SUMMARYNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide1. Chemotherapies such as the topoisomerase II inhibitor (TopoIIi) etoposide effectively reduce disease in a minority of NSCLC patients2,3; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention4. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the Polycomb Repressive Complex 2 (PRC2) is well known to tri-methylate Histone H3 at lysine 27 (H3K27me3) and elicit gene silencing5. Here, we demonstrate that EZH2 inhibition (EZH2i) had differential effects on TopoIIi response of NSCLCs in vitro and in vivo. EGFR and BRG1 mutations were genetic biomarkers that predicted enhanced sensitivity to TopoIIi in response to EZH2i. BRG1 loss-of-function mutant tumors responded to EZH2i with increased S phase, anaphase bridging, apoptosis, and TopoIIi sensitivity. Conversely, EGFR and BRG1 wild-type tumors up-regulated BRG1 in response to EZH2i and ultimately became more resistant to TopoIIi. EGFR gain-of-function mutant tumors were also sensitive to dual EZH2i and TopoIIi, due to genetic antagonism between EGFR and BRG1. These findings suggest an exciting opportunity for precision medicine in the genetically complex disease of NSCLC.

Recently, near-infrared (NIR) fluorescence light has been applied to image various biological events in vivo, because it penetrates tissue more efficiently than light in the visible spectrum. Compounds exhibiting fluorescent properties in the NIR range are key elements for this upcoming optical imaging technology. In this paper, we report the synthesis of four new, water-soluble NIR cyanine fluorochromes which have superior chemical stability and optical properties. Each fluorochrome was designed with a monoreactive carboxyl group for labeling purposes. When multiple fluorochromes were attached to a single macromolecule, fluorescence quenching was observed. On the basis of this property, a novel autoquenched enzyme sensitive NIR fluorescence probe was prepared.

Purpose: This study assesses the sensitivity and specificity of Mandarin versions of two psychosocial screening tools for adjustment, anxiety and depressive disorders: the Hospital Anxiety and Depression Scale (HADS), and the Distress Thermometer (DT).Methods: The two scales were used to screen 103 consecutive cancer patients seen for psychiatric evaluation at KF-SYSCC between May and November 2004 prior to their psychiatric interviews. Each scale was tested against clinical psychiatric diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition for their sensitivity and specificity.Results: For the Mandarin version of the DT, receiver operating characteristic (ROC) analyses identified a DT score of 4 as the optimal cut-off, with sensitivity and specificity of 98 and 73%, respectively. For the Mandarin version of the HADS, ROC identified a score of 9 and 8 as the optimal cutoffs for the respective anxiety and depression subscales (HADS-a and HADS-d), with sensitivities and specificities of 84 and 73, 72 and 86%, respectively. For the full scale of the HADS (HADS-t), 15 was identified as the optimal cutoff, which yielded sensitivity and specificity of 84 and 68%, respectively. Using the frequency table, the concordance rate of the two scales was found to be 72-80% based on the above optimal cut-offs.Conclusion: The Mandarin versions of the HADS and the DT are efficacious for screening anxiety and depression for our population. Compared with the HADS-t, the DT appears to have not only higher sensitivity, but also higher specificity.

Fluorescence optical imaging technologies are currently being developed to image specific molecular targets in vivo. Detection technologies range from those providing microscopic detail to whole body imaging systems with potential clinical use. A number of target-specific near-infrared imaging probes have recently been developed to image receptors, antigens, and enzymes. The goal of the current study was to evaluate a new near-infrared (NIR) folate receptor (FR)-targeted imaging probe for its ability to improve detection of FR-positive cancers. We hypothesized that modification of folate would retain receptor affinity in vivo, despite the bulkier NIR fluorochrome, NIR2 (em = 682 nm). Cellular uptake of the NIR conjugates was significantly higher in FR-positive nasopharyngeal epidermoid carcinoma, KB cells, compared to FR-negative human fibrosarcoma, HT1080 cells. When tumors were implanted in vivo, equal-sized KB tumors showed a 2.4-fold higher signal intensity compared to HT1080 tumors (24 h). The maximum signal-to-background ratio (3-fold) was observed at 24 h in KB tumor. Injection of the unmodified NIR2 fluorochrome did not result in persistent contrast increases under similar conditions. Furthermore, tumor enhancement with the NIR2-folate probe persisted over 48 h and was inhibitable in vivo by administration of unlabeled folate. These results indicate that folate-modified NIR fluorochrome conjugate can be used for improved detection of FR-positive tumors.

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Highlights d Ras G13D proteins have open active sites with disconnected switches I and II d KRas G13D shows unique destabilization of the nucleotidebinding pocket d KRas G13D has attenuated oncogenic phenotype relative to KRas G12D d KRas G13D and KRas G12D are more sensitive to Erk than to Akt inhibition

A flexible, porous TiOxNy sheet consisting of numerous conductive fibers was synthesized by nitridation of titanate and further used as an electrochemical electrode. The high surface area and mixed-oxidation state of titanium make TiOxNy sheets to be promising candidates for a good supercapacitor.

Objective: We evaluated the psychiatric comorbidities in adults who were diagnosed with Diagnostic and Statistical Manual of Mental disorders, 5th edition attention-deficit/hyperactivity disorder as a function of recalled symptom onset before and after the age of 7 years and whether the childhood attention-deficit/hyperactivity disorder symptoms were associated with psychiatric comorbidities. Method:In all, 214 adults who were diagnosed with Diagnostic and Statistical Manual of Mental disorders, 5th edition attention-deficit/hyperactivity disorder and 174 non-attention-deficit/hyperactivity disorder controls (aged 17-40 years) received psychiatric interviews to confirm their previous and current attention-deficit/hyperactivity disorder status and other psychiatric diagnoses. Demographics and risks of lifetime psychiatric disorders were compared among three groups: (1) attention-deficit/hyperactivity disorder, onset <7 years (early-onset); (2) attention-deficit/hyperactivity disorder, onset between 7 and 12 years (late-onset) and (3) non-attention-deficit/hyperactivity disorder controls. We also tested the effects of attention-deficit/hyperactivity disorder symptoms on the risk of later psychiatric comorbidities by Cox regression analyses. Results:Regardless of the age of onset, attention-deficit/hyperactivity disorder was significantly associated with a wide range of psychiatric comorbidities. There were similar comorbid patterns between early-and late-onset attentiondeficit/hyperactivity disorder. Regardless of attention-deficit/hyperactivity disorder diagnosis, increased severity of attention-deficit/hyperactivity disorder symptoms was associated with higher risks of oppositional defiant disorder, conduct disorder, dysthymia and sleep disorder but not major depression, which was associated with the attention-deficit/ hyperactivity disorder diagnosis. Conclusion:Our findings suggest that elevating the threshold of age of onset to 12 years in Diagnostic and Statistical Manual of Mental disorders, 5th edition would not over-diagnose attention-deficit/hyperactivity disorder in the adult population. Recalled childhood attention-deficit/hyperactivity disorder symptom severity was correlated with conduct disorder, oppositional defiant disorder, dysthymia and sleep disorders.