Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.

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Efficient and precise genome editing is essential for clinical applications and generating animal models, which requires engineered nucleases with high editing ability while low off-target activity. Here we present a high-throughput sequencing method, primer-extension-mediated sequencing (PEM-seq), to comprehensively assess both editing ability and specificity of engineered nucleases. We showed CRISPR/Cas9-generated breaks could lead to chromosomal translocations and large deletions by PEM-seq. We also found that Cas9 nickase possessed lower off-target activity while with some loss of target cleavage ability. However, high-fidelity Cas9 variants, including both eCas9 and the new FeCas9, could significantly reduce the Cas9 off-target activity with no obvious editing retardation. Moreover, we found AcrIIA4 inhibitor could greatly reduce the activities of Cas9, but off-target loci were not so effectively suppressed as the on-target sites. Therefore, PEM-seq fully evaluating engineered nucleases could help choose better genome editing strategy at given loci than other methods detecting only off-target activity.

Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a -mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium.

Conduct problems, substance use, and risky sexual behavior have been shown to coexist among adolescents, which may lead to significant health problems. The current study was designed to examine relations among these problem behaviors in a community sample of children at high risk for conduct disorder. A latent growth model of childhood conduct problems showed a decreasing trend from grades K to 5. During adolescence, four concurrent conduct problem and substance use trajectory classes were identified (high conduct problems and high substance use, increasing conduct problems and increasing substance use, minimal conduct problems and increasing substance use, and minimal conduct problems and minimal substance use) using a parallel process growth mixture model. Across all substances (tobacco, binge drinking, and marijuana use), higher levels of childhood conduct problems during kindergarten predicted a greater probability of classification into more problematic adolescent trajectory classes relative to less problematic classes. For tobacco and binge drinking models, increases in childhood conduct problems over time also predicted a greater probability of classification into more problematic classes. For all models, individuals classified into more problematic classes showed higher proportions of early sexual intercourse, infrequent condom use, receiving money for sexual services, and ever contracting an STD. Specifically, tobacco use and binge drinking during early adolescence predicted higher levels of sexual risk taking into late adolescence. Results highlight the importance of studying the conjoint relations among conduct problems, substance use, and risky sexual behavior in a unified model.

The authors examined life stress and self-efficacy as predictors of time to relapse for 113 adults with comorbid major depressive disorder and alcohol and/or substance dependence in a randomized clinical trial comparing 2 psychotherapy interventions (integrated cognitive- behavioral therapy and 12-step facilitation therapy). Life stress, self-efficacy, and substance use were assessed at treatment entry, 12 weeks (mid-treatment), and 24 weeks (end of treatment). Time to relapse was defined as the number of days from treatment initiation until first alcohol and/or drug use. Half of the sample relapsed within the study period of 24 weeks. There was no significant difference between treatment groups. Individuals experiencing life stressors were more likely to relapse early than those not experiencing life stressors. Lower self-efficacy also predicted earlier relapse. Chronic stress levels and self-efficacy were stable across time for most individuals. In contrast, acute stress events occurred at differing times, and survival analyses provided evidence of heightened relapse risk in the month following acute stressors. The interaction of self-efficacy and life stress was not significant. The results highlight the significance of life stress and self-efficacy as predictors of early relapse.

Background Clear cell renal cell carcinoma is susceptible to ferroptosis, and immunotherapy is recently recommended as a priority for the initial treatment of metastatic clear cell renal carcinoma. Increased ferroptosis and immune activation can synergistically reinforce each other in killing cancer cells. NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis. Here, we aim to identify and validate the association between NCOA4 expression, clinicopathologic characteristics, and overall survival in ccRCC by using The Cancer Genome Atlas and Gene Expression Omnibus databases. We further analyze the interacted proteins of NCOA4 and infiltrated immune cells via TIMER and GEPIA databases. Methods NCOA4 expression in clear cell renal carcinoma (ccRCC) tissues and normal adjacent tissues in The Cancer Genome Atlas (TCGA) data were primarily screened, and further validated in another independent cohort from the gene expression omnibus (GEO) database and human protein atlas. The relationships of NCOA4 expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which NCOA4 interacted were also built using the online STRING website. Meanwhile, we use TIMER and GEPIA databases to investigate the relationships between NCOA4 expression and infiltrated immune cells and their corresponding gene marker sets. Results Contrast to normal tissue, NCOA4 expression was lower in ccRCC tumor tissue(p < 0.05). Lower NCOA4 expression was closely associated with high-grade malignancy and advanced TNM stage. Univariate and multivariate analysis indicated the overall survival of ccRCC cases with low NCOA4 level is shorter than those of patients with high NCOA4 expression (p < 0.05). FTL and FTH1 were the important proteins interacting with NCOA4. ccRCC with NCOA4 deficiency presented the paucity of infiltrated immune cells and their matching marker sets, including CD8+ T cells. Conclusion Deficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.

Marriage has been cited as a protective factor against drug use, but the relationship between marriage and drug use has not been explored longitudinally during addiction treatment. The current study assessed individual trajectories of substance use during treatment as a function of marital status and perceived closeness of the marital relationship. A parallel-process growth model was used to (1) estimate the rate of change in percentage of cocaine-positive and heroin-positive urine samples, and (2) examine the relationship between marital status and drug use trajectories over 35 weeks, during and after treatment. Percent days of use for both drugs were lowest for married participants across all time points. Among married participants, reporting a close relationship with one's partner predicted less cocaine and heroin use. These findings suggest that being married and having a close relationship with one's spouse are associated with better outcomes over time. The causal nature of the association is suggested by previous research that has demonstrated the effectiveness of couples therapy as an adjunct to methadone maintenance.