A pilot study on the validity and reliability of the Patient Enablement Instrument (PEI) in a Chinese population.

BACKGROUND: The Patient Enablement Instrument (PEI) was developed to measure patients' enablement, which is an indicator of the effectiveness of a primary care consultation; however, to date, the PEI has not been tested in Asian populations. OBJECTIVES: The purpose of this study is to test the acceptability, validity, reliability and other psychometric properties of a Chinese [Hong Kong (HK)] translation of the PEI in Chinese patients in Hong Kong and whether these properties would be affected by different timing of administration. METHODS: A Chinese (HK) translation of the PEI was developed by iterative forward-backward translations and the content validity was assessed by a cognitive debriefing interview with 10 Chinese patients. It was then administered to 152 adult patients attending a government-funded primary care clinic in Hong Kong both immediately after the consultation and 2-3 weeks later by telephone. Internal construct validity was assessed by item-scale correlations and factor analysis, test-retest reliability was assessed by intraclass correlation (ICC) and sensitivity was assessed by known group comparison. RESULTS: The Chinese (HK) PEI was semantically equivalent to the original PEI for all items. Acceptability of the PEI was high with 83.1% response and 100% completion rates. Statistical analyses showed no difference between test and retest means as well as good reproducibility (ICC 0.75). Internal reliability determined by Cronbach's alpha was >0.8 irrespective of timing of administration. Scale construct validity was confirmed by strong (r>0.4) item-scale correlations and resumed to a one-factor hypothesized structure. PEI scores were significantly higher in younger patients supporting sensitivity. There was no significant difference in the psychometric properties or scores between the assessment results from immediately after and 2-weeks post-consultation. CONCLUSIONS: A Chinese (HK) translation of the PEI equivalent to the original is now available for application to Chinese populations. Pilot testing supported its acceptability, validity, reliability and sensitivity. Further studies to confirm its construct validity and responsiveness will help to establish the Chinese (HK) PEI as an outcome measure of the effectiveness of primary care consultations in Chinese patients.

Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1).

Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).

Exacerbated brain edema in a rat streptozotocin model of hyperglycemic ischemic stroke: Evidence for involvement of blood-brain barrier Na-K-Cl cotransport and Na/H exchange.

Cerebral edema is exacerbated in diabetic ischemic stroke through poorly understood mechanisms. We showed previously that blood-brain barrier (BBB) Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) are major contributors to edema formation in normoglycemic ischemic stroke. Here, we investigated whether hyperglycemia-exacerbated edema involves changes in BBB NKCC and NHE expression and/or activity and whether inhibition of NKCC or NHE effectively reduces edema and injury in a type I diabetic model of hyperglycemic stroke. Cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundances and activities were determined by Western blot, radioisotopic flux and microspectrofluorometric methods. Cerebral edema and Na in rats subjected to middle cerebral artery occlusion (MCAO) were assessed by nuclear magnetic resonance methods. Hyperglycemia exposures of 1-7d significantly increased CMEC NKCC and NHE abundance and activity. Subsequent exposure to ischemic factors caused more robust increases in NKCC and NHE activities than in normoglycemic CMEC. MCAO-induced edema and brain Na uptake were greater in hyperglycemic rats. Intravenous bumetanide and HOE-642 significantly attenuated edema, brain Na uptake and ischemic injury. Our findings provide evidence that BBB NKCC and NHE contribute to increased edema in hyperglycemic stroke, suggesting that these Na transporters are promising therapeutic targets for reducing damage in diabetic stroke.

Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.