Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.

Clusterin (CLU) has been implicated in various cell functions involved in carcinogenesis and tumour progression. There are two known CLU protein isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is proapoptotic, and a secretory form (sCLU) is prosurvival. CLU expression has been associated with tumorigenesis of various malignancies, including tumours of prostate, colon, and breast. Furthermore, CLU expression is modulated by many factors that are believed to regulate tumour growth and/or apoptosis, including 1,25-dihydroxyvitamin D3, transforming growth factor beta-1, ultraviolet radiation, and IR. sCLU upregulation appears to be a general molecular stress response. Presently, preliminary results indicate that therapeutic modalities targeting CLU may be effective in cancer treatment. However, such strategies should make sure that nCLU is not eliminated or reduced. This review summarizes our present understanding of the importance of CLU in various physiological functions including tumour growth, and discusses its relevance to future cancer therapy.

Clusterin over-expression modulates proapoptotic and antiproliferative effects of 1,25(OH)2D3 in prostate cancer cells in vitro.

Prostate cancer is the most commonly diagnosed cancer in the majority of western countries. Due to their antiproliferative and proapoptotic activity, vitamin D analogues have been introduced recently as an experimental therapy for prostate cancer. Clusterin (CLU) is a glycoprotein that has two known isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is pro-apoptotic, and a secretory form (sCLU) is pro-survival. In this study, we analyzed whether proapoptotic and antiproliferative effects of 1,25(OH)(2)D(3) on LNCaP prostate cancer cells are modulated by expression of sCLU. Using colony forming assay, we studied the effect of treatment with different doses of 1,25(OH)(2)D(3) (10(-6), 10(-7), 10(-10)M) on proliferation of LNCaP cells that were stable transfected and over-express sCLU (LNT-1) as compared to empty vector-transfected cells (LN/C). We also measured apoptosis using TUNEL assay. sCLU over-expression protected against both antiproliferative (30%) and proapoptotic (15%) effects of 1,25(OH)(2)D(3), although this effect was statistically not significant. In conclusion, our findings demonstrate that expression of sCLU modulates growth regulatory effects of 1,25(OH)(2)D(3) in prostate cancer indicating that CLU interferes with vitamin D signalling pathways.

Information processing biases and panic disorder: relationships among cognitive and symptom measures.

To test cognitive models of panic disorder, a range of information processing biases were examined among persons with panic disorder (N=43) and healthy control participants (N=38). Evidence for automatic associations in memory was assessed using the Implicit Association Test, interference effects related to attention biases were assessed using a modified supraliminal Stroop task, and interpretation biases were assessed using the Brief Body Sensations Interpretation Questionnaire. In addition, the relationship between information processing biases and clinical markers of panic (including affective, behavioral, and cognitive symptom measures) was investigated, along with the relationships among biases. Results indicated more threat biases among the panic (relative to control) group on each of the information processing measures, providing some of the first evidence for an implicit measure of panic associations. Further, structural equation modeling indicated that the information processing bias measures were each unique predictors of panic symptoms, but that the bias indicators did not relate to one another. These findings suggest that cognitive factors may independently predict panic symptoms, but not covary. Results are discussed in terms of their support for cognitive models of panic and the potential for automatic versus strategic processing differences across the tasks to explain the low relationships across the biases.

Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control.

The glycoprotein clusterin (CLU), has two known isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is pro-apoptotic, while a secretory form (sCLU) is pro-survival. Both forms are implicated in various cell functions, including DNA repair, cell cycle regulation, and apoptotic cell death. CLU expression has been associated with tumorigenesis and the progression of various malignancies. In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms, while simultaneously stimulating energy-expensive cell cycle checkpoints that delay the cell cycle progression to allow more time for DNA repair. This review summarizes our current understanding of the role of clusterin in DNA repair, apoptosis, and cell cycle control and the relevance.

Clusterin (CLU) and melanoma growth: CLU is expressed in malignant melanoma and 1,25-dihydroxyvitamin D3 modulates expression of CLU in melanoma cell lines in vitro.

BACKGROUND: The glycoprotein clusterin (CLU) has two known isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is pro-apoptotic, while a secretory form (sCLU) is pro-survival. CLU expression has been associated with tumorigenesis and the progression of various malignancies. MATERIALS AND METHODS: The expression of CLU was studied immunohistochemically in paraffin sections of primary cutaneous malignant melanomas, metastases of malignant melanomas and acquired melanocytic naevi. Using PCR and Western blotting, the expression of CLU was also investigated in various vitamin D-responsive (MeWo, SK-MEL-28) and vitamin D-resistant melanoma cell lines (SK-MEL-5, SK-MEL-25), as well as in normal human melanocytes (NHM), along with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] treatment. RESULTS: In contrast to acquired melanocytic naevi, CLU immunoreactivity was found in primary cutaneous malignant melanomas and metastases of malignant melanomas in situ. Both CLU protein and RNA were detected in melanoma cell lines and NHM. Treatment with 1,25(OH)2D3 modulated CLU's expression in vitamin D-responsive but not in -resistant melanoma cell lines. CONCLUSION: CLU may be of importance for the progression of malignant melanoma. The growth regulatory effects of 1,25(OH)2D3 in melanoma cell lines may, at least in part, be mediated via modulation of CLU expression.

Relationship between Disgust and Memory Biases in Spider Fear.

The literatures examining disgust's role in information processing biases and evidence for memory biases in anxiety disorders are both mixed, suggesting small or fragile effects. Thus, to maximize power and reliability, a mega-analytic approach was used to examine data across two studies to determine whether a memory bias for spider-relevant information exists under conditions when disgust is elevated and if the bias is specific to highly fearful individuals. Disgust was manipulated by having a large tarantula present or absent (at encoding and/or at recall) when individuals high (N=158) or low (N=108) in spider fear completed a free recall task. Results indicated that, as expected, the spider's presence was related to enhanced recall of spider information. However, this bias was driven by the presence of the spider during encoding only (as opposed to during recall), and high trait spider fear was not necessary for the memory bias to be expressed. Finally, there was a small effect for individual differences in trait and state disgust to predict spider recall, but this effect disappeared when anxiety was also included as a predictor, suggesting only a limited role for disgust in memory biases related to specific fears.

Sudden gains in group cognitive-behavioral therapy for panic disorder.

The current study investigates sudden gains (rapid symptom reduction) in group cognitive-behavioral therapy for panic disorder. Sudden gains occurring after session 2 of treatment predicted overall symptom reduction at treatment termination and some changes in cognitive biases. Meanwhile, sudden gains occurring immediately following session 1 were not associated with symptom reduction or cognitive change. Together, this research points to the importance of examining sudden gains across the entire span of treatment, as well as the potential role of sudden gains in recovery from panic disorder.

Automatic associations and panic disorder: trajectories of change over the course of treatment.

Cognitive models of anxiety and panic suggest that symptom reduction during treatment should be preceded by changes in cognitive processing, including modifying the anxious schema. The current study tested these hypotheses by using a repeated measures design to evaluate whether the trajectory of change in automatic panic associations over a 12-week course of cognitive behavior therapy (CBT) is related to the trajectory of change in panic symptoms. Individuals with panic disorder (N = 43) completed a measure of automatic panic associations--the Implicit Association Test (A. G. Greenwald, D. E. McGhee, & J. L. K. Schwartz, 1998), which reflects elements of the schema construct--every 3 weeks over the course of therapy and measures of panic symptoms each week. Dynamic bivariate latent difference score modeling not only indicated that automatic panic associations changed over the course of CBT for panic disorder but showed these changes were correlated with symptom reduction. Moreover, change in automatic panic associations was a significant predictor of change in panic symptom severity. These findings permit inferences about the temporality of change, suggesting that cognitive change does in fact precede and contribute to symptom change.