Pharmacophore modelling as useful tool in the lead compounds identification and optimization

The goal of computer-aided molecular design methods in modern medicinal chemistry is to reduce the overall cost and time associated to the discovery and development of a new drug by identifying the most promising candidates to focus the experimental efforts on. Very often, many drug discovery projects have reached already a well-advanced stage before detailed structural data on the protein target have become available. A possible consequence is that often, medicinal chemists develop novel compounds for a target using preliminary structure–activity information, together with the theoretical models of interactions. Only responses that are consistent with the working hypothesis contribute to an evolution of the used models. Within this framework, the pharmacophore approach has proven to be successful, allowing the perception and understanding of key interactions between a receptor and a ligand[1]. In recent years, our research group exploited this useful modeling tool with the aim to identify new chemical entities and/or optimizing known lead compounds to obtain more active drugs in the field of antitumor, antiviral, and antibacterial drugs. In this communication, we present an overview of our recent works in which we used the pharmacophore modelling approach combined with induced fit docking, 3D-QSAR approach, and HTVS for the analysis of drug-receptor interactions and the discovery of new inhibitors of IKKβ, Bcl-xl, and c-kit tyrosine kinase, all targets involved into the initiation and the development of different types of cancer[2-5]

Lymph node metastases displaying lower Ki-67 immunostaining activity than the primary breast cancer

The aim of the study was to verify by Ki-67 immunostaining if any difference exists in the cell proliferating fraction between primary breast tumors (PTs) and matching positive axillary lymph nodes (ALNs). PATIENTS AND METHODS: Immunohistochemistry with the monoclonal antibody against Ki-67 was performed in 160 node-positive breast carcinomas and in their respective lymph node metastases. RESULTS: An increase of Ki-67 immunoreactive cells in ALN compared with that of PTs was observed in 84% of cases (ALN: mean 17%, PTs: mean 8%; p < 0.001), whereas 16% of the cases showed Ki-67 value two to six times lower in the ALNs than in the corresponding PTs (ALN: mean 3.2%, PTs mean 12.5%; p < 0.005). The decrease of Ki-67 positive cells in the ALN was independent from the histotype and the histological grade of the tumor. CONCLUSION: A different cell proliferation fraction between PTs and matching positive ALNs was demonstrated and underlined that the existence of a group of patients with decreased number of Ki-67 immunoreactive cells in lymph node metastases compared with that of the primary tumors could be taken into account in the choice of therapeutic strategy

Thymidylate synthase gene promoter polymorphisms are associated with TSmRNA expressions but not with microsatellite instability in colorectal cancer

Abstract BACKGROUND: Microsatellite instability (MSI) is a biological characteristic of most tumours, being involved in 85% of hereditary non-polyposis colorectal cancer (HNPCC). It also occurs in 10-15% of sporadic colorectal cancers (CRC). HNPCC appears to be caused by germline mutations in mismatch repair (MMR) genes, which are responsible for repairing single base-pair mismatches. MSI is also associated with a better response of CRC to adjuvant chemotherapy with fluoropyrimidines. We investigated any relationship between the MSI status and the TSmRNA expression, the polymorphisms of 5-Fluorouracil (5-FU cellular target, the enzyme thymidylate synthase (TS) and TS expression evaluated by means of immunohistochemistry. MATERIALS AND METHODS: A series of 80 colorectal cancers was evaluated for MSI and polymorphisms in the 3'UTR and the 5'UTR of the TS gene by a PCR assay. TSmRNA was quantified by real-time PCR and the TS expression by immunohistochemical assay. RESULTS: There was no significant association between the polymorphisms in the TS gene and the MSI or between the TSmRNA expression and the MSI status. CRC with a 3R/3R or 2R/3R genotype showed a significantly higher TSmRNA expression than those with the 2R/2R genotype (p = 0.001 and p = 0.028, respectively). Another significant association was found between the TSmRNA expression and the TS immunohistochemical determination (p = < 0.05). No association was found between the polymorphism of the 3'UTR and the TSmRNA expression. CONCLUSION: Our data show that there is no association between MSI status and the polymorphisms in the 3' and 5' UTRs and the TS expression. Tumour samples displaying the 3R/3R or 2R/3R genotype of TS have higher TSmRNA levels than the 2R/2R genotype. Polymorphic variant of the 3'UTR does not influence the TSmRNA level. We found a relationship between the TSmRNA expression, evaluated by real-time PCR, and with the TS level determined by immunohistochemical assay. Thus, genotyping of the 5'UTR and quantification of the TSmRNA expression in human CRC could be considered as predictors for response to SFU-based chemotherapy. The evaluation of the TS expression by means of immunohistochemistry assay remains a safe and reliable assay in CRC

Analisi e progettazione di un sistema di misure quantitative per il monitoraggio dei rischi finanziari delle garanzie di origine.

Lo scopo che si prefigge questo lavoro \ue8 quello di analizzare il mercato emergente delle Garanzie d\u2019Origine (GO), con particolare riferimento alla gestione dei rischi ad esse associati. Malgrado negli ultimi anni i volumi scambiati di queste certificazioni elettroniche abbiano segnato un incremento significativo, i mercati ad esse associati continuano ad essere poco trasparenti ed incompleti, per cui le informazioni e i dati a disposizione risultano essere molto limitati. A questo proposito, in letteratura non esiste quasi nessuno studio di riferimento, n\ue9 tantomeno una specifica normativa per la valutazione del rischio associato a tali strumenti. Questo lavoro suggerisce un possibile approccio alla gestione dei rischi associati alle GO che pu\uf2 costituire un utile riferimento per gli operatori che negoziano tali strumenti. A tal fine saranno presentate diverse tecniche di stima dei rischi di mercato, di liquidit\ue0 e di controparte che non devono essere considerate tra loro alternative, ma parti integranti di un approccio pi\uf9 generale. Poich\ue9 le serie storiche a disposizione sono brevi e caratterizzate da prezzi costanti per lunghi intervalli temporali, si intende proporre metodologie quantitative volte a valutare e gestire, in modo prudenziale, i principali rischi non sempre trattabili con approcci convenzionali

A conservative treatment for eosinophilic cystitis

Introduction: Eosinophilic cystitis is a rare condition which causes common symptoms and may mimic other conditions. Eosinophilic cystitis has several causes such as hypereosinophilic syndrome, inflammatory diseases, neoplasia, parasites or fungal infection, IgE-related diseases, Drug Reaction and Eosinophilia and Systemic Symptoms (DRESS) syndrome, or Churg-Strauss syndrome. Therefore, differential diagnosis is difficult. Case presentation: We report the case of a middle-aged man affected by eosinophilic cystitis with persistent hematuria and other peculiar symptoms that may be brought back to hypereosinophilic crisis. Conclusion: Conservative approach is preferred, avoiding radical cystectomy rather than corticosteroid, antihistaminic and second line therapy. Hyperbaric therapy is an innovative approach for severe relapsing gross hematuria without specific literature and should be studied for further indications

Biological aggressiveness evaluation in prostate carcinomas: Immunohistochemical analysis of PCNA and p53 in a series of Gleason 6 (3+3) adenocarcinomas

We selected 63 prostate tumors with Gleason's grade 6 (3+3), commonly showing both tubular and cribrous patterns. We compared in both patterns the expression of two of the most used biologic markers: PCNA and p53, with the aim to verify the validity of the Gleason's grading system to compare the morphologic grade with biologic aggressiveness and prognostic value. We did not find any statistical difference in the protein immunopositivity, indicating that both patterns could have identical biologic behaviour; then we confirmed the validity of Gleason's system for considering both tubular and cribrous patterns as an intermediate grade of tumoral differentiation. Moreover, we found a linear relationship between the increase of PCNA and the accumulation of mutated p53; this datum could confirm the hypothesis that p53 mutation is a late event in prostate carcinogenesis

Correlation among job-induced stress, overall well-being, and cardiovascular risk in Italian workers of logistics and distribution

IntroductionWork-related stress is an occupational risk that has been linked to the development of cardiovascular disease (CVD). While previous studies have explored this association in various work contexts, none have focused specifically on logistics and distribution personnel. These workers may be exposed to significant job stress, which potentially increases the risk of CVD.MethodsIn this study, we aimed to examine the relationship between work-related stress and cardiovascular risk in a sample of 413 healthy workers of a logistics and distribution company. To assess work-related stress and cardiovascular risk, we used the organisational well-being questionnaire proposed by the Italian National Anti-Corruption Authority, the Framingham Heart Study General Cardiovascular Disease (CVD) Risk Prediction Score and the WHO General Wellbeing Index (WHO-5).ResultsOur results revealed that individuals with low job support had a significantly higher CVD risk score and lower well-being index than those reporting high job support. Furthermore, workers with high-stress tasks showed higher well-being index scores than those with passive tasks. Approximately 58% of the subjects were classified as low CVD risk (CVD risk &lt;10%), approximately 31% were classified as moderate risk (CVD risk between 10 and 20%) and 11% were considered high risk (CVD risk &gt;20%). The overall median CVD risk for the population was moderate (6.9%), with individual scores ranging from 1 to 58%.DiscussionFurther analyses confirmed the protective effect of work support, also identifying physical inactivity, regular alcohol consumption and low educational level as factors contributing to an increased risk of CVD. Interestingly, factors such as job control and work support demonstrated a positive impact on psychological well-being. These results emphasise the importance of intervention strategies aimed at promoting health in the workplace. By addressing these combined factors, organisations can effectively reduce the risk of CVD and improve the general well-being of their workforce