LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

Real-time feedback on nonverbal clinical communication. Theoretical framework and clinician acceptance of ambient visual design.

INTRODUCTION: This article is part of the focus theme of Methods of Information in Medicine on "Pervasive Intelligent Technologies for Health". BACKGROUND: Effective nonverbal communication between patients and clinicians fosters both the delivery of empathic patient-centered care and positive patient outcomes. Although nonverbal skill training is a recognized need, few efforts to enhance patient-clinician communication provide visual feedback on nonverbal aspects of the clinical encounter. OBJECTIVES: We describe a novel approach that uses social signal processing technology (SSP) to capture nonverbal cues in real time and to display ambient visual feedback on control and affiliation--two primary, yet distinct dimensions of interpersonal nonverbal communication. To examine the design and clinician acceptance of ambient visual feedback on nonverbal communication, we 1) formulated a model of relational communication to ground SSP and 2) conducted a formative user study using mixed methods to explore the design of visual feedback. METHODS: Based on a model of relational communication, we reviewed interpersonal communication research to map nonverbal cues to signals of affiliation and control evidenced in patient-clinician interaction. Corresponding with our formulation of this theoretical framework, we designed ambient real-time visualizations that reflect variations of affiliation and control. To explore clinicians' acceptance of this visual feedback, we conducted a lab study using the Wizard-of-Oz technique to simulate system use with 16 healthcare professionals. We followed up with seven of those participants through interviews to iterate on the design with a revised visualization that addressed emergent design considerations. RESULTS: Ambient visual feedback on non- verbal communication provides a theoretically grounded and acceptable way to provide clinicians with awareness of their nonverbal communication style. We provide implications for the design of such visual feedback that encourages empathic patient-centered communication and include considerations of metaphor, color, size, position, and timing of feedback. CONCLUSIONS: Ambient visual feedback from SSP holds promise as an acceptable means for facilitating empathic patient-centered nonverbal communication.

Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities.

ROCK1 and ROCK2 mediate important processes such as cell migration, invasion and metastasis, making them good targets for the development of antitumor agents. Recently, using a fragment-based approach and X-ray crystallography, we reported on the design and synthesis of novel Rho-kinase inhibitors (RKIs). Here, we selected a pair of RKIs, the closely related structural analogs RKI-18 (potent; IC50 values of 397 nM (ROCK1) and 349 nM (ROCK2)) and RKI-11 (weak/inactive; IC50 values of 38 µM (ROCK1) and 45 µM (ROCK2)), as chemical probes and determined their effects on cytoskeleton organization, signaling, apoptosis, anchorage-dependent and independent growth, migration and invasion. RKI-18 but not RKI-11 suppresses potently the phosphorylation of the ROCK substrate myosin light chain 2 (MLC2) in intact human breast, lung, colon and prostate cancer cells. Furthermore, RKI-18 is highly selective at decreasing the levels of P-MLC2 over those of P-Akt, P-S6 and P-Erk ½. RKI-18 suppresses ROCK-mediated actin fiber formation, following stimulation with LPA as well as p21-activated kinase (PAK)-mediated lamellipodia and filopodia formation following bradykinin or PDGF stimulation. Furthermore, RKI-18 but not RKI-11 inhibits migration, invasion and anchorage-independent growth of human breast cancer cells. The fact that the active ROCK inhibitor RKI-18, but not the inactive closely related structural analog RKI-11 is effective at suppressing malignant transformation suggests that inhibition of ROCK with RKI-18 results in preventing migration, invasion and anchorage-independent growth. The potential of this class of RKIs as anti-tumor agents warrants further advanced preclinical studies.

The effect of smoking on bone healing: A systematic review.

OBJECTIVES: To review the systemic impact of smoking on bone healing as evidenced within the orthopaedic literature. METHODS: A protocol was established and studies were sourced from five electronic databases. Screening, data abstraction and quality assessment was conducted by two review authors. Prospective and retrospective clinical studies were included. The primary outcome measures were based on clinical and/or radiological indicators of bone healing. This review specifically focused on non-spinal orthopaedic studies. RESULTS: Nine tibia studies and eight other orthopaedic studies were considered for systematic review. Of these 17 studies, 13 concluded that smoking negatively influenced bone healing. CONCLUSIONS: Smoking has a negative effect on bone healing, in terms of delayed union, nonunion and more complications.

Tips and tricks in renal artery angioplasty and stenting: angiography, stent placement, embolic protection, complications, and contrast induced nephropathy.

Patient selection and a thorough understanding of the technical aspects of percutaneous transluminal renal artery stent placement (PTRS) are paramount to obtaining optimal outcomes. The purpose of this paper is to review renal artery angiography and stent placement techniques. Tips and tricks for successful procedural outcome are described. The potential role of embolic protection devices is discussed and practices for avoiding complications including contrast induced nephropathy are reviewed.

Hypersensitivity pneumonitis: patterns on high-resolution CT.

Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is caused by inhalation of specific environmental organic antigens. This disease may have typical high-resolution CT findings that, in the appropriate clinical setting, can be sufficiently characteristic to allow a confident diagnosis without the need for a lung biopsy. In this pictorial essay, the high-resolution CT patterns of hypersensitivity pneumonitis are illustrated. The authors emphasize the correlation among the radiologic presentation, functional abnormalities, and pathologic findings.

Helical CT for the evaluation of suspected acute pulmonary embolism: diagnostic pitfalls.

Helical CT is being increasingly utilized for the evaluation of suspected pulmonary embolism (PE). Proper scan interpretation depends on the awareness of several diagnostic pitfalls that may simulate PE, including normal bronchovascular structures such as pulmonary veins, bronchi, and lymph nodes, technical considerations such as improper bolus timing and streak artifacts, and patient-related factors such as motion artifacts, pulmonary arterial catheters, and vascular shunts. An understanding of these pitfalls facilitates accurate diagnosis.

Preliminary experience with use of a selective 5HT3 receptor antagonist (ondansetron) to prevent high dose chemotherapy induced emesis.

Ondansetron was used as an antiemetic along with dexamethasone during 16 cycles of highly or moderately ematogenic chemotherapy. There was major control in two cycles and complete control in the remaining 14. Side effects were minor and did not require discontinuation of the drug. This combination, therefore, appears to be safe and effective in preventing chemotherapy induced emesis.

Epstein-Barr virus infectivity of Raji and Molt 4 cells: differences in cellular membrane lipids and apparent microviscosity.

Infection of lymphocytes by the Epstein-Barr virus (EBV) is initiated by attachment of the major virus glycoprotein gp350/220 to a cell surface glycoprotein, known as CR2 (CD21). In a productive infection the virus envelope fuses with host cell membranes either at the cell surface or within endocytic vesicles. To investigate the relevance of host cell membrane properties in the fusion process, we used the lymphoblastoid cell lines Raji and Molt 4. Both cell lines express CR2 and bind EBV; however, only the Raji cell supports virus-cell fusion. Lipid analysis of the two cell lines indicated that Raji cells had a significantly lower cholesterol to phospholipid molar ratio due to a greater membrane content of phospholipid relative to protein. Determination of cell membrane fluid dynamics by fluorescence polarization indicated that the apparent membrane microviscosity of Molt 4 cells was significantly greater than that of Raji. Increasing Raji cell membrane apparent microviscosity to values similar to those of Molt 4 cells by incubation with cholesteryl-hemisuccinate caused a reduction in EBV fusion with Raji cells. However, experiments designed to allow EBV infection of Molt 4 cells whose plasma membranes had been fluidized were unsuccessful. These studies suggest that the lipid composition and other as yet unidentified factors are involved in entry of EBV into cells.

Insulin stimulates phosphatidylinositol 3-kinase activity in rat neuronal primary cultures.

We investigated the effect of insulin on phosphatidylinositol (PtdIns) 3-kinase (PtdIns 3-kinase) activity in neuronal cultures to determine if this enzyme is involved with the neurotrophic actions of insulin. Insulin caused a concentration-dependent increase in PtdIns 3-kinase activity in anti-phosphotyrosine immunoprecipitates. The kinase activity was able to phosphorylate PtdIns, PtdIns 4-phosphate, and PtdIns 4,5-bisphosphate. In intact neurons, a 10-min 1 mM insulin treatment in the presence of [32P]orthophosphate increased the levels of both 3-[32P]PtdIns phosphate and 3,4-[32P]PtdIns bisphosphate by 55 and 193%, respectively. This increase was associated with an increase in neurite outgrowth mediated by insulin. Our results indicate that insulin treatment of neuronal cells in primary culture increases PtdIns 3-kinase activity and the formation of the unique D-3-phosphorylated phosphoinositides, suggesting that growth factor-mediated neuronal growth may include the formation of novel phosphoinositide 3-phosphate phospholipids.

Bayesian forecasting of serum lithium concentrations. Comparison with traditional methods.

Twelve pharmacokinetic methods of estimating lithium maintenance dosage requirements were compared in 21 patients with bipolar illness. Methods which were compared included the single- and multiple-point methods of Perry, 4 non-linear regression and 6 Bayesian methods. The REVOL algorithm was employed for converging on to estimates of clearance and apparent volume of distribution for the non-linear regression and Bayesian methods. Data analysis was based on an evaluation of prediction error as a measure of bias, and absolute prediction error as a measure of precision. In a direct comparison, there were no statistically significant differences in bias or precision between any of the methods.

Comparison of pharmacokinetic procedures for dosing lithium based on analysis of prediction error.

Five pharmacokinetic methods for estimating maintenance dosage requirements of lithium carbonate were compared retrospectively in 20 inpatients with acute bipolar illness. Specific pharmacokinetic methods tested included the method of Cooper, the multiple-point method of Perry, the single-point method of Perry, the method of Zetin, and the method of Pepin. Data analysis was based on evaluation of prediction error or the difference between the predicted steady-state lithium concentration and the measured steady-state lithium concentration at equivalent daily doses. Each dosing method was assessed in regard to accuracy and bias of predicted steady-state serum lithium concentrations. Bias was assessed by comparison of the median value of the prediction error with zero. The dosing recommendation based on the Cooper nomogram resulted in a significant positive bias (p less than or equal to 0.05). Intermethod accuracy was assessed by comparison of the absolute prediction errors of each dosing method. Significant differences in accuracy were observed between the method of Pepin when compared with the single-point method of Perry (p less than or equal to 0.05, k-sample sign test). All other comparisons were nonsignificant.

Transdermal delivery of isoproterenol HCl: an investigation of stability, solubility, partition coefficient, and vehicle effects.

Effects of solubility, partition coefficient, and selected adjuvants (propylene glycol and Azone) on percutaneous penetration of isoproterenol HCl have been investigated using human cadaver skin. Isoproterenol was found to be stable (less than 1% decomposition) for 24 hr at 22 +/- 0.5 degrees C in the pH range 1 to 7 in the following solvents: water, normal saline, propylene glycol and a series of propylene glycol-water mixtures (10, 20, 40, and 60%; v/v); however, decomposition was significant beyond pH 8. In normal saline, the rate of decomposition increased significantly with an increase in temperature to 37 degrees C. The solubility of isoproterenol HCl decreased and its skin/vehicle partition coefficient increased with increasing proportions of propylene glycol in the vehicle, while the product of the solubility and partition coefficient appeared to plateau at 20% propylene glycol in water. Optimal penetration enhancing effects of Azone were seen when incorporated at a concentration of 1% (v/v) in the 20% (v/v) propylene glycol-water blend and, more significantly, when skin was pretreated with pure Azone for 60 min prior to application of the drug formulation.