The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anticancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibition and uncover potential resistance mechanisms, identification of these currently unknown genes is necessary. The aim of this study was therefore to identify gene mutations that determine Wee1 inhibitor sensitivity. We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G 1 /S regulatory genes, including SKP2, CUL1, and CDK2. Stable depletion of SKP2, CUL1, or CDK2 or chemical Cdk2 inhibition rescued the γ-H2AX induction and abrogation of G 2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patients. Conversely, loss of the identified S-phase genes could serve as a mechanism of acquired resistance, which goes along with development of severe genomic instability.cell cycle | checkpoint | AZD-1775 | MK-1775 | polyploidy

Sacubitril/valsartan can be considered a cost-effective treatment at a daily price of €5.25. Unless priced lower than enalapril (<€0.045 per day), sacubitril/valsartan is very unlikely to be cost-saving/dominant.

Background Acute coronary syndrome patients receiving dual antiplatelet therapy who need emergent or urgent cardiac surgery are at high risk of major bleeding, which can impair postoperative outcomes. CytoSorb ® , a blood purification technology based on adsorbent polymer, has been demonstrated to remove ticagrelor from blood during on-pump cardiac surgery. Objective The aim of this study was to evaluate the cost utility of intraoperative removal of ticagrelor using CytoSorb versus usual care among patients requiring emergent or urgent cardiac surgery in the UK. Methods A de novo decision analytic model, based on current treatment pathways, was developed to estimate the short-and long-term costs and outcomes. Results from randomised clinical trials and national standard sources such as National Health Service (NHS) reference costs were used to inform the model. Costs were estimated from the NHS and Personal Social Services perspective. Deterministic and probabilistic sensitivity analyses (PSAs) explored the uncertainty surrounding the input parameters. Results In emergent cardiac surgery, intraoperative removal of ticagrelor using CytoSorb was less costly (£12,933 vs. £16,874) and more effective (0.06201vs. 0.06091 quality-adjusted life-years) than cardiac surgery without physiologic clearance of ticagrelor over a 30-day time horizon. For urgent cardiac surgery, the use of CytoSorb was less costly than any of the three comparators-delaying surgery for natural washout without adjunctive therapy, adjunctive therapy with short-acting antiplatelet agents, or adjunctive therapy with low-molecular-weight heparin. Results from the PSAs showed that CytoSorb has a high probability of being cost saving (99% in emergent cardiac surgery and 53-77% in urgent cardiac surgery, depending on the comparators). Cost savings derive from fewer transfusions of blood products and re-thoracotomies, and shorter stay in the hospital/intensive care unit. Conclusions The implementation of CytoSorb as an intraoperative intervention for patients receiving ticagrelor undergoing emergent or urgent cardiac surgery is a cost-saving strategy, yielding improvement in perioperative and postoperative outcomes and decreased health resource use.

Arabia Methods: Retrospective cohort study for patients admitted to surgical wards at a tertiary care center in Jeddah, Saudi Arabia over 3 months. Three broad spectrum antibiotics were targeted; piperacillin/tazobactam, imipenem, and meropenem. De-escalation delay was measured in days from the time of getting the culture identification and susceptibility until narrowing the antimicrobial therapy to target the identified organism. The cost impact was measured by multiplying the period that patients were on broad spectrum antibiotics after the final identification and susceptibility of microorganism by the cost of broadspectrum antibiotics per day. Results: One hundred sixty-three patients received broad spectrum antibiotics over 3 months on surgical wards at our institution. Sixty four out 163 patient (39.2%) had identified organism and susceptibility for other antibiotics. Thirty one patients (48.4%) had de-escalation of antimicrobial therapy within 24 hrs of culture identification and susceptibility result. Thirty three patients (51.6%) had a delay in their broad spectrum antibiotics therapy de-esclation despite getting the culture identification and susceptibility. The total delay of broad spectrum antibiotics and cost impact were as follow: piperacillin/ tazobactam 267 days (3,920 USD); imipenem 5 days (230 USD); meropenem 110 days (9,925 USD). ConClusions: the delay of broad spectrum antibiotics deescalation on surgical wards at our hospital has resulted in a cost impact of 14,075 USD over 3 months period. Pharmacy intervention program on surgical wards to enforce the de-escalation process is needed.