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F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients. The most effective compound, PP028, showed synergy when combined with VX-809 and VX-661 but not with VX-445. By testing the ability of correctors to stabilize CFTR fragments of different length, we found that VX-809 is effective on the amino-terminal portion of the protein that includes the first membrane-spanning domain (amino acids 1–387). Instead, PP028 and VX-445 only show a stabilizing effect when the second membrane-spanning domain is included (amino acids 1–1181). Our results indicate that tricyclic pyrrolo-quinolines are a novel class of CFTR correctors that, similarly to VX-445, interact with CFTR at a site different from that of VX-809. Tricyclic pirrolo-quinolines may represent novel CFTR correctors suitable for combinatorial pharmacological treatments to treat the basic defect in CF.

Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3′,4':3,4]cyclohepta[1,2-d] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC50's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC50 value of 0.10 μM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments.

The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Sono riportati i risultati di un’indagine sulla qualità del latte d’asina prelevato presso quattro aziende siciliane da 27 animali nel corso della lattazione. La ricerca approfondisce alcuni aspetti relativi alla composizione ed all’assetto igienico-sanitario del prodotto, anche in funzione di quanto esplicitato nel Regolamento (CE) 853/2004 che include “altre specie” lattifere e sottolinea la futura emanazione di una normativa più specifica sulla qualità del latte e dei derivati. Gli AA auspicano che la presente indagine, unitamente ad altri studi sull’argomento, fornisca un contributo al fondamento scientifico sul quale dovrebbe essere basata la formulazione di specifici criteri normativi applicabili al latte d’asina; ciò soprattutto in funzione dell’utilizzo del prodotto per fini terapeutici in soggetti in età infantile. Sulla base dei risultati ottenuti il latte di asina si è confermato a basso contenuto in grasso e proteine e con un buon contenuto in lattosio. Piuttosto elevato è stato riscontrato il contenuto medio in urea. I valori in cellule somatiche e carica batterica totale, nonché l’assenza di batteri potenzialmente patogeni, hanno dimostrato la buona qualità igienico-sanitaria del prodotto esaminato. In conclusione, si incoraggiano interventi migliorativi applicabili al particolare settore produttivo, atti a garantire un’ottimale utilizzazione del latte. The results of a study on the quality of donkey’s milk from four farms in Sicily, from 27 animals during lactation, are showed. The article gives a better knowledge on some aspects of composition, sanitary and safety parameters of donkey’s milk, also in view of some specifications of EC regulation 853/2004. This latter includes “other species” as milk animal species and underlines the formulation of specific rules related to the quality of raw milk and of dairy products. The authors wish that the survey, as others of the same topic, will contribute to the scientific basis that would inspire the formulation of specific criteria for donkey’s milk, in view of the hoped-for future therapeutic use for infants. On the basis of the showed results, low fat and protein contents, but high lactose percentage, were confirmed for donkey’s milk. An high urea content was found. Means for somatic cell count and standard plate count and the absence of pathogens showed a good sanitary and safety condition of donkey’s milk samples. Concerted efforts are needed to improve the field of donkey’s farms management and to guarantee a better exploitation of donkey’s milk.

Disorders of the upper digestive tract have a high impact on modern society, in terms of both direct and indirect health care costs and of social burden. The most common presenting symptom is either dysphagia or dyspepsia. Discriminating specific diagnoses within this wide group of diseases requires sound clinical judgment and application of procedures to distinguish organic from nonorganic disease and to further characterize the functional or motility disturbance of nonorganic diseases. Non-radionuclide-based diagnostic techniques include both noninvasive tests (upper gastrointestinal barium series, ultrasonography, and breath test for gastric emptying) and invasive procedures (fiberoptic endoscopy, esophagogastroduodenoscopy, pharyngeal manometry, stationary esophageal manometry, 24-h pH monitoring, esophageal biliary reflux monitoring, multichannel intraluminal impedance, and electrogastrography). Some of these techniques are not well tolerated by patients or not widely available. Radionuclide transit/emptying scintigraphy provides a means of characterizing exquisite functional abnormalities with a set of low-cost procedures that are easy to perform and widely available, entail a low radiation burden, closely reflect the physiology of the tract under evaluation, are well tolerated and require minimum cooperation by patients, and provide quantitative data for better intersubject comparison and for monitoring response to therapy. Despite the relatively low degree of standardization both in the scintigraphic technique per se and in image processing, these methods have shown excellent diagnostic performance in several function or motility disorders of the upper digestive tract. Dynamic scintigraphy with a radioactive liquid or semisolid bolus provides important information on both the oropharyngeal and the esophageal phases of swallowing, thus representing a useful complement or even a valid alternative to conventional invasive tests (such as stationary esophageal manometry) for evaluating abnormalities of oropharyngoesophageal transit. Clinical applications of esophageal transit scintigraphy include disorders such as nutcracker esophagus, esophageal spasm, noncardiac chest pain of presumed esophageal origin, achalasia, esophageal involvement of scleroderma, and gastroesophageal reflux and monitoring of response to therapy (either medical or surgical treatment of disease-for example, organic disease such as esophageal cancer). Scintigraphy with a radiolabeled test meal represents the gold standard for evaluating gastric emptying, whereas more recent radionuclide methods include dynamic antral scintigraphy and gastric SPECT for assessing gastric accommodation. Clinical applications of gastric-emptying scintigraphy include, among others, evaluation of patients with dyspepsia and evaluation of gastric function in various systemic diseases affecting gastric emptying. The present review includes the proposal of clinical algorithms for evaluating patients with the main disorders of the upper digestive tract. These algorithms, originally derived from available literature, have been developed on the basis of a vast clinical experience in conjunction with the specialists more deeply involved in the care of patients with such disorders (medical and surgical gastroenterologists and nuclear medicine physicians). The role of radionuclide gastroesophageal motor studies is clearly identified in the various steps of patients' management, from the initial diagnostic approach to functional characterization to postoperative follow-up or monitoring of medical therapy.