Anger and aggression in borderline personality disorder and attention deficithyperactivity disorder – does stress matter?

BACKGROUND: The impact of stress on anger and aggression in Borderline Personality Disorder (BPD) and Attention Deficit Hyperactivity Disorder (ADHD) has not been thoroughly investigated. The goal of this study was to investigate different aspects of anger and aggression in patients with these disorders. METHODS: Twenty-nine unmedicated female BPD patients, 28 ADHD patients and 30 healthy controls (HC) completed self-reports measuring trait anger, aggression and emotion regulation capacities. A modified version of the Point Subtraction Aggression Paradigm and a state anger measurement were applied under resting and stress conditions. Stress was induced by the Mannheim Multicomponent Stress Test (MMST). RESULTS: Both patient groups scored significantly higher on all self-report measures compared to HCs. Compared to ADHD patients, BPD patients reported higher trait aggression and hostility, a stronger tendency to express anger when provoked and to direct anger inwardly. Furthermore, BPD patients exhibited higher state anger than HCs and ADHD patients under both conditions and showed a stress-dependent anger increase. At the behavioral level, no significant effects were found. In BPD patients, aggression and anger were positively correlated with emotion regulation deficits. CONCLUSIONS: Our findings suggest a significant impact of stress on self-perceived state anger in BPD patients but not on aggressive behavior towards others in females with BPD or ADHD. However, it appears to be pronounced inwardly directed anger which is of clinical importance in BPD patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40479-017-0057-5) contains supplementary material, which is available to authorized users

Growth Arrest‐Specific 6 (GAS6) Promotes Prostate Cancer Survival by G1 Arrest/S Phase Delay and Inhibition of Apoptosis During Chemotherapy in Bone Marrow

Prostate cancer (PCa) is known to develop resistance to chemotherapy. Growth arrest‐specific 6 (GAS6), plays a role in tumor progression by regulating growth in many cancers. Here, we explored how GAS6 regulates the cell cycle and apoptosis of PCa cells in response to chemotherapy. We found that GAS6 is sufficient to significantly increase the fraction of cells in G1 and the duration of phase in PCa cells. Importantly, the effect of GAS6 on G1 is potentiated during docetaxel chemotherapy. GAS6 altered the levels of several key cell cycle regulators, including the downregulation of Cyclin B1 (G2/M phase), CDC25A, Cyclin E1, and CDK2 (S phase entry), while the upregulation of cell cycle inhibitors p27 and p21, Cyclin D1, and CDK4. Importantly, these changes became further accentuated during docetaxel treatment in the presence of GAS6. Moreover, GAS6 alters the apoptotic response of PCa cells during docetaxel chemotherapy. Docetaxel induced PCa cell apoptosis is efficiently suppressed in PCa cell culture in the presence of GAS6 or GAS6 secreted from co‐cultured osteoblasts. Similarly, the GAS6‐expressing bone environment protects PCa cells from apoptosis within primary tumors in vivo studies. Docetaxel induced significant levels of Caspase‐3 and PARP cleavage in PCa cells, while GAS6 protected PCa cells from docetaxel‐induced apoptotic signaling. Together, these data suggest that GAS6, expressed by osteoblasts in the bone marrow, plays a significant role in the regulation of PCa cell survival during chemotherapy, which will have important implications for targeting metastatic disease. J. Cell. Biochem. 117: 2815–2824, 2016. © 2016 Wiley Periodicals, Inc.We explored how GAS6, expressed by osteoblasts, regulates the cell cycle and apoptosis in PCa cells during chemotherapy in the bone marrow. We demonstrate that GAS6 significantly increases the number of G1 arrested cells by altering signaling networks associated with G1 arrest and S phase delay. Our results suggest that GAS6 contributes to the regulation of PCa cell survival during chemotherapy in the bone marrow microenvironment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134410/1/jcb25582_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134410/2/jcb25582.pd

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL, and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of Pâ Erk1/2 to Pâ p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knockdown of MERTK in PCa cells increased metastasis free survival in an intraâ cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates PCa dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation. J. Cell. Biochem. 118: 891â 902, 2017. © 2016 Wiley Periodicals, Inc.Escape from cellular dormancy is the process where previously dormant single disseminated tumor cells reactivate to form cancer microâ metastases, which continue to grow and ultimately make the disease incurable. Here, were show that Mer tyrosine kinase is important for prostate cancer dormancy escape through a mechanism involving MAP kinases, cell cycle inhibitors, epigenetics, and transcription factors associated with pluripotent cells.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136285/1/jcb25768_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136285/2/jcb25768.pd

Detection and isolation of disseminated tumor cells in bone marrow of patients with clinically localized prostate cancer

BackgroundDisseminated tumor cells (DTCs) have been reported in the bone marrow (BM) of patients with localized prostate cancer (PCa). However, the existence of these cells continues to be questioned, and few methods exist for viable DTC isolation. Therefore, we sought to develop novel approaches to identify and, if detected, analyze localized PCa patient DTCs.MethodsWe used fluorescence‐activated cell sorting (FACS) to isolate a putative DTC population, which was negative for CD45, CD235a, alkaline phosphatase, and CD34, and strongly expressed EPCAM. We examined tumor cell content by bulk cell RNA sequencing (RNA‐Seq) and whole‐exome sequencing after whole genome amplification. We also enriched for BM DTCs with α‐EPCAM immunomagnetic beads and performed quantitative reverse trancriptase polymerase chain reaction (qRT‐PCR) for PCa markers.ResultsAt a threshold of 4 cells per million BM cells, the putative DTC population was present in 10 of 58 patients (17%) with localized PCa, 4 of 8 patients with metastatic PCa of varying disease control, and 1 of 8 patients with no known cancer, and was positively correlated with patients’ plasma PSA values. RNA‐Seq analysis of the putative DTC population collected from samples above (3 patients) and below (5 patients) the threshold of 4 putative DTCs per million showed increased expression of PCa marker genes in 4 of 8 patients with localized PCa, but not the one normal donor who had the putative DTC population present. Whole‐exome sequencing also showed the presence of single nucleotide polymorphisms and structural variants in the gene characteristics of PCa in 2 of 3 localized PCa patients. To examine the likely contaminating cell types, we used a myeloid colony formation assay, differential counts of cell smears, and analysis of the RNA‐Seq data using the CIBERSORT algorithm, which most strongly suggested the presence of B‐cell lineages as a contaminant. Finally, we used EPCAM enrichment and qRT‐PCR for PCa markers to estimate DTC prevalence and found evidence of DTCs in 21 of 44 samples (47%).ConclusionThese data support the presence of DTCs in the BM of a subset of patients with localized PCa and describe a novel FACS method for isolation and analysis of viable DTCs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151343/1/pros23896.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151343/2/pros23896_am.pd

Breast cancer metastasis to the bone: mechanisms of bone loss

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals. Metastatic dissemination in breast cancer patients occurs early in malignant transformation, raising questions about how disseminated cancer cells (DCC) progress at distant sites. Here, the authors show that DCCs in bone marrow are activated via IL6-trans-signaling and thereby acquire stemness traits relevant for metastasis formation

Out of control? Acting out anger is associated with deficient prefrontal emotional action control in male patients with borderline personality disorder

Item does not contain fulltextDifficulty in anger control and anger-related aggressive outbursts against others are frequently reported by patients with borderline personality disorder (BPD). Although male sex is a known predictor for aggression, hardly any study has addressed the neural correlates of deficient anger control in male patients with BPD. Building on previous reports in female BPD, we investigated the involvement of lateral antero- and dorsal prefrontal cortex in the control of fast emotional actions and its relation to self-reported tendencies to act out anger. 15 medication-free male patients with BPD and 25 age- and intelligence-matched healthy men took part in a social Approach-Avoidance task in the MR-scanner. This task allows the measurement of neural correlates underlying the control of fast behavioral tendencies to approach happy and avoid angry faces. Hypothesis-driven region-of-interest and exploratory whole brain analyses were used to test for activations of antero- and dorsolateral prefrontal regions and their relation with the amygdala during emotional action control as well as their association with self-reported anger out in male patients with BPD and healthy volunteers. Male patients with BPD showed reduced anterolateral prefrontal activations during emotional action control compared to healthy volunteers. Furthermore, anger out was negatively related to antero- and dorsolateral prefrontal activations, while it was positively related to amygdala activity in male patients with BPD. The current results suggest the involvement of antero- and dorsolateral prefrontal regions in controlling and overriding fast emotional actions. Deficits in lateral prefrontal emotion control seem to be a common neural mechanism underlying anger-related aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.8 p

Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer

Neuroendocrine prostate cancer (NE PCa) is an aggressive malignancy, often presenting with advanced metastasis. We previously reported that reduction of histone marks regulated by DNMT1 following epidrug (5‐Azacitidine, 5‐Aza) treatment controls induction of epithelial to mesenchymal (EMT) and a cancer stem cell (CSC) phenotype, which facilitates tumorigenesis in PCa cells. Here, we use the epidrug 5‐Aza as a model for how histone marks may regulate the reprogramming of prostate adenocarcinoma into NE phenotypic cells. First, we observed that 5‐Aza treatment of PCa cells in vitro induces a neuron‐like phenotype. In addition, significant increases in the expression of the NE markers N‐Myc downstream regulated gene 1 (NDRG1), enolase‐2 (ENO2), and synaptophysin were observed. Critically, a high density of NE cells with synaptophysin expression was found in tumors generated by 5‐Aza pretreatment of PCa cells. Importantly, induction of NE differentiation of PCa cells was associated with an enhancement of NDRG1 expression by reduction of two histone marks, H3K9me3 and H3K27me3. Further, more NDRG1 expression was detected in the subset of PCa cells with reduced expression of H3K9me3 or H3K27me3 in the tumors generated by 5‐Aza pretreated PCa cells and critically, these biological differences are also observed in small cell carcinoma in advanced stage of human primary PCa tumors. Our results suggest that reduction of histone marks regulated by the epidrug 5‐Aza may control induction of a NE phenotype, which facilitates PCa progression. These studies suggest a strong rationale for developing therapeutics, which target epigenetic regulation.Reduction of histone marks induces an neuroendocrine phenotype in PCa.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142487/1/jcb26586.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142487/2/jcb26586_am.pd

Delay discounting and response disinhibition under acute experimental stress in women with borderline personality disorder and adult attention deficit hyperactivity disorder

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ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder

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