Unmutated IGHV at diagnosis in patients with early stage CLL independently predicts for shorter follow-up time to first treatment (TTFT).

The mutational status of the IGHV gene is routinely assessed in patients with chronic lymphocytic leukaemia (CLL), since it is both prognostic of clinical outcome and predictive of response to treatment. This study evaluates the IGHV mutational status, assessed in newly diagnosed CLL patients, as a stand-alone predictor of time to first treatment (TTFT). We analysed the data of 236 CLL patients, diagnosed at our centre between January 2004 and September 2020, with a minimum follow-up period of 3.

Multi-Gram Scale Synthesis and Characterization of Mometasone Furoate EP Impurity C.

Mometasone furoate is a synthetic corticosteroid used in the treatment of skin inflammatory conditions, hay fever and asthma. The industrial manufacturing routes to mometasone furoate are generally accompanied by the formation of numerous process impurities that need to be detected and quantified, as requested by regulatory authorities. The ready availability of such impurities in the required quantity and purity is therefore essential for toxicological studies, analytical method development and process validation.

Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography.

A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values.

Boosting Immunity and Management against Wheat Diseases by a Sustainable, Circular Nanostructured Delivery Platform.

Fusarium head blight (FHB) and Fusarium crown rot (FCR) are managed by the application of imidazole fungicides, which will be strictly limited by 2030, as stated by the European Green Deal. Here, a novel and eco-sustainable nanostructured particle formulation (NPF) is presented by following the principles of the circular economy. Cellulose nanocrystals (CNC) and resistant starch were obtained from the bran of a high amylose (HA) bread wheat and employed as carrier and excipient, while chitosan and gallic acid were functionalized as antifungal and elicitor active principles.

Sustainable Protocols for Cellulose Nanocrystals Synthesis from Tomato Waste and Their Antimicrobial Properties against pv. .

Nanotechnology is rapidly gaining ground in crop protection, with the growing quest for sustainable nanopesticides and nanocarriers for plant pathogen management. Among them, cellulose nanocrystals (CNC) are emerging as innovative agrofood-waste-derived antimicrobial materials. In this work, new chemical and enzymatic CNC extraction methods from tomato harvest residues were evaluated.

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls.

Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns.

A Green Nanostructured Pesticide to Control Tomato Bacterial Speck Disease.

Bacterial speck disease, caused by pv. (Pst), is one of the most pervasive biological adversities in tomato cultivation, in both industrial and in table varieties. In this work synthesis, biochemical and antibacterial properties of a novel organic nanostructured pesticide composed of chitosan hydrochloride (CH) as active ingredient, cellulose nanocrystals (CNC) as nanocarriers and starch as excipient were evaluated.

Recent advances in urea- and thiourea-containing compounds: focus on innovative approaches in medicinal chemistry and organic synthesis.

Urea and thiourea represent privileged structures in medicinal chemistry. Indeed, these moieties constitute a common framework of a variety of drugs and bioactive compounds endowed with a broad range of therapeutic and pharmacological properties. Herein, we provide an overview of the state-of-the-art of urea and thiourea-containing pharmaceuticals.

Adenosine deaminase - A target for new piperazine derivatives.

The level of adenosine deaminase (ADA) activity increases in pathological effusions. Therefore, the concentration of its substrate, anti-inflammatory adenosine, decreases, thereby aggravating inflammation. Hence, the quest for ADA inhibiting compounds is an actual problem in medicine and pharmacology.

One Key and Multiple Locks: Substrate Binding in Structures of Tryptophan Dioxygenases and Hydroxylases.

Since its discovery at the beginning of the past century, the essential nutrient l-Tryptophan (l-Trp) and its catabolic pathways have acquired an increasing interest in an ever wider scientific community for their pivotal roles in underlying many important physiological functions and associated pathological conditions. As a consequence, enzymes catalyzing rate limiting steps along l-Trp catabolic pathways - including IDO1, TDO, TPH1 and TPH2 - have turned to be interesting drug targets for the design and development of novel therapeutic agents for different disorders such as carcinoid syndrome, cancer and autoimmune diseases. This article provides a fresh comparative overview on the most recent advancements that crystallographic studies, biophysical and computational works have brought on structural aspects and molecular recognition patterns of these enzymes toward l-Trp.

The detection of circulating plasma cells may improve the Revised International Staging System (R-ISS) risk stratification of patients with newly diagnosed multiple myeloma.

The Revised International Staging System (R-ISS) stratifies patients affected by Multiple Myeloma (MM) into three distinct risk groups: R-ISS I [ISS Stage I, Standard-Risk cytogenetics and normal Lactase DeHydrogenase (LDH)], R-ISS III (ISS stage III and either high-risk cytogenetics or high LDH) and R-ISS II (any other characteristics). With the aim to verify whether the three R-ISS groups could be divided into subgroups with different prognostic factors based on the detection of Circulating Plasma Cells (CPCs) at diagnosis, in this retrospective analysis, we evaluated 161 patients with MM treated at our centre between 2005 and 2017. In all, 57 patients (33·9%) were staged as R-ISS III, 98 (58·3%) as R-ISS II and six (3·6%) as R-ISS I.

Fragment based drug design and diversity-oriented synthesis of carboxylic acid isosteres.

The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery stages for a better analog design. Herein in this work, to enable decision making on a project, we have synthesized by employing a Diversity-Oriented Synthetic (DOS) methodology, a small library of molecular fragments endowed with acidic properties.

Quantitative analysis of cucurbitane-type triterpenes in Ibervillea sonorae extracts: Relationship study with their antiproliferative activity.

Ibervillea sonorae (Cucurbitaceae) is a Mexican plant commonly used by local population for its hypoglycaemic activity. Root extracts showed also other different biological activities, including antimicrobial, antifungal, antioxidant and anti-inflammatory activity. Main components of this plant are cucurbitacins, steroid-like triterpenes that possess, among others, antiproliferative activity.

New Insights from Crystallographic Data: Diversity of Structural Motifs and Molecular Recognition Properties between Groups of IDO1 Structures.

A large number of crystallographic structures of IDO1 in different ligand-bound and -unbound states have been disclosed over the last decade. Yet, only a few of them have been exploited for structure-based drug design (SBDD) campaigns. In this study, we analyzed the structural motifs and molecular-recognition properties of three groups of IDO1 structures: 1) structures containing the heme group and inhibitors in the catalytic site; 2) heme-free structures of IDO1; 3) substrate-bound structures of IDO1.

Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines.

In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak IB column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica gel was used for the enantioselective HPLC analysis of chiral imidazolines synthesized in the frame of hit-to-lead explorations and designed for exploring the effect of diverse amide substitutions. Very profitably, reversed-phase (RP) conditions succeeded in resolving the enantiomers in nine out of the 10 investigated enantiomeric pairs, with α values always higher than 1.

Dexpramipexole blocks Nav1.8 sodium channels and provides analgesia in multiple nociceptive and neuropathic pain models.

Selective targeting of sodium channel subtypes Nav1.7, Nav1.8, and Nav1.

The Relationship between and Branched-Chain Amino Acids Content in Composite Cow Milk.

The early diagnosis of mastitis is an essential factor for the prompt detection of the animal for further actions. In fact, if not culled, infected cows must be segregated from the milking herd and milked last, or milked with separate milking units. Besides microbiological analysis, the somatic cell count (SCC) commonly used as predictor of intramammary infection, frequently lead to a misclassification of milk samples.

Hydrophobic Amino Acid Content in Onions as Potential Fingerprints of Geographical Origin: The Case of .

In this study, we were interested in comparing the amino acid profile in a specific variety of onion, , produced in two different Italian sites: the Cannara (Umbria region) and Imola (Emilia Romagna region) sites. Onions were cultivated in a comparable manner, mostly in terms of the mineral fertilization, seeding, and harvesting stages, as well as good weed control. Furthermore, in both regions, the plants were irrigated by the water sprinkler method and subjected to similar temperature and weather conditions.

Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites.

Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified.

Chiral separation of helical chromenes with chloromethyl phenylcarbamate polysaccharide-based stationary phases.

Two chloromethyl phenylcarbamate-based chiral stationary phases, one containing an amylose-type chiral selector (Lux Amylose 2, from Phenomenex) and the other a cellulose-type one (Lux Cellulose-4, from Phenomenex), were successfully used for the chiral resolution of three helical chromenes featuring a helicene-like structure. The compound bearing a phenyl substituent on the helicene-like structure was enantioresolved at 25°C with Lux Cellulose-4 and a n-hexane/1-propanol 99:1 v/v eluent. With a n-hexane/2-propanol 99.

Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors.

Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the molecular interactions with the target, we discuss only those ones acting against Wnt cancer cell lines.