Abemaciclib: A CDK4/6 inhibitor for the treatment of HR+/HEeR2- advanced breast cancer

Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials

Inhibition of RNA helicases of ssRNA⁺ virus belonging to <i>Flaviviridae</i>, <i>Coronaviridae</i> and <i>Picornaviridae</i> families

Many viral pathogens encode the motor proteins named RNA helicases which display various functions in genome replication. General strategies to design specific and selective drugs targeting helicase for the treatment of viral infections could act via one or more of the following mechanisms: inhibition of the NTPase activity, by interferences with ATP binding and therefore by limiting the energy required for the unwinding and translocation, or by allosteric mechanism and therefore by stabilizing the conformation of the enzyme in low helicase activity state; inhibition of nucleic acids binding to the helicase; inhibition of coupling of ATP hydrolysis to unwinding; inhibition of unwinding by sterically blocking helicase translocation. Recently, by in vitro screening studies, it has been reported that several benzotriazole, imidazole, imidazodiazepine, phenothiazine, quinoline, anthracycline, triphenylmethane, tropolone, pyrrole, acridone, small peptide, and Bananin derivatives are endowed with helicase inhibition of pathogen viruses belonging to Flaviviridae, Coronaviridae, and Picornaviridae families

Corticosteroid switch after progression on abiraterone acetate plus prednisone

Introduction: Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone. Materials and Methods: The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option. Results: A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223. Conclusion: Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone

Influence of pre-fermentative addition of aqueous solution tannins extracted from oak wood (Quercus petraea) on the composition of Grillo wines

In this research, the chemical characterization of fxed and volatile compounds of two diferent tannins in aqueous solution (Pratiko® L-Harvest and L-Fruit) extracted from oak wood, has been studied. The infuence of the above tannins, at diferent concentrations, on the alcoholic fermentation kinetics and on the composition and sensorial characteristics of a white wine were then evaluated. The wines added tannins in aqueous solution compared to control wines showed signifcant diferences in fxed compounds (colloids, polyphenols and ellagitannins) and volatile compounds (phenolic aldehydes, volatile phenols, furanic and piranic compounds). The diferences of aqueous solution tannins extracted from oak wood were partly due to the drying/maturing and roasting methods used in barrel production. Alcoholic fermentation was partially facilitated by the addition of tannins in aqueous solution. The wines obtained showed a higher content of ethyl esters of medium-chain fatty acids (from 22 to 31%) and, in some cases, higher acetate alcohols (from 15 to 28%), relevant to the olfactory sensations provided to the wines. The tannins added to the must before fermentation also made it possible to obtain an additional supply of polyphenols (from 25 to 85%) able to induce more complex sensory profles in the wines, with increased persistent taste notes

Modulation of LPS-induced nitric oxide production in intestinal cells by hydroxytyrosol and tyrosol metabolites:Insight into the mechanism of action

At intestinal level, after acute or chronic exposure to iNOS-derived NO, a toxic mechanism of action leads to inflammation and degenerative diseases. The aim of this study was to investigate the effect of glucuronide and sulfate metabolites of the extra virgin olive oil phenols tyrosol (Tyr) and hydroxytyrosol (HT), in comparison with their parent compounds, on the release of NO following exposure to a pro-inflammatory stimulus, the bacterial lipopolysaccharide (LPS). Human colon adenocarcinoma cells (Caco-2), differentiated as normal enterocytes, were treated with pathological concentrations of LPS, in order to stimulate iNOS pathway, which involves NF-ĸB activation through IĸBα phosphorylation and subsequent degradation induced by Akt or MAPKs. All the tested metabolites inhibited NO release induced by LPS, acting as inhibitors of iNOS expression, with an efficacy comparable to that of the parent compounds. HT and Tyr metabolites were effective in the inhibition of IĸBα degradation. No one of the compounds was able to inhibit Akt activation, whereas they modulated p38 and ERK1/2 MAPK. Obtained data show that HT and Tyr metabolites are able to prevent a pathological NO overproduction at intestinal level, where they concentrate, thus significantly contributing to the protective activity exerted by their parent compounds against inflammation

University setting and infrastructure for the people’s well-being: Universidad de Guadalajara in the face of the pandemic

From the beginning of the COVID-19 pandemic in Mexico, the University of Guadalajara (UdeG) placed its infrastructure, —particularly schools, laboratories, research centers and institutes, and departments related to the areas of health and human resources— at the service of civil authorities and the population in general. Before any other public university in Mexico, UdeG implemented and published measures to prevent COVID-19 infections, which began with the suspension of public meetings and face-to-face activities, and the installation of a Health Situation Room, and which continued with the Enabling of the Active COVID-19 Detection System, the reconversion of the Civil Hospitals of Guadalajara, until reaching the Design of the Vaccination Plan, to name a few. The objective of this article is to describe how actions related to the management of the university environment and infrastructure not only put the largest state public university in the country at people’s service as never before, but also about how we have been forced to reconceptualize the mission and vision of higher education based on the needs identified during the pandemic, from a humanistic, integrative, unitary, global and interdisciplinary perspective.Keyword: COVID-19, universities, setting and infrastructure, health sciences, innovatio

[1,2,3]triazolo[4,5-<i>H</i>]chinoloni: una nuova classe di promettenti chemioterapici antitubercolari

Alcuni acidi triazolo[4,5-h] e [4,5-f]chinoloncarbossilici angolari, sintetizzati in precedenza come antiinfettivi del tratto urinario, hanno mostrato interessanti valori di MIC90 nei confronti di M. tuberculosis H37Rv. Allo scopo di approfondire le nostre conoscenze sui rapporti struttura-attività di questa classe, abbiamo pertanto preparato una nuove serie di derivati