Dataset Information

Playing the Devil's Advocate: Should We Give a Second Chance to mTOR Inhibition in Renal Clear Cell Carcinoma? - ie Strategies to Revert Resistance to mTOR Inhibitors.

ABSTRACT: In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician's expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of this class of drugs. Moreover, we describe some of the possible strategies to overcome the mechanisms of resistance and their clinical experimentation, with particular focus on novel mTOR inhibitors and the combinations of mTOR inhibitors and other anti-cancer drugs.

SUBMITTER: Pezzicoli G

PROVIDER: S-EPMC8500499 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Playing the Devil's Advocate: Should We Give a Second Chance to mTOR Inhibition in Renal Clear Cell Carcinoma? - ie Strategies to Revert Resistance to mTOR Inhibitors.

Pezzicoli Gaetano G Filoni Elisabetta E Gernone Angela A Cosmai Laura L Rizzo Mimma M Porta Camillo C

Cancer management and research 20211004

In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician's expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of th ...[more]

PMID: 34675658

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Project description:The main objective of this research was to determine the existence of relative age effect (RAE) in five European soccer leagues and their second-tier competitions. Even though RAE is a well-known phenomenon in professional sports environments it seems that the effect does not decline over the years. Moreover, additional information is required, especially when taking into account second-tier leagues. Birthdates from 1,332 first-tier domestic players from France, England, Spain, Germany and Italy and birthdates from 1,992 second-tier domestic players for the 2014/2015 season were taken for statistical analysis. In addition to standard statistical tests, the data were analyzed using econometric techniques for count data using Poisson and negative binomial regressions. The results obtained confirmed a biased distribution of birthdates in favor of players born earlier in the calendar year. For all of the five first-tier soccer leagues there was an unequal distribution of birthdates (France χ2 = 40.976, P<0.001; England χ2 = 21.892, P = 0.025; Spain χ2 = 24.690, P = 0.010; Germany χ2 = 22.889, P = 0.018; Italy χ2 = 28.583, P = 0.003). The results for second-tier leagues were similar (France χ2 = 46.741, P<0.001; England χ2 = 27.301, P = 0.004; Spain χ2 = 49.745, P<0.001; Germany χ2 = 30.633, P = 0.001; Italy χ2 = 36.973, P<0.001). Econometric techniques achieved similar results: estimated effect of month of birth, i.e., long-term RAE on players' representativeness, is negative (statistically significant at the 1% level). On average, one month closer to the end of the year reduces the logs of expected counts of players by 6.9%. Assuming this effect as linear, being born in the month immediately before the cut-off date (i.e., December/August), reduces the logs of expected counts of players by approximately 75.9%. Further, ID (index of discrimination, that is, the ratio between the expected counts of players born in the middle of the first and the twelfth month of the selection year) is 2.13 and 2.22 for the first- and second-tier, respectively. In other words, in the top five European first-tier and second-tier leagues, one should expect the number of players born in the first month of the calendar year to be twice the number of those born in the last month. The RAE in the second-tiers is the same as in the first-tiers, so it appears that there is no second chance for later born players. This reduces the chances to recover talented players discarded in youth simply because of lower maturity.

Project description:BackgroundIndividuals with borderline personality disorder (BPD) frequently alter between idealizing and devaluing other persons, which has been linked to an increased tendency to update self-relevant beliefs and impressions. We hypothesized that increased impression updating could stem from reduced attitude contextualization, i.e., a process in which impression-disconfirming information is linked to contextual cues.MethodsIndividuals diagnosed with BPD and controls (recruited online, with unknown diagnostic status) completed an impression formation paradigm. They first learned about the positive or negative behaviors of others in one Context A (e.g., Person 1 is helpful), followed by learning about behaviors of the opposite valence in a second Context B (Person 1 is rude). We also manipulated between participants whether the observed behaviors were directed toward the study participants (self-relevant) or, more generally, at other people (other-relevant). The contexts were marked by differently-colored backgrounds (e.g., yellow vs. blue), to avoid influences of prior knowledge or experiences. After exposure to information in both contexts, participants rated their impressions of the persons in Context A, Context B, and, crucially, a previously unknown Context C (white background). We examined whether the initial or an updated impression (re-)emerged in Context C.ResultsInitial impressions remained stable and dominated the ratings of controls across contexts A, B, and C for both self-relevant and other-relevant behaviors, consistent with contextualizing impression-disconfirming information. As expected, however, individuals with BPD only showed updated impression ratings in Context C for self-relevant behaviors, consistent with the assumed reduced tendency to contextualize impression-disconfirming self-relevant information. Further exploratory analyses suggest that more severe BPD symptoms predicted more pronounced impression updating in the self-relevant condition.ConclusionsThe findings help to illuminate the mechanisms underlying interpersonal problems in individuals with BPD. People with BPD are not just more inclined to discard positive first impressions but to re-evaluate disliked others when they behave positively, contributing to the volatility of interactions with others. Contextualization has known and modifiable antecedents, and the study may thus provide potential targets for therapeutic intervention. Future studies will need to replicate the findings with specified controls.

Dataset Information

Playing the Devil's Advocate: Should We Give a Second Chance to mTOR Inhibition in Renal Clear Cell Carcinoma? - ie Strategies to Revert Resistance to mTOR Inhibitors.

Publications

Playing the Devil's Advocate: Should We Give a Second Chance to mTOR Inhibition in Renal Clear Cell Carcinoma? - ie Strategies to Revert Resistance to mTOR Inhibitors.

Similar Datasets

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