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"Knudsen, Michelle"
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The dragon of Trelian
A mage's apprentice, a princess, and a dragon combine their strength and magic to bring down a traitor and restore peace to the kingdom of Trelian.
Book
Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle
Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2, pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.
It is becoming clear that heterogeneity in cancer cell cycles corresponds to variability of response to therapies targeting cyclin dependent kinases (CDKs). Here, the authors investigate CDK2-dependancy and response to CDK2 inhibition across different cancers, identifying markers of sensitivity and combinatorial therapeutic strategies.
Journal Article
The princess of Trelian
Princess Meglynne of Trelian will soon be named the princess-heir, next in line to be queen, but her link to the dragon Jakl makes the kingdom's people more than a little uneasy, while a mysterious magical attack and some ominous divinations reveal that a much more powerful enemy may soon reappear and endanger them all.
Book
Barriers and facilitators to scaling up medications for opioid use disorder in Kentucky: qualitative perspectives of treatment organization staff
Background
Underutilization of medications for opioid use disorder (MOUD) remains a persistent obstacle to addressing the opioid epidemic. This study explores MOUD agency experiences with patient census growth as well as multi-level barriers and facilitators to expanding MOUD from the perspectives of agency staff.
Methods
Semi-structured qualitative interviews were conducted with 66 employees representing 30 MOUD agencies in eight Kentucky counties in the United States from December 2022 to June 2023 as part of the HEALing (Helping to End Addiction Long-term®) Communities Study in Kentucky (HCS-KY). Interviews were conducted prior to the development of partnerships to implement strategies focused on expanding MOUD census and increasing MOUD retention. Facility administrators/directors, prescribers, and clinicians were prioritized for recruitment, but agencies could identify other staff to participate. Interviews were recorded and transcribed. A consensus-based approach to coding and thematic analysis was used.
Results
Although some agencies had a fairly static number of patients, most described recent experiences with modest growth in MOUD census and the ability to provide same day/next day MOUD. Multi-level factors, including organizational, patient, and community factors, were perceived to impact MOUD census. Organizational characteristics impacting growth included the physical space of the clinic and staffing. Organizational policies in some agencies constrained treatment retention, while other agencies implemented innovations to better meet patients’ needs. Patients often encountered numerous obstacles to treatment initiation and retention, including limited access to transportation, technology, stable housing, and childcare. These patient-level barriers often reflected community characteristics, while community stigma also impeded MOUD growth.
Conclusions
Although some degree of growth in MOUD has occurred, multiple barriers are impeding further increases in treatment initiation and retention. Overcoming some barriers would likely require policy changes related to financing and regulation, while other barriers would require community-level efforts to decrease stigma and greater community investment in infrastructure, such as transportation and housing.
Trial registration
ClinicalTrials.gov, NCT04111939. Registered 30 September 2019,
https://clinicaltrials.gov/ct2/show/NCT04111939
.
Journal Article
Curse of the evil librarian
\"After sending the evil librarian, Mr. Gabriel, back to the demon world once and for all at theater camp last summer, Cynthia is ready to enjoy a completely demon-free senior year of high school, especially once she learns the fall musical will be Les Misâerables. She can't wait to create the most incredible barricade set design in all of high-school theater. And her boyfriend, Ryan, is sure to land his dream role of Javert. But down in the demon realm, an epic mishandling of Mr. Gabriel's essence leads to his escape -- and soon he's gathering strength, bent once again on revenge against Cyn and everyone she loves. Best-selling author Michelle Knudsen's Evil Librarian series overflows with horror, humor, and hot guys -- and it looks like this show's got a third act\"--Provided by publisher.
Book
SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
Viral infections usually cause disease through direct cytopathogenic effects and excessive inflammatory responses. Here, Olagnier et al. show that two NRF2 agonists, 4-OI and DMF, possess broad IFN-independent antiviral activity and decrease host inflammatory response to SARS-CoV-2 infection.
Journal Article
Big Mean Mike
Mike is proud to be the biggest, toughest dog in the neighborhood, so when tiny, fuzzy bunnies start showing up in his big, mean car he sees them only as a threat to his reputation, no matter how adorable they are.
Book
A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
This study presents OncoTreat, a framework for the prioritization of compounds targeting mechanistic tumor dependencies in individual patients.
Journal Article
Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis
Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.
Journal Article