Jakobsenmoesgaard5887

Glucocorticoids are widely used for therapy of hematological malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, ~50% of top putative REDD1 inhibitors selected by bioinformatics screening of LINCS database were PI3K/Akt/mTOR inhibitors. We selected Wortmannin, LY294002 and AZD8055 for our studies, and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it towards therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that co-administration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematological malignancies using PI3K/Akt/mTOR inhibitors.Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacological inhibitors of these kinases function to inhibit cell cycle progression and exert other important effects on the tumor and host environment. Due to their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the anti-tumor effects of cytotoxic chemotherapy in tumors that are CDK4/6 dependent. However, there are multiple preclinical studies that illustrate potent cooperation between CDK4/6i and chemotherapy. Furthermore, the combination of CDK4/6i and chemotherapy is being tested in clinical trials to both enhance anti-tumor efficacy and limit toxicity. Exploitation of the non-canonical effects of CDK4/6i could also provide an impetus for future studies in combination with chemotherapy. Thus, while seemingly mutually exclusive mechanisms are at play, the combination of CDK4/6 inhibition and chemotherapy could exemplify rational medicine.Antibody drug conjugates (ADCs) are targeted agents that have shown promise in treating cancer. A central challenge in development of ADCs is the relatively narrow therapeutic index observed in clinical studies. Patient selection strategies based on expression of the target in tumors have the potential to maximize benefit and provide the best chance of clinical success; however, implementation of biomarker-driven trials can be difficult both practically and scientifically. We conducted a survey of recent clinical experience from early phase ADC trials completed between 2000 and 2019, to (i) evaluate the different approaches to patient selection currently being used and (ii) assess whether there is evidence that target expression is associated with clinical activity. Our analysis of patient selection strategies indicates that optimal trial design for early stage trials should be based on multiple factors, including prevalence and heterogeneity of target expression among intent-to-treat patients, as well as biological factors influencing expression of cell surface and soluble target. To ensure a high probability of success, early implementation of patient selection strategies centered around target expression are pivotal to development of ADCs. In this review, we propose a strategic approach that can be applied for optimization of trial design.During the COVID-19 pandemic, the media have repeatedly praised healthcare workers for their 'heroic' work. Although this gratitude is undoubtedly appreciated by many, we must be cautious about overuse of the term 'hero' in such discussions. The challenges currently faced by healthcare workers are substantially greater than those encountered in their normal work, and it is understandable that the language of heroism has been evoked to praise them for their actions. Yet such language can have potentially negative consequences. Here, I examine what heroism is and why it is being applied to the healthcare workers currently, before outlining some of the problems associated with the heroism narrative currently being employed by the media. Healthcare workers have a clear and limited duty to treat during the COVID-19 pandemic, which can be grounded in a broad social contract and is strongly associated with certain reciprocal duties that society has towards healthcare workers. I argue that the heroism narrative can be damaging, as it stifles meaningful discussion about what the limits of this duty to treat are. It fails to acknowledge the importance of reciprocity, and through its implication that all healthcare workers have to be heroic, it can have negative psychological effects on workers themselves. I conclude that rather than invoking the language of heroism to praise healthcare workers, we should examine, as a society, what duties healthcare workers have to work in this pandemic, and how we can support them in fulfilling these.Some ethicists assert that there is a consensus that maximising medical outcomes takes precedence as a principle of resource allocation in emergency triage of absolutely scarce resources. But the nature of the current severe acute respiratory syndrome-related coronavirus 2 pandemic and the history of debate about balancing equity and efficiency in resource allocation do not support this assertion. I distinguish a number of concerns with justice and balancing considerations that should play a role in critical care triage policy, focusing on discrimination and on fundamental egalitarian and social justice concerns.Objective To determine predicting factors and frequency of phenoconversion from pure autonomic failure (PAF) into a synucleinopathy with motor or cognitive involvement of multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB). Methods We performed a retrospective review of all PAF patients from 2001-2011 evaluated at Mayo Clinic, Rochester. Clinical follow-up and patient telephone calls were used to assess for development of symptoms and diagnosis of MSA, PD or DLB. Clinical and laboratory variables were extracted with factors predictive of evolution assessed using group comparison, odds ratio, and logistical regression. Results Among 275 patients with PAF at presentation, 67 (24%) phenoconverted to a synucleinopathy with motor or cognitive involvement; 34 met criteria for MSA while 33 met criteria for PD or DLB. Age of onset was younger in MSA phenoconverters. Selleck CAL-101 Clinical features at presentation influenced phenoconversion severe bladder symptoms were more common in MSA phenoconverters; subtle motor signs were more frequent in MSA and PD/DLB phenoconverters.