synthesized compounds have been analyzed with regard to their inhibitory activity (IC50) of nucleotide pyrophosphatases h-NPP1 and h-NPP3. The activity lies in the nanomolar range. The results were rationalized based on docking studies.

9.
Cochrane Database Syst Rev ; 2019(11)2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31765002

RESUMO

BACKGROUND: Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide. OBJECTIVES: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines. SEARCH METHODS: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma. SELECTION CRITERIA: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated. MAIN RESULTS: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens. AUTHORS' CONCLUSIONS: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Humanos , Lenalidomida/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Talidomida/uso terapêutico
10.
Daru ; 27(2): 613-626, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31410781

RESUMO

BACKGROUND: Among the different types of cancers, breast cancer, bone cancer and cervical cancer are the most common gender specific cancer types that are affecting the women worldwide. Currently, many enzymatic and cellular pathways are known as drug targets for the treatment of cancer. Even though many improvements have been made in the therapy of various types of cancer, but the major disadvantage of available anti-cancer drugs is their non-selective behavior towards cancer cells as well as normal cells. OBJECTIVES: In the light of this fact, the searching of new compounds with selective behavior only towards cancer cells is critically important. Previously, we have identified several series of compounds as the potential inhibitors of these families. METHODS: Herein, we investigate quinolones and quinolines for their anti-cancer activity against breast cancer cells (MCF-7), bone marrow cancer cells (K-562) and cervical cancer cells (HeLa) by MTT assay. The most effective derivatives were further subjected to flow cytometry analysis followed by fluorescence microscopic analysis by using 4´,6-diamidine-2´-phenylindole (DAPI) and propidium staining (PI) staining. RESULTS: All the tested compounds were found selective only towards cancer cells. The identified compounds also induced either G2 or S-phase cell cycle arrest within the respective cancer cell line, chromatin condensation and the nuclear fragmentation, as well as maximum interaction with DNA. CONCLUSIONS: These results provide evidence that the characteristic chemical features of attached groups are the key factors for their anticancer effects and play a useful role in revealing the mechanisms of action in relation to the known compounds in future research programs. Graphical abstract Flow cytometric analysis of cell cycle using propidium iodide staining. Cell apoptosis observed under fluorescence microscope using DAPI and PI staining.


Assuntos
Fragmentação do DNA , Neoplasias/genética , Quinolinas/farmacologia , Quinolonas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células K562 , Células MCF-7 , Neoplasias/tratamento farmacológico
11.
Med Chem ; 15(8): 883-891, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223093

RESUMO

BACKGROUND: Previously, we have identified 3,3'-carbonyl-bis(chromones) (1a-h, 5e) and 3-(5-(benzylideneamino)thiozol-3-yl)-2H-chromen-2-ones (7a-j) as potent inhibitors of tissue non-specific alkaline phosphatase (TNAP). The present study was designed to investigate the cytotoxic and pro-apoptotic effect of the said derivatives. METHODS: The anti-proliferative effect of the derivatives was investigated in three cancer cell lines i.e., MCF-7, K-562, HeLa and normal BHK21 cells using MTT assay. The pro-apoptotic effect of the most potent derivatives was investigated by using flow cytometry, DAPI and PI staining and DNA binding studies. RESULTS: Among all the screened compounds, 1f, 1d, 1c (from 3,3'-carbonyl-bis(chromones), 7c, 7h and 7i (from 3-(5-(benzylideneamino)thiozol-3-yl)-2H-chromen-2-ones) exhibited remarkable growth inhibitory effects. Compounds 1f and 7c were found to be the most potent cytotoxic derivatives against MCF-7; 1d and 7h inhibited most of the proliferation of K-562 cells, whereas 1c and 7i showed maximum growth inhibition in HeLa cells. The identified compounds exerted lower micromolar potency against the respective cell line with significant selectivity over the normal cells (BHK-21). The identified compounds also induced either G2 or S-phase arrest within the respective cancer cells, chromatin condensation and nuclear fragmentation, as well as maximum interaction with DNA. CONCLUSIONS: These results provide evidence that the characteristic chemical features of attached groups are the key factors for their anticancer effects and play a useful role in revealing the mechanisms of action in relation to the known compounds in future research programs.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Medula Óssea/patologia , Neoplasias da Mama/patologia , Cromonas/química , Cromonas/farmacologia , Neoplasias do Colo do Útero/patologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos
12.
JMIR Res Protoc ; 8(5): e12061, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31094340

RESUMO

BACKGROUND: Philip Morris International (PMI) has developed a novel heat-not-burn tobacco product, Tobacco Heating System (THS), which is marketed under the brand name of IQOS with HEETS (IQOS). The aerosol generated by THS has substantially fewer toxicants than combustible cigarette smoke, although the extent of the reduction of harmful and potentially harmful constituents reported varies between studies. To evaluate the potential harm reduction associated with IQOS use, the assessment of the uptake and continued use of IQOS in the context of all other tobacco- and nicotine-containing products is crucial. In March 2018, PMI launched cross-sectional surveys in Germany, Italy, and the United Kingdom (Greater London) to estimate the prevalence and use patterns of IQOS and other tobacco- and nicotine-containing products use in these 3 markets following the commercialization of IQOS. This study describes the protocol of the surveys. OBJECTIVE: The objectives of these surveys are to estimate the prevalence of tobacco- and nicotine-containing products use; describe past and current patterns of use; and explore their associations with self-reported health, motivation to use, risk perceptions, and perceived aesthetic changes. METHODS: The overall design of the surveys is similar in all 3 countries. Repeated cross-sectional surveys are being conducted annually over 3 consecutive years (2018 to 2020) and in 2 samples: a representative sample of the general population and a sample of IQOS users. A total of 6085 adults per year will be selected from the general population for each survey through multistage stratified sampling, and participants will respond to face-to-face computer-assisted personal interviews. In addition, 1404, 1384, and 1246 IQOS users per year in Germany, Italy, and Greater London, respectively, will be randomly selected from the PMI IQOS user database and will be invited to complete the Web-based survey using computer-assisted self-interviews. The Smoking Questionnaire is used to assess the tobacco use patterns of the participants. RESULTS: The recruitment of the general population sample began in March 2018 and that of the IQOS user sample began in April 2018. The data collection is ongoing, and the results of the first year data analysis are expected to be available by June 2019. CONCLUSIONS: As the design of the 3 surveys is similar, the results will allow for cross-countries comparison of the prevalence of IQOS and other tobacco- and nicotine-containing products use as well as patterns of use and associated factors. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12061.

13.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866411

RESUMO

Cutaneous T-cell lymphoma (CTCL) may develop a highly malignant phenotype in its late phase, and patients may profit from innovative therapies. The plant extract indirubin and its chemical derivatives represent new and promising antitumor strategies. This first report on the effects of an indirubin derivative in CTCL cells shows a strong decrease of cell proliferation and cell viability as well as an induction of apoptosis, suggesting indirubin derivatives for therapy of CTCL. As concerning the mode of activity, the indirubin derivative DKP-071 activated the extrinsic apoptosis cascade via caspase-8 and caspase-3 through downregulation of the caspase antagonistic proteins c-FLIP and XIAP. Importantly, a strong increase of reactive oxygen species (ROS) was observed as an immediate early effect in response to DKP-071 treatment. The use of antioxidative pre-treatment proved the decisive role of ROS, which turned out upstream of all other proapoptotic effects monitored. Thus, reactive oxygen species appear as a highly active proapoptotic pathway in CTCL, which may be promising for therapeutic intervention. This pathway can be efficiently activated by an indirubin derivative.


Assuntos
Linfoma Cutâneo de Células T/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico
14.
Respir Physiol Neurobiol ; 259: 86-92, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30086386

RESUMO

Respiratory sinus arrhythmia (RSA) is an index of cardiovagal regulation, emotional and cognitive processing. RSA is quantified using heart rate variability (HRV) spectral analysis at respiratory-linked high-frequency band (HF-HRV) using Fast Fourier transformation (FFT) or autoregressive (AR) method, both requiring resampling of recordings - a potential source of error. We hypothesized that rarely used HRV time-frequency analysis with Lomb-Scargle periodogram (LSP) without resampling could be more sensitive to detect neurocardiac response to posture change than FFT and AR. Orthostasis (posture change from supine to standing) evoked significant decrease of HF-HRV well detectable by FFT, AR, and LSP. In contrast, during posture change from sitting to lying, significant increase of HF-HRV and peak HF was best detected using LSP. In regression analysis, the associations between RR-interval, HF-HRV, and peak HF were best detected when evaluated using LSP. Time-frequency HRV analysis with LSP could represent an important alternative to conventional FFT and AR methods for assessment of cardiovagal regulation indexed by RSA.


Assuntos
Frequência Cardíaca/fisiologia , Taxa Respiratória/fisiologia , Arritmia Sinusal Respiratória/fisiologia , Adolescente , Eletrocardiografia , Feminino , Análise de Fourier , Humanos , Masculino , Análise de Regressão , Estatísticas não Paramétricas , Fatores de Tempo
15.
Mol Carcinog ; 58(2): 258-269, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30320471

RESUMO

Melanoma represents a prime example demonstrating the success of targeted therapy in cancer. Nevertheless, it remained a deadly disease until now, and the identification of new, independent strategies as well as the understanding of their molecular mechanisms may help to finally overcome the high mortality. Both indirubins and TNF-related apoptosis-inducing ligand (TRAIL) represent promising candidates. Here, the indirubin derivative DKP-073 is shown to trigger apoptosis in melanoma cells, which is enhanced by the combination with TRAIL and is accompanied by complete loss of cell viability. Addressing the signaling cascade, characteristic molecular steps were identified as caspase-3 activation, downregulation of XIAP, upregulation of p53 and TRAIL receptor 2, loss of mitochondrial membrane potential, and STAT-3 dephosphorylation. The decisive step, however, turned out to be the early production of ROS already at 1 h. This was proven by antioxidant pretreatment, which completely abolished apoptosis induction and loss of cell viability as well as abrogated all signaling effects listed above. Thus, ROS appeared as upstream of all proapoptotic signaling. The data indicate a dominant role of ROS in apoptosis regulation, and the new pathway may expose a possible Achilles heel of melanoma.


Assuntos
Indóis/farmacologia , Melanoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/química , Melanoma/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
16.
J Org Chem ; 83(22): 14195-14202, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30376332

RESUMO

We report base-mediated reactions of 1-bromo-2-(2,2-difluorovinyl)benzenes with phenols followed by Pd-catalyzed intramolecular C-H arylation, which offers a novel route to a pharmaceutically relevant class of compounds, oxepines. Construction of these medium-sized ring structures proceeds as a one-pot two-step reaction through diaryl ketene acetals as intermediates. It allows to obtain various dibenz[ b, d]oxepine derivatives in moderate to high yields.

17.
Org Biomol Chem ; 16(35): 6543-6551, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30168561

RESUMO

An efficient two-step palladium catalyzed synthesis of furo[3,2-b:4,5-b']diindoles, a hitherto unknown symmetrical heterocyclic core structure, was developed. The synthesis is based on a regioselective Suzuki-Miyaura cross coupling reaction of tetrabromofuran and subsequent double N-arylation. Selected compounds were studied with regard to their optical and electrochemical properties. The compounds show fluorescence with high quantum yields and non-reversible oxidation events. The compounds possess similar HOMO-LUMO band gaps compared to their sulfur and nitrogen analogs. Variation of the substituents hardly affects the HOMO-LUMO gap, but allows for some fine-tuning of the electron affinity and ionization potential as well as quantum yields. The compounds prepared represent interesting candidates for the development of organic electronic materials.

18.
Int J Biol Macromol ; 117: 762-772, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29857108

RESUMO

Five different samples of chitosan based polyurethane bio-nanocomposites (PUBNCs) were synthesized by step growth polymerization technique. Five different diisocyanates were used by keeping hydroxyl terminated polybutadiene (HTPB)/1,4-butane diol (1,4-BDO)/chitosan (CS) and montmorillonite (MMT) clay ratios constant (PUR1-PUR5). For comparative studies, PUR-6 was prepared without CS and clay components. Molecular characterizations of polyurethane (PU) films were carried out by FTIR and NMR which was found to have confirmatory evidence of the proposed structures. X-ray diffraction angles (2θ), d-spacing and intensities of chitosan based samples (PUR1-PUR5) and PUR-6 indicated that crystalline behavior of PUBNCs is influenced by varying diisocyanate structures. TGA/DTA results revealed that chitosan increased thermal stability of PU samples; it also enhanced the mechanical strength and decreased the glass transition temperature (Tg) of all the samples. Based on the above mentioned facts this study suggests the best usage of PUs according to the operational and environmental conditions.


Assuntos
Quitosana/química , Dimerização , Isocianatos/química , Nanocompostos/química , Poliuretanos/química , Difração de Raios X , Temperatura
19.
Carbohydr Res ; 466: 30-38, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29499901

RESUMO

Palladium-catalyzed cross-couplings of O-peracylated and O-permethylated 2,6-anhydro-aldose tosylhydrazones with aryl halides were studied under thermic conditions in the presence of LiOtBu and phosphine ligands. The reactions gave the corresponding aryl substituted exo-glycals as mixtures of diastereomers in 11-75% yields. The transformations represent a new access to these types of glycomimetic compounds. The double bond of some aryl substituted exo-glycals was saturated to give good yields of benzylic C-glycosyl derivatives.


Assuntos
Carboidratos/química , Hidrazonas/química , Hidrocarbonetos Bromados/química , Paládio/química , Compostos de Tosil/química , Catálise , Conformação Molecular
20.
Med Chem ; 14(8): 809-817, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29473519

RESUMO

BACKGROUND: Alzheimer's Disease (AD) is the leading cause of dementia among the aging population. This devastating disorder is generally associated with the gradual memory loss, specified by a decrease of acetylcholine level in the cortex hippocampus of the brain due to hyperactivation of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). OBJECTIVE: Therefore, inactivation of AChE and BChE by inhibitors can increase the acetylcholine level and hence may be an encouraging strategy for the treatment of AD and related neurological problems. METHOD: In this contribution, two series of chromenone-based derivatives were tested by Ellmann's calorimetric method for AChE and BChE inhibition. RESULTS: All the compounds showed inhibitory activity against cholinesterases and some of them exhibited dual inhibition of AChE as well as BChE. The most potent inhibitor of AChE was 2l having an IC50 value of 0.08 ± 0.03 µM, while 3q inhibited the BChE with an IC50 value of 0.04 ± 0.01 µM. In case of dual inhibition, 3h showed an inhibitory concentration of 0.15 ± 0.01 µM for AChE, and 0.09 ± 0.01 µM for BChE. Molecular docking studies were performed to explore the probable binding modes of the most potent dual inhibitors. CONCLUSION: It can be hypothesized that the inhibitors are able to target cholinesterase pathways and may emerge as a suitable outset for the further development process.


Assuntos
Inibidores da Colinesterase/química , Cumarínicos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Cumarínicos/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Tacrina/química
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