Background: Bright light therapy (BLT) has been increasingly used as an experimental treatment in non-seasonal unipolar depression. While clinical trials have demonstrated the efficacy of BLT in ameliorating depression for outpatients, studies examining BLT in the psychiatric inpatient setting are currently lacking. Aim: The purpose of this study is to explore whether BLT as adjunctive treatment for depressive symptoms on an acute psychiatric floor is feasible and explore associated changes in depressive symptoms. Methods: An observational, cross-sectional study was conducted at State University of New York (SUNY) Upstate 4B acute inpatient psychiatric unit. BLT was administered to participating patients as adjunctive therapy to their psychopharmacological and psychotherapy treatments on a daily basis throughout their hospitalization. Beck Depression Inventory-II (BDI-II), Hamilton Rating Scale for Depression (HAM-D), and Outcome Questionnaire-45.2 (OQ-45.2) were administered before commencing BLT and after their last BLT session. Changes to the aforementioned measures before and after BLT treatment, the dose response of measure changes based on number of sessions, and the hospital length of stay along with the secondary factors such as age, gender, other psychiatric comorbidities, social factors, and psychiatric medications were analyzed. Results: BLT is feasible on acute psychiatric inpatient floor with adherence of 94% and has very few side effects. The repeated measures of depression and functioning demonstrated significant decrease in depression and improvement in functioning. Although not statistically significant, clinical meaningful dose-response relationship was found between a number of BLT sessions and improvement in depressive symptoms with five BLT sessions being an optimal amount for depression amelioration. Conclusion: BLT combined with the ongoing psychopharmacological treatment was well tolerated and easy to administer. It offers a simple, safe, and cost-effective approach to augmenting depressive treatment on an acute psychiatric floor.

Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibited colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activate PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduced the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibited the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, which resulted in caspase activation and apoptosis. This was determined to be through a PKG mediated pathway through the use of small molecule inhibitors of PKG and PKA. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues in a cDNA array. We also report the increase in PDE10 mRNA in 50% of a small collection of human clinical specimens collected at the Mitchell Cancer Institute (n = 13). In addition, novel PDE10 inhibitor, MCI-030, reduced tumor size and activated PDE10 signaling mechanisms in vivo. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells. Citation Format: Kevin J. Lee, Ashley S. Lindsey, Luciana Madeira da Silva, Alisa Trinh, Bernard Gary, Joel Andrews, Veronica Ramirez-Alcantara, Adam B. Keeton, Wen-Chi Chang, Margie Clapper, Gary A. Piazza. Beta-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 331.

IntroductionPalinacousis, the phenomenon in which sounds are internally perseverated or repeated has not heretofore been reported occurring exclusively to an individual’s own voice.MethodsA 52-year-old woman started to experience auditory hallucinations of her voice at 3 years old when she began talking out loud. The auditory hallucinations of her own voice, yclept autopalinacousis, consisting of one to three words, were affectively neutral, rarely disruptive, and unchanged by psychiatric medications. During these palinacoustic phenomena, she would hear the last few words she had spoken out loud repeat inside her head in both ears. When the autopalinacousis occurred, the words were repeated just once. Sound quality was an exact replication of how it was originally spoken. She only experienced the palinacousis to her own voice and never to any other sounds. For the palinacousis to occur, she had to verbally state the words loud enough for her to hear. If she spoke out loud but could not hear her own voice, via occlusion of her external auditory canal or presence of loud noise, the internal auditory repetition would not occur. However, after the auditory stimulus was sensed, nothing could reduce the palinacousis. The palinacousis could occur if she read out loud, but not if she read silently. The frequency of the autopalinacousis ranged from a few times a week to several times a day and was associated with reduced sleep, but unaffected by mood, psychiatric medications, or headaches. Five months prior to her psychiatric hospitalization, she began to experience paranoid delusions, decreased sleep, increased activity, rapid speech, and auditory hallucinations of one male and two female voices. In contrast to autopalinacousis, these auditory hallucinations consisted of full phrases or sentences, were affectively charged, intrusive, and diminished by psychiatric medications. No palinacousis occurred with the hallucinated voices.ResultsAbnormalities: Mental Status Examination: Speech: pressured. Oriented x2. Memory: ability to remember 5 digits forwards and 2 digits backwards. She is not able to spell with word “world.” Calculation ability: poor. MRI of brain with and without contrast: normal.DiscussionIn cases where patients with psychotic illness experience palinacousis, the palinacousis always appear after the psychotic illness has already manifested, anywhere from less than a year to 15 years later. Our patient’s palinacousis presented almost 5 decades before the onset of her auditory hallucinations and paranoid delusions. Furthermore, her palinacousis only occurred to her own spoken voice and never to any other voices. In those who present with auditory hallucinations, query as to the presence and characteristics of palinacousis is warranted.FundingNo Funding

Introduction: Mutations in ras genes that result in constitutive activation of Ras proteins are key drivers of oncogenesis, but no effective drugs have been developed that target these aberrant gene products. Through iterative chemical synthesis and screening using a phenotypic assay designed to select for Ras inhibitors, we identified a small-molecule lead compound that was then optimized for potency and selectivity to inhibit the growth of tumor cells harboring activated Ras relative to cells lacking activated Ras. Materials and methods: Viable cell number was measured using the CellTiter-Glo® ATP assay (Promega) following 72 hr of treatment. Ras activation status was measured by precipitating GTP-bound Ras from cell lysates with GST-Raf1-RBD/GSH sepharose followed by western blotting using anti-Ras antibody. Ras binding was determined by pre-incubating cell lysates with GST-Raf1-RBD/GSH sepharose, treating with test compounds for 30 min, followed by western blotting using anti-Ras antibody. Cell cycle distribution was measured by DNA content following DyeCycle Green labeling. Results: Low nanomolar concentrations of DC070-547 inhibited the growth of multiple tumor cell lines harboring activated K-Ras, N-Ras or H-Ras with selectivity indices greater than 100-fold over cells lacking activated Ras. By surveying a large panel of human colon, breast, and lung tumor cell lines, a strong correlation was measured between potency to inhibit tumor cell growth and Ras activation status. Ras selectivity was confirmed by transfecting human H322 lung tumor cells that lack activated Ras with mutant H-Ras and inducing sensitivity to DC070-547. The compound inhibited Ras-Raf binding as shown by Ras-pull down in cell lysates following treatment with DC070-547 at concentrations that inhibit tumor cell growth. DC070-547 also caused cell cycle arrest in the G2 phase selectively in tumor cells containing activated Ras. Interestingly, cultured epithelial cells derived from normal colon, mammary, and lung tissues were essentially refractory to treatment. Conclusion: While Ras is widely considered to be non-druggable, we have identified a series of compounds that potently and selectively inhibit the growth of tumor cells harboring activated Ras. With promising drug-like properties, DC070-547 has been selected from this series as a prospective drug development candidate that is being evaluated for anti-tumor efficacy and toxicity in preclinical models. Citation Format: Gary A. Piazza, Bing Zhu, Kevin Lee, Joshua Canzoneri, Sara Sigler, Ashley Lindsey, Veronica Ramirez-Alcantara, Luciana Madeira da Silva, Haddon Mullins, Alisa Trinh, Kristy Berry, Jacob Valiyaveettil, Adam B. Keeton, Xi Chen, Michael R. Boyd. Novel drug development candidate potently and selectively inhibits growth of tumor cells harboring activated Ras. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A140.