Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies.

CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

Nanoparticle-mediated tumor cell expression of mIL-12 via systemic gene delivery treats syngeneic models of murine lung cancers.

Treatment of cancers in the lung remains a critical challenge in the clinic for which gene therapy could offer valuable options. We describe an effective approach through systemic injection of engineered polymer/DNA nanoparticles that mediate tumor-specific expression of a therapeutic gene, under the control of the cancer-selective progression elevated gene 3 (PEG-3) promoter, to treat tumors in the lungs of diseased mice. A clinically tested, untargeted, polyethylenimine carrier was selected to aid rapid transition to clinical studies, and a CpG-free plasmid backbone and coding sequences were used to reduce inflammation. Intravenous administration of nanoparticles expressing murine single-chain interleukin 12, under the control of PEG-3 promoter, significantly improved the survival of mice in both an orthotopic and a metastatic model of lung cancer with no marked symptoms of systemic toxicity. These outcomes achieved using clinically relevant nanoparticle components raises the promise of translation to human therapy.

Organizing for innovation: towards successful translational research.

The current productivity crisis in drug discovery has prompted the pharmaceutical industry to decentralize R&D, which is now more responsive, more flexible and better connected to research in academia and biotechnology firms. Organizational changes are also under way in academia. Universities are expanding their technology transfer offices and research funders are investing more in translational research. This article explains how organizational changes in industry and academia can complement each other. Successful translation of research into innovative drugs needs to take account of the increasing organizational complexity of drug discovery as the knowledge to be integrated becomes more diffuse, specialized and valuable.

Investigations in subjects with cough following upper respiratory tract infection.

The study aimed to investigate subjects with cough following acute upper respiratory tract infection (URTI), and to compare those subjects unable to suppress cough ("non-suppressors") with those who were able to suppress cough ("suppressors"). Forty-three URTI subjects participated, 31 with cough associated with acute URTI and 12 healthy controls; 21 of the coughing subjects were "suppressors", 10 were "non-suppressors". We obtained responses to chemical and mechanical stimulation of the nasal cavity or the pharynx using both psychophysical measures and event-related potentials. The study provided the following results: (1) "non-suppressors" did not exhibit significantly different intensity ratings or event-related potentials in comparison to "suppressors" in terms of responses to intranasal irritant, mechanical, or olfactory stimuli; (2) when pharyngeal mechanical stimuli were investigated "suppressors" rated the stimuli as more intense than "non-suppressors" and controls; (3) latencies of event-related potentials to pharyngeal stimuli were longest in "non-suppressors". Keeping in mind the relatively small sample size, it appears possible to differentiate certain types of cough during uncomplicated URTI. This may help to explain interindividual differences in responsiveness to cough medication.

The antitussive effect of placebo treatment on cough associated with acute upper respiratory infection.

OBJECTIVE: The objective of this study was to determine the effects of a placebo treatment on cough in patients with cough associated with acute upper respiratory tract infection (URTI). METHODS: Patients with dry or slightly productive cough associated with a history of URTI were recruited. Cough frequency (CF) over 15 minutes was recorded by means of a microphone connected to a pen recorder. Cough suppression time (CST) was recorded when patients were instructed by means of a red light to try not to cough. Patients received either a single dose of vitamin E (placebo treatment) or no treatment. CF and CST were recorded before and 15 minutes after treatment. RESULTS: Twenty-seven patients were randomized to placebo treatment and 27 to the no-treatment group (mean age 22.6 years). The median difference between post- and pretreatment CF was -3 in the no-treatment group and -18 in the placebo group (p = .0003). There was a significant increase in CST in the placebo group compared with no treatment (p = .027). CONCLUSIONS: The results demonstrate that placebo treatment has significant antitussive activity. This placebo effect may be related to generation of central neurotransmitters such as endogenous opioids.

Evaluation of an experimental patch test model for the detection of irritant skin reactions to moisturisers.

BACKGROUND/AIMS: Moisturisers are used daily by a large number of people to prevent dryness of the skin. Irritant skin reactions to moisturisers are, however, known to occur. In order to prevent such irritant reactions reliable test methods for irritancy testing of moisturisers are needed. This study was undertaken to evaluate a non-invasive patch test model for the detection of irritant skin reactions to moisturisers. METHODS: Twenty healthy volunteers were patch tested with three different moisturisers: empty chamber, sodium lauryl sulphate and a moisturizer known to be non-irritating. Skin reactions were evaluated by visual scoring, measurement of transepidermal water loss (TEWL) by an Evaporimeter, blood flow by laser Doppler flowmetry and electrical capacitance by a Corneometer. RESULTS: A statistically significant increase in blood flow was found 48 h after application of one of the moisturisers tested, indicating an irritant effect of the product. A statistically significant decrease in skin hydration was found for the same moisturiser after 48 h. No statistically significant differences between the moisturisers were found by visual scoring. None of the products tested had any negative effect on the skin barrier function. CONCLUSION: The non-invasive patch test model was found useful for detecting irritant skin reactions to moisturisers.