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Background: The diagnosis of periprocedural myocardial infarction (PMI) after coronary artery bypass graft (CABG) is based on biochemical markers along with clinical and instrumental findings. However, there is not a clear cutoff value of high-sensitivity cardiac troponin (hs-cTn) to identify PMI. We hypothesized that isolated hs-cTn concentrations in the first 24 h following CABG could predict cardiac adverse events (in-hospital death and PMI) and/or left ventricular ejection fraction (LVEF) decrease., Methods: We retrospectively enrolled all consecutive adult patients undergoing CABG, alone or in association with other cardiac surgery procedures, over 1 year. Hs-cTn I concentrations (Access, Beckman Coulter) were serially measured in the post-operative period and analyzed according to post-operative outcomes., Results: 300 patients were enrolled; 71.3% underwent CABG alone, 33.7% for acute coronary syndrome. Most patients showed hs-cTn I values superior to the limit required by the latest guidelines for the diagnosis of PMI. Five patients (1.7%) died, 8% developed a PMI, 10.6% showed a LVEF decrease ≥ 10%. Hs-cTn I concentrations did not significantly differ with respect to death and/or PMI whereas they were associated with LVEF decrease ≥ 10% (p value < 0.005 at any time interval), in particular hs-cTn I values at 9-12 h post-operatively. A hs-cTn I cutoff of 5556 ng/L, a value 281 (for males) and 479 (for females) times higher than the URL, at 9-12 h post-operatively was identified, representing the best balance between sensitivity (55%) and specificity (79%) in predicting LVEF decrease ≥ 10%., Conclusions: Hs-cTn I at 9-12 h post-CABG may be useful to early identify patients at risk for LVEF decrease and to guide early investigation and management of possible post-operative complications., (© 2022. The Author(s).)

Background: Circulating tumor cells (CTCs) are responsible for the metastatic dissemination of colorectal cancer (CRC) to the liver, lungs and lymph nodes. CTCs rarity and heterogeneity strongly limit the elucidation of their biological features, as well as preclinical drug sensitivity studies aimed at metastasis prevention., Methods: We generated organoids from CTCs isolated from an orthotopic CRC xenograft model. CTCs-derived organoids (CTCDOs) were characterized through proteome profiling, immunohistochemistry, immunofluorescence, flow cytometry, tumor-forming capacity and drug screening assays. The expression of intra- and extracellular markers found in CTCDOs was validated on CTCs isolated from the peripheral blood of CRC patients., Results: CTCDOs exhibited a hybrid epithelial-mesenchymal transition (EMT) state and an increased expression of stemness-associated markers including the two homeobox transcription factors Goosecoid and Pancreatic Duodenal Homeobox Gene-1 (PDX1), which were also detected in CTCs from CRC patients. Functionally, CTCDOs showed a higher migratory/invasive ability and a different response to pathway-targeted drugs as compared to xenograft-derived organoids (XDOs). Specifically, CTCDOs were more sensitive than XDOs to drugs affecting the Survivin pathway, which decreased the levels of Survivin and X-Linked Inhibitor of Apoptosis Protein (XIAP) inducing CTCDOs death., Conclusions: These results indicate that CTCDOs recapitulate several features of colorectal CTCs and may be used to investigate the features of metastatic CRC cells, to identify new prognostic biomarkers and to devise new potential strategies for metastasis prevention., (© 2022. The Author(s).)

Background: Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown., Methods: A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets., Results: Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes., Conclusions: These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials., Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy., Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent., Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.

Background: Sexual violence against adolescents is prevalent worldwide and results in significant physical and mental injuries as well as loss of economic and personal potential. Urban informal settlements such as those around Nairobi, Kenya have been shown to have especially high incidences of violence. Research has shown that empowerment interventions for female adolescents can reduce sexual assault. However, these interventions have had limited testing in urban informal settlements, with young adolescents, or in coordination with complementary programs for male adolescents., Methods/design: This study was a two-arm, parallel, cluster-randomized trial testing a combination of a previously-tested girls' intervention, IMPower, and a newly revised boys' intervention, Source of Strength. Clusters were defined as schools within the informal settlements; participants were adolescent girls and boys in class 6, generally between the ages of 10-14 at baseline. Data collection began in January 2016 and continued through December 2018. The primary outcome was the change in incidence of self-reported sexual assault among girls from baseline, compared to a life skills standard of care intervention. Secondary outcomes included experiences of physical and emotional violence, as well as determining the effects of the intervention on self-efficacy, self-esteem, and gender attitudes and beliefs, and how those effects led to changes in experience of sexual assault. For the primary outcome and several of the secondary outcomes, we used an intention to treat estimand., Discussion: This was the first randomized controlled trial with longitudinal follow-up of an empowerment self-defense approach to violence prevention for adolescents in informal settlements. The large size and rigorous design supported analysis to understand multiple subgroup experiences in the hypothesized reduction in sexual assault. The study was also unique in its focus on young (10-14 years of age) adolescents and in engaging both boys and girls in separate but coordinated curriculums. The focus on a highly vulnerable and understudied population will make it a significant contribution to the literature on violence prevention., Trial Registration: Clinical Trials.gov # NCT02771132 . Version 3.1 registered May 2017, first participant enrolled January 2017. Retrospectively registered.

Background: Heterogeneous treatment effects (HTEs), or systematic differences in treatment effectiveness among participants with different observable features, may be important when applying trial results to clinical practice. Current methods suffer from a potential for false detection of HTEs due to imbalances in covariates between candidate subgroups., Methods: We introduce a new method, matching plus classification and regression trees (mCART), that yields balance in covariates in identified HTE subgroups. We compared mCART to a classical method (logistic regression [LR] with backwards covariate selection using the Akaike information criterion ) and two machine-learning approaches increasingly applied to HTE detection (random forest [RF] and gradient RF) in simulations with a binary outcome with known HTE subgroups. We considered an N = 200 phase II oncology trial where there were either no HTEs (1A) or two HTE subgroups (1B) and an N = 6000 phase III cardiovascular disease trial where there were either no HTEs (2A) or four HTE subgroups (2B). Additionally, we considered an N = 6000 phase III cardiovascular disease trial where there was no average treatment effect but there were four HTE subgroups (2C)., Results: In simulations 1A and 2A (no HTEs), mCART did not identify any HTE subgroups, whereas LR found 2 and 448, RF 5 and 2, and gradient RF 5 and 24, respectively (all false positives). In simulation 1B, mCART failed to identify the two true HTE subgroups whereas LR found 4, RF 6, and gradient RF 10 (half or more of which were false positives). In simulations 2B and 2C, mCART captured the four true HTE subgroups, whereas the other methods found only false positives. All HTE subgroups identified by mCART had acceptable treated vs. control covariate balance with absolute standardized differences less than 0.2, whereas the absolute standardized differences for the other methods typically exceeded 0.2. The imbalance in covariates in identified subgroups for LR, RF, and gradient RF indicates the false HTE detection may have been due to confounding., Conclusions: Covariate imbalances may be producing false positives in subgroup analyses. mCART could be a useful tool to help prevent the false discovery of HTE subgroups in secondary analyses of randomized trial data.