Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

Optimism/pessimism and future orientation as predictors of suicidal ideation: Are there ethnic differences?

OBJECTIVE: The present study sought to test the generalizability of Chang et al.'s (2013) model, which suggests that optimism/pessimism and future orientation function as additive and interactive predictors of suicidal risk, to specific ethnic minority college student groups (i.e., Asian Americans, African Americans, and Latino Americans). METHOD: The present study used Chang et al.'s (2013) model to predict suicidal ideation among 81 (34 male and 47 female) Asian-American, 71 (22 male and 49 female) African-American adults, and 83 (34 male and 49 female) Latino-American college students. RESULTS: Our results indicated that this model did not predict suicidal ideation well for Asian-American college students; however, it did work well to predict suicidal ideation for African-American and Latino-American college students. CONCLUSIONS: Our findings indicate that optimism/pessimism and future orientation are important positive cognitions involved with suicidal ideation for African-American and Latino-American college students. Further research is needed to better understand the cultural underpinnings of how these positive cognitions work to predict suicide-related outcomes. (PsycINFO Database Record

Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2ß.

Insulinoma-associated protein (IA)-2 and IA-2ß are transmembrane proteins involved in neurotransmitter secretion. Mice with targeted disruption of both IA-2 and IA-2ß (double-knockout, or DKO mice) have numerous endocrine and physiological disruptions, including disruption of circadian and diurnal rhythms. In the present study, we have assessed the impact of disruption of IA-2 and IA-2ß on molecular rhythms in the brain and peripheral oscillators. We used in situ hybridization to assess molecular rhythms in the hypothalamic suprachiasmatic nuclei (SCN) of wild-type (WT) and DKO mice. The results indicate significant disruption of molecular rhythmicity in the SCN, which serves as the central pacemaker regulating circadian behavior. We also used quantitative PCR to assess gene expression rhythms in peripheral tissues of DKO, single-knockout, and WT mice. The results indicate significant attenuation of gene expression rhythms in several peripheral tissues of DKO mice but not in either single knockout. To distinguish whether this reduction in rhythmicity reflects defective oscillatory function in peripheral tissues or lack of entrainment of peripheral tissues, animals were injected with dexamethasone daily for 15 days, and then molecular rhythms were assessed throughout the day after discontinuation of injections. Dexamethasone injections improved gene expression rhythms in liver and heart of DKO mice. These results are consistent with the hypothesis that peripheral tissues of DKO mice have a functioning circadian clockwork, but rhythmicity is greatly reduced in the absence of robust, rhythmic physiological signals originating from the SCN. Thus, IA-2 and IA-2ß play an important role in the regulation of circadian rhythms, likely through their participation in neurochemical communication among SCN neurons.

Trauma and Suicide Risk in College Students: Does Lack of Agency, Lack of Pathways, or Both Add to Further Risk?

The present study sought to examine trauma history and hope as predictors of suicide risk in a sample of 561 college students. Furthermore, authors aimed to understand whether the lack of hope agency and hope pathways contributed to further risk for suicide, above and beyond trauma history. Results suggested that trauma history and hope agency were significant and unique predictors of suicide risk among college students. More specifically, hope agency accounted for additional variance in the prediction model of suicide risk, beyond that accounted for by trauma history. Some implications of the present findings for social work practice are discussed.

How Future Orientation is Associated with Depressive Symptoms in Multiethnoracial Adults: Basic Psychological Needs as a Mediator.

We examined the role of basic psychological needs as a mediator of the association between future orientation and depressive symptoms in a sample of 202 (159 female and 43 male) multiethnoracial adults. Multiple mediation analysis with 10,000 bootstraps was conducted to test for mediation. The association between future orientation and depressive symptoms was found to be accounted for by dimensions of basic psychological needs. Specifically, future orientation was negatively related to depressive symptoms through positive associations involving autonomy and competence, but not relatedness. The present findings are the first to not only point to the importance of examining future orientation in understanding depressive symptoms in multiethnoracial adults, but they are also the first to suggest possible mechanisms by which believing in a changeable future might foster stronger satisfaction of basic psychological needs, especially autonomy and competence, that might help multiethnoracials garner greater protection when encountering stressful situations in their lives.

Depression, Loneliness, and Suicide Risk among Latino College Students: A Test of a Psychosocial Interaction Model.

This study tested a psychosocial model of suicide risk in a sample of 156 Latino college students. Specifically, depression and loneliness were hypothesized to be important predictors of suicide risk (namely, hopelessness and suicidal behaviors) in Latino students. Results of conducting regression analyses indicated that, independent of age and gender, depression and loneliness were significant predictors of both indices of suicide risk examined in the present study. It is noteworthy that within the psychosocial predictor set of depression and loneliness, depression was consistently found to be nearly twice as strong a predictor than was loneliness. Moreover, we found evidence for a significant depression-loneliness interaction effect in predicting suicide risk. That is, the highest level of suicide risk was found among dysphoric Latino students who were also socially isolated. Our findings indicate that depression and loneliness are important factors to consider in understanding suicide risk among Latino college students.

The Relationship Between Domestic Partner Violence and Suicidal Behaviors in an Adult Community Sample: Examining Hope Agency and Pathways as Protective Factors.

We examined an additive and interactive model involving domestic partner violence (DPV) and hope in accounting for suicidal behaviors in a sample of 98 community adults. Results showed that DPV accounted for a significant amount of variance in suicidal behaviors. Hope further augmented the prediction model and accounted for suicidal behaviors beyond DPV. Finally, we found that DPV significantly interacted with both dimensions of hope to further account for additional variance in suicidal behaviors above and beyond the independent effects of DPV and hope. Implications for the role of hope in the relationship between DPV and suicidal behaviors are discussed.

Sexual Assault and Depressive Symptoms in College Students: Do Psychological Needs Account for the Relationship?

In this study, authors examined basic psychological needs (namely, competence, autonomy, and relatedness) as potential mediators of the association between sexual assault and depressive symptoms in a sample of 342 college students. Results from conducting a multiple mediation test provided support for partial mediation involving the indirect effects of competence and autonomy. In contrast, no support for mediation was found involving relatedness. It is notable that sexual assault remained a significant predictor of depressive symptoms in students. Therefore, findings indicate how sexual assault may both directly and indirectly (through psychological needs) lead to greater depressive symptoms in students. Authors concluded the article with a discussion of the implications of their findings for expanding the study of basic psychological needs in college students and the need for greater efforts to prevent and treat sexual assault on campus.

BMI, body discrepancy, and self-construal as predictors of eating disturbances in European and Asian American females.

This study examined for ethnic variations in the predictive utility of body discrepancy and self-construal in eating disturbances between 156 European American and 129 Asian American females. We found important ethnic variations in the prediction model between these two groups, especially in the value of self-construal. Some implications of the present findings are discussed.

Understanding the relationship between domestic abuse and suicide behavior in adults receiving primary care: does forgiveness matter?

This study examined the interrelation of domestic abuse, forgiveness of self, forgiveness of others, and suicide behavior in a community sample of 101 patients receiving primary care from a clinic in the southeastern United States. As expected, it was found that more frequent experience of domestic abuse was associated with more frequent suicide behavior. Results from conducting mediation analyses and using bootstrapping techniques provided support for a model in which the relationship between domestic abuse and suicide behavior was accounted for by forgiveness of self, but not by forgiveness of others. The article concludes with a discussion of some of the implications of the present findings for practice and the study's limitations.

Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes.

The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al., Aging 2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer.

Casein kinase 1 delta (CK1delta) regulates period length of the mouse suprachiasmatic circadian clock in vitro.

BACKGROUND: Casein kinase 1 delta (CK1delta) plays a more prominent role in the regulation of circadian cycle length than its homologue casein kinase 1 epsilon (CK1epsilon) in peripheral tissues such as liver and embryonic fibroblasts. Mice lacking CK1delta die shortly after birth, so it has not been possible to assess the impact of loss of CK1delta on behavioral rhythms controlled by the master circadian oscillator in the suprachiasmatic nuclei (SCN). METHODOLOGY/PRINCIPAL FINDINGS: In the present study, mPER2::LUCIFERASE bioluminescence rhythms were monitored from SCN explants collected from neonatal mice. The data demonstrate that SCN explants from neonatal CK1delta-deficient mice oscillate, but with a longer circadian period than littermate controls. The cycle length of rhythms recorded from neonatal SCN explants of CK1epsilon-deficient mice did not differ from control explants. CONCLUSIONS/SIGNIFICANCE: The results indicate that CK1delta plays a more prominent role than CK1epsilon in the maintenance of 24-hour rhythms in the master circadian oscillator.

Casein kinase 1 delta regulates the pace of the mammalian circadian clock.

Both casein kinase 1 delta (CK1delta) and epsilon (CK1epsilon) phosphorylate core clock proteins of the mammalian circadian oscillator. To assess the roles of CK1delta and CK1epsilon in the circadian clock mechanism, we generated mice in which the genes encoding these proteins (Csnk1d and Csnk1e, respectively) could be disrupted using the Cre-loxP system. Cre-mediated excision of the floxed exon 2 from Csnk1d led to in-frame splicing and production of a deletion mutant protein (CK1delta(Delta2)). This product is nonfunctional. Mice homozygous for the allele lacking exon 2 die in the perinatal period, so we generated mice with liver-specific disruption of CK1delta. In livers from these mice, daytime levels of nuclear PER proteins, and PER-CRY-CLOCK complexes were elevated. In vitro, the half-life of PER2 was increased by approximately 20%, and the period of PER2::luciferase bioluminescence rhythms was 2 h longer than in controls. Fibroblast cultures from CK1delta-deficient embryos also had long-period rhythms. In contrast, disruption of the gene encoding CK1epsilon did not alter these circadian endpoints. These results reveal important functional differences between CK1delta and CK1epsilon: CK1delta plays an unexpectedly important role in maintaining the 24-h circadian cycle length.