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

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

Psychometric properties of the Italian Tinnitus Functional Index (TFI)

Diversi questionari sono utilizzati per valutare l\u2019impatto dell\u2019acufene sulla qualit\ue0 della vita. Il Tinnitus Functional Index (TFI) proposto da Meikle et al, nel 2012, ha dimostrato propriet\ue0 eccellenti per misurare la gravit\ue0 e le modificazioni indotte dal trattamento degli acufeni, sia in ambito clinico che di ricerca. Lo scopo di questo studio \ue8 stato valutare le propriet\ue0 psicometriche della versione italiana del TFI, in particolare, l\u2019analisi fattoriale, la consistenza interna, l\u2019affidabilit\ue0 e la validit\ue0. La versione originale inglese del TFI \ue8 stata tradotta in italiano secondo la procedura translation - back translation; 137 partecipanti con acufeni da almeno 3 mesi (39,4% femmine, et\ue0: 18-80 anni, et\ue0 media: 48,26, SD: 14,08), reclutati presso la Tinnitus Clinic di Milano, hanno completato la versione italiana del TFI, il Tinnitus Handicap Inventory, la Beck Depression Inventory - Versione Primary Care e la scala di valutazione numerica per il fastidio. Una parte del campione, 57 pazienti, ha completato la versione italiana del TFI in una seconda visita, dopo 7-14 giorni, prima di ricevere qualsiasi tipo di trattamen- to, per ricavare i dati per la valutazione della riproducibilit\ue0. Le propriet\ue0 psicometriche sono state studiate attraverso un\u2019analisi fattoriale esplorativa ed il calcolo di misure di consistenza interna e affidabilit\ue0 test-retest. La validit\ue0 convergente \ue8 stata valutata mediante i coefficienti di correlazione con le restanti misure. La versione italiana del TFI ha mostrato una struttura a quattro fattori, parzialmente diversa dalla struttura originale a otto fattori. L\u2019adattamento italiano del TFI ha rivelato buoni livelli di consistenza interna (0,92 64 \u3b1 64 0,96) e affidabilit\ue0 test-retest (0,79 64 \u3b1 64 0,85). In termini di validit\ue0 convergente, ha mostrato buone correlazioni con i punteggi del THI (r = 0,77) e della scala del fastidio (r = 0,70) e correlazioni medie con i punteggi del BDI (r = 0,46). Le difficolt\ue0 nel riprodurre la struttura originale a otto fattori sono coerenti con altri studi di validazione del TFI nelle lingue europee. Nonostante tali discrepanze, la versione italiana del TFI ha mostrato una struttura fattoriale caratterizzata da alti livelli di affidabilit\ue0 e validit\ue0. Nel complesso, l\u2019adattamento italiano di TFI si \ue8 rivelato idoneo a misurare l\u2019impatto degli acufeni sulla vita quotidiana degli individui.Various questionnaires are used to assess the impact of tinnitus on the quality of life. The Tinnitus Functional Index (TFI) has excellent properties for scaling the severity of tinnitus and treatment-related changes in both clinical and research settings. The aim of this study was to evaluate the psychometric properties of the Italian version of the TFI with particular emphasis on factor analysis, internal consistency, reliability and validity. The original English version of the TFI was translated into Italian using the translation/back - translation process; 137 participants who were re- cruited at the Tinnitus Clinic in Milan and had suffered from tinnitus for at least three months (39.4% females, age: 18-80 years, mean age: 48.26, SD: 14.08) completed the Italian version of the TFI, the Tinnitus Handicap Inventory (THI), the Beck Depression Inventory - Primary Care Version (BDI-PC) and the Numeric Rating Scale of annoyance (NRS-A). Of these patients, 57 completed the TFI again at a second visit 7-14 days later, before undergoing any intervention, in order to provide data for reproducibility assessment. The psychometric properties were investigated using exploratory factor analysis and internal consistency and test-retest reliability instruments. The convergent validity of the TFI was evalu- ated using correlation coefficients obtained from the remaining measurements. The Italian TFI has a four-factor structure that was somewhat different from the original. The internal consistency proved to be good (0.92 64 \u3b1 64 0.96) as did the test-retest reliability (0.79 64 \u3b1 64 0.85). In terms of convergent validity, the TFI showed high correlations with the THI (r = 0.77) and the NRS-A (r = 0.70) scores, and moderate correlations with the BDI-PC scores (r = 0.46). The difficulties encountered when attempting to reproduce the original eight-factor structure were consistent with other studies in which the TFI was translated into European languages. In spite of this, the factorial structure of the Italian version of the TFI was characterised by high levels of reliability and validity. Overall, the Italian adaptation of the TFI was shown to be suitable to measure the impact of tinnitus on the daily lives of individuals

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

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS: This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS: Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS: Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival