PDE4 Inhibitors: Profiling Hits through the Multitude of Structural Classes

Cyclic nucleotide phosphodiesterases 4 (PDE4) are a family of enzymes which specifically promote the hydrolysis and degradation of cAMP. The inhibition of PDE4 enzymes has been widely investigated as a possible alternative strategy for the treatment of a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma, as well as psoriasis and other autoimmune disorders. In this context, the identification of new molecules as PDE4 inhibitors continues to be an active field of investigation within drug discovery. This review summarizes the medicinal chemistry journey in the design and development of effective PDE4 inhibitors, analyzed through chemical classes and taking into consideration structural aspects and binding properties, as well as inhibitory efficacy, PDE4 selectivity and the potential as therapeutic agents

A Data-Driven Slip Estimation Approach for Effective Braking Control under Varying Road Conditions

The performances of braking control systems for robotic platforms, e.g., assisted and autonomous vehicles, airplanes and drones, are deeply influenced by the road-tire friction experienced during the maneuver. Therefore, the availability of accurate estimation algorithms is of major importance in the development of advanced control schemes. The focus of this paper is on the estimation problem. In particular, a novel estimation algorithm is proposed, based on a multi-layer neural network. The training is based on a synthetic data set, derived from a widely used friction model. The open loop performances of the proposed algorithm are evaluated in a number of simulated scenarios. Moreover, different control schemes are used to test the closed loop scenario, where the estimated optimal slip is used as the set-point. The experimental results and the comparison with a model based baseline show that the proposed approach can provide an effective best slip estimation

Basic knowledge and new advances in panoramic radiography imaging techniques: A narrative review on what dentists and radiologists should know

Objectives: A panoramic radiograph (PAN) is the most frequently diagnostic imaging technique carried out in dentistry and oral surgery. The correct performance of image acquisition is crucial to obtain adequate image quality. The aim of the present study is to (i) review the principles of PAN image acquisition and (ii) describe positioning errors and artefacts that may affect PAN image quality. Methods: Articles regarding PAN acquisition principles, patient’s positioning errors, artefacts, and image quality were retrieved from the literature. Results: Head orientation is of the utmost importance in guaranteeing correct image acquisition. Symmetry, occlusal plane inclination, mandibular condyles localization, cervical spine position, aspect of upper teeth root apexes, exposure parameters, and metal and motion artefacts are factors that greatly affect the image quality of a successful PAN. Conclusions: Several factors are the basis for PAN performance; therefore, a systematic approach that takes into account correct patient positioning and preparation is strongly suggested to improve overall examination quality

Optimization of 4-amino-pyridazin-3(2H)-one as a valid core scaffold for FABP4 inhibitors

Current clinical research suggests that fatty acid-binding protein 4 inhibitors (FABP4is), which are of biological and therapeutic interest, may show potential in treating cancer and other illnesses. We sought to uncover new structures through the optimization of the previously reported 4-amino and 4-ureido pyridazinone-based series of FABP4is as part of a larger research effort to create more potent FABP4 inhibitors. This led to the identification of 14e as the most potent analog with IC₅₀ = 1.57 μM, which is lower than the IC₅₀ of the positive control. Advanced modeling investigations and in silico absorption, distribution, metabolism, and excretion - toxicity calculations suggested that 14e represents a potential candidate for in vivo studies such as FABP4i

Further studies on pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective human A1 adenosine receptor antagonists.

A new series of pyrazolo[1',5':1,6]pyrimido[4,5-dlpyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays on human A(1), A(2A) and A(3) adenosine receptors. Most of the compounds showed high selectivity of action towards A(1) receptor and high affinity with K-i values in the low nanomolar range. The pharmacological profile of the most active molecules towards A(1) adenosine receptors was evaluated in cAMP functional assay. Compounds demonstrated their ability to completely counteract the effect of the agonist NECA, thus demonstrating their antagonist profile. Moreover, the most interesting compound, tested in the mouse passive avoidance, exhibited an antiamnesic effect at the doses of 10 and 30 mg/kg. (C) 2014 Published by Elsevier Masson SAS

Cancer incidence in Italian contaminated sites

INTRODUCTION: The incidence of cancer among residents in sites contaminated by pollutants with a possible health impact is not adequately studied. In Italy, SENTIERI Project (Epidemiological study of residents in National Priority Contaminated Sites, NPCSs) was implemented to study major health outcomes for residents in 44 NPCSs. METHODS: The Italian Association of Cancer Registries (AIRTUM) records cancer incidence in 23 NPCSs. For each NPCSs, the incidence of all malignant cancers combined and 35 cancer sites (coded according to ICD-10), was analysed (1996-2005). The observed cases were compared to the expected based on age (5-year period,18 classes), gender, calendar period (1996-2000; 2001-2005), geographical area (North-Centre and Centre-South) and cancer sites specific rates. Standardized Incidence Ratios (SIR) with 90% Confidence Intervals were computed. RESULTS: In both genders an excess was observed for overall cancer incidence (9% in men and 7% in women) as well as for specific cancer sites (colon and rectum, liver, gallblad-der, pancreas, lung, skin melanoma, bladder and Non Hodgkin lymphoma). Deficits were observed for gastric cancer in both genders, chronic lymphoid leukemia (men), malignant thyroid neoplasms, corpus uteri and connective and soft-tissue tumours and sarcomas (women). DISCUSSION: This report is, to our knowledge, the first one on cancer risk of residents in NPCSs. The study, although not aiming to estimate the cancer burden attributable to the environment as compared to occupation or life-style, supports the credibility of an etiologic role of environmental exposures in contaminated sites. Ongoing analyses focus on the interpretation of risk factors for excesses of specific cancer types overall and in specific NPCSs in relation to the presence of carcinogenic pollutants

Is lung ultrasound imaging a worthwhile procedure for severe acute respiratory syndrome coronavirus 2 pneumonia detection?

Objectives: We compared 2 imaging modalities in patients suspected of having coronavirus disease 2019 (COVID-19) pneumonia. Blinded to the results of real-time reverse transcriptase polymerase chain reaction (rRT-PCR) testing, lung ultrasound (LUS) examinations and chest computed tomography (CT) were performed, and the specific characteristics of these imaging studies were assessed. Methods: From March 15, 2020, to April 15, 2020, 63 consecutive patients were enrolled in this prospective pilot study. All patients underwent hematochemical tests, LUS examinations, chest CT, and confirmatory rRT-PCR. The diagnostic performance of LUS and chest CT was calculated with rRT-PCR as a reference. The interobserver agreement of radiologists and ultrasound examiners was calculated. Ultrasound and CT features were compared to assess the sensitivity, specificity, positive predictive value, and negative predictive value. Positive and negative likelihood ratios measured the diagnostic accuracy. Results: Nineteen (30%) patients were COVID-19 negative, and 44 (70%) were positive. No differences in demographics and clinical data at presentation were observed among positive and negative patients. Interobserver agreement for CT had a κ value of 0.877, whereas for LUS, it was 0.714. The sensitivity, specificity, positive predictive value, and negative predictive value of chest CT for COVID-19 pneumonia were 93%, 90%, 85%, and 95%, respectively; whereas for LUS, they were 68%, 79%, 88%, and 52%. On receiver operating characteristic curves, area under the curve values were 0.834 (95% confidence interval, 0.711–0.958) and 0.745 (95% confidence interval, 0.606–0.884) for chest CT and LUS. Conclusions: Lung ultrasound had good reliability compared to chest CT. Therefore, our results indicate that LUS may be used to assess patients suspected of having COVID-19 pneumonia