The Goldilocks Time for Remdesivir - Is Any Indication Just Right?
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ABSTRACT:
SUBMITTER: Heil EL
PROVIDER: S-EPMC8757566 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:: We present Goldilocks: a Python package providing functionality for collecting summary statistics, identifying shifts in variation, discovering outlier regions and locating and extracting interesting regions from one or more arbitrary genomes for further analysis, for a user-provided definition of interesting.Goldilocks is freely available open-source software distributed under the MIT licence. Source code is hosted publicly at https://github.com/SamStudio8/goldilocks and the package may also be installed using pip install goldilocks. Documentation can be found at https://goldilocks.readthedocs.org: msn@aber.ac.ukSupplementary data are available at Bioinformatics online.
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Project description:The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right," we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control. SIGNIFICANCE: To maximize the synergy between chemotherapy and antitumor immune response, lymphodepleting therapy must be balanced in a "Goldilocks Window" of optimal dosing.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5302/F1.large.jpg.
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Project description:IntroductionFaculty and residents strive for appropriate autonomy and entrustment. Initial direct supervision of clinical care gradually shifts to increasing levels of resident independence over time. Faculty members are inconsistent in resident supervision leading to missed opportunities for resident independence.MethodsFamily medicine faculty workshop participants completed teaching style self-evaluations prior to discussion of clinical examples with excessive or insufficient autonomy. Participants reviewed real resident feedback examples to increase insight into teaching styles. Participants were presented with cases to discuss varying degrees of resident autonomy and entrustment. Learners committed to one specific behavior to calibrate the degree of autonomy they provide.ResultsOf the faculty, 113 members participated in the workshop with the majority (98%) finding the workshop relevant in helping them to identify strategies for reflecting on their degree of autonomy allowed and to look for appropriate situations for enhancing their resident entrustment.DiscussionThis interactive workshop provided clear ways for addressing the issue of independence versus control in supervision of patient care. It provided a feedback mechanism for educators who provide too much or too little autonomy for the best resident learning. Additionally, this conversation encouraged participants to engage in self-reflection on the autonomy given to their resident.
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Project description:To examine predictors of understanding preemptive CYP2D6 pharmacogenomics test results and to identify key features required to improve future educational efforts of preemptive pharmacogenomics testing.One thousand ten participants were surveyed after receiving preemptive CYP2D6 pharmacogenomics test results.Eighty-six percent (n = 869) of patients responded. Of the responders, 98% were white and 55% were female; 57% had 4 years or more of post-secondary education and an average age of 58.9?±?5.5 years. Twenty-six percent said that they only somewhat understood their results and 7% reported they did not understand them at all. Only education predicted understanding. The most common suggestion for improvement was the use of layperson's terms when reporting results. In addition, responders suggested that results should be personalized by referring to medications that they were currently using. Of those reporting imperfect drug adherence, most (91%) reported they would be more likely to use medication as prescribed if pharmacogenomic information was used to help select the drug or dose.Despite great efforts to simplify pharmacogenomic results (or because of them), approximately one-third of responders did not understand their results. Future efforts need to provide more examples and tailor results to the individual. Incorporation of pharmacogenomics is likely to improve medication adherence.Genet Med advance online publication 05 January 2017.
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Project description:Transforming growth factor (TGF)-? antagonizes mitogenic Ras signaling during epithelial regeneration, but TGF-? and Ras act synergistically in driving tumor progression. Insights into these apparently contradictory effects have come from recent detailed analyses of the TGF-? signaling process. Here, we summarize the different modes of TGF-?/Ras signaling in normal epithelium and neoplasms and show how perturbation of TGF-? signaling by Ras may contribute to a shift from tumor-suppressive to protumorigenic TGF-? activity during tumor progression. Smad proteins, which convey signals from TGF-? receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-? Type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. In epithelial homeostasis, TGF-?-mediated pSmad3C signaling opposes proliferative responses induced by mitogenic signals. During carcinogenesis, activation of cytoplasmic Ras-associated kinases including mitogen-activated protein kinase confers a selective advantage on benign tumors by shifting Smad3 signaling from a tumor-suppressive pSmad3C to an oncogenic pSmad3L pathway, leading to carcinoma in situ. Finally, at the edges of advanced carcinomas invading adjacent tissues, nuclear Ras-associated kinases such as cyclin-dependent kinases, together with cytoplasmic kinases, alter TGF-? signals to more invasive and proliferative pSmad2L/C and pSmad3L/C signaling. Taken together, TGF-? signaling specificity arises from spatiotemporal dynamics of Smad phosphoisoforms. Based on these findings, we have reason to hope that pharmacologic inhibition of linker phosphorylation might suppress progression to human advanced carcinomas by switching from protumorigenic to tumor-suppressive TGF-? signaling.
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