A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors.

BackgroundThis first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.MethodsThree to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208.ResultsFifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed.ConclusionsIn this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer

C3G mediated suppression of malignant transformation involves activation of PP2A phosphatases at the subcortical actin cytoskeleton

In previous work, we demonstrated that C3G suppresses Ras oncogenic transformation by a mechanism involving inhibition of ERK phosphorylation. Here we present evidences indicating that this suppression mechanism is mediated, at least in part, by serine/threonine phosphatases of the PP2A family. Thus: (i) ectopic expression of C3G or C3GΔCat (mutant lacking the GEF activity) increases specific ERK-associated PP2A phosphatase activities; (ii) C3G and PP2A interact, as demonstrated by immunofluorescence and co-immunoprecipitation experiments; (iii) association between PP2A and MEK or ERK increases in C3G overexpressing cells; (iv) phosphorylated-inactive PP2A level decreases in C3G expressing clones and, most importantly, (v) okadaic acid reverts the inhibitory effect of C3G on ERK phosphorylation. Moreover, C3G interacts with Ksr-1, a scaffold protein of the Ras-ERK pathway that also associates with PP2A. The fraction of C3G involved in transformation suppression is restricted to the subcortical actin cytoskeleton where it interacts with actin. Furthermore, the association between C3G and PP2A remains stable even after cytoskeleton disruption with cytochalasin D, suggesting that the three proteins form a complex at this subcellular compartment. Finally, C3G- and C3GΔCat-mediated inhibition of ERK phosphorylation is reverted by incubation with cytochalasin D. We hypothesize that C3G triggers PP2A activation and binding to MEK and ERK at the subcortical actin cytoskeleton, thus favouring ERK dephosphorylation. © 2007 Elsevier Inc. All rights reserved.This work was supported by grants SAF2003-04177 andGEN2003- 20239-C06-02 from MEC, Spain, FIS-FEDERPI030651, PI041324 and PI061274 from ISCIII,MSC, Spain, as well as institutional support from Redes Temáticas (C03/10 and RD06/0020/0000) de investigación en cáncer from ISCIII, MSC, Spain. S. M-E is a postodoctoral fellow supported by grant GEN2003-20239-C06-02. C.G. was supported by the Ramón y Cajal Program from the Spanish Ministry of Education.Peer Reviewe

Task-oriented reading efficiency: interplay of general cognitive ability, task demands, strategies and reading fluency

The associations among readers’ cognitive skills (general cognitive ability, reading skills, and attentional functioning), task demands (easy versus difficult questions), and process measures (total fixation time on relevant and irrelevant paragraphs) was investigated to explain task-oriented reading accuracy and efficiency (number of scores in a given time unit). Structural equation modeling was applied to a large dataset collected with sixth-grade students, which included samples of dysfluent readers and those with attention difficulties. The results are in line with previous findings regarding the dominant role of general cognitive ability in the accuracy of task-oriented reading. However, efficiency in task-oriented reading was mostly explained by the shorter viewing times of both paragraph types (i.e., relevant and irrelevant), which were modestly explained by general cognitive ability and reading fluency. These findings suggest that high efficiency in task orientation is obtained by relying on a selective reading strategy when reading both irrelevant and relevant paragraphs. The selective reading strategy seems to be specifically learned, and this potentially applies to most students, even those with low cognitive abilities

Precision measurement of the half-life and the decay branches of 62Ga

In an experiment performed at the Accelerator Laboratory of the University of Jyvaskyla, the beta-decay half-life of 62Ga has been studied with high precision using the IGISOL technique. A half-life of T1/2 = 116.09(17)ms was measured. Using beta-gamma coincidences, the gamma intensity of the 954keV transition and an upper limit of the beta-decay feeding of the 0+_2 state have been extracted. The present experimental results are compared to previous measurements and their impact on our understanding of the weak interaction is discussed.Comment: 7 pages, 7 figures, submitted to EPJ

Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML

A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell–microenvironment interactions

The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous “hurdle” to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile “soil” that prevents the “seed” from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48763/1/20522_ftp.pd

Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis

UNLABELLED: Clonal hematopoiesis resulting from the enhanced fitness of mutant hematopoietic stem cells (HSC) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, whereas the loss of TNFR2 resulted in the overproduction of mutant myeloid cells without altering HSC fitness. These results nominate TNFR1 as a target to reduce clonal hematopoiesis and the risk of associated diseases and support a model in which clone size and mature blood lineage production can be independently controlled to modulate favorable and unfavorable clonal hematopoiesis outcomes. SIGNIFICANCE: Through the identification and dissection of TNFα signaling as a key driver of murine Dnmt3a-mutant hematopoiesis, we report the discovery that clone size and production of specific mature blood cell types can be independently regulated. See related commentary by Niño and Pietras, p. 2724. This article is highlighted in the In This Issue feature, p. 2711

Sex differences in antipsychotic efficacy and side effects in schizophrenia spectrum disorder:results from the BeSt InTro study

Current guidelines for patients with schizophrenia spectrum disease do not take sex differences into account, which may result in inappropriate sex-specific treatment. In the BeSt InTro study, a total of 144 patients (93 men and 51 women) with a schizophrenia spectrum diagnosis and ongoing psychosis were included and randomized to amisulpride, aripiprazole, or olanzapine in flexible dose. This trial is registered with ClinicalTrials.gov (NCT01446328). Primary outcomes were sex differences in dose, dose-corrected serum levels, efficacy, and tolerability. Dosing was higher for men than for women in the aripiprazole group (p = 0.025) and, at trend level, in the olanzapine group (p = 0.056). Dose-corrected serum levels were 71.9% higher in women than in men for amisulpride (p = 0.019) and 55.8% higher in women than in men for aripiprazole (p = 0.049). In the amisulpride group, men had a faster decrease in psychotic symptoms than women (p = 0.003). Moreover, amisulpride was more effective than the other medications in men but not in women. Prolactin levels were higher in women than in men, especially for amisulpride (p < 0.001). Also, women had higher BMI increase on amisulpride compared to the two other antipsychotics (p < 0.001). We conclude that clinicians should be aware of the risks of overdosing in women, especially for amisulpride and aripiprazole. Amisulpride is highly effective in men, but in women, amisulpride showed more severe side effects and may thus not be the drug of first choice. Our study shows that sex differences should be taken into account in future studies on antipsychotics. Future research is warranted to evaluate these preliminary results

Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1

Cell-cell junctions are an integral part of epithelia and are often disrupted in cancer cells during epithelial-to-mesenchymal transition (EMT), which is a main driver of metastatic spread. We show here that Metastasis suppressor-1 (Mtss1; Missing in Metastasis, MIM), a member of the IMD-family of proteins, inhibits cell-cell junction disassembly in wound healing or HGF-induced scatter assays by enhancing cell-cell junction strength. Mtss1 not only makes cells more resistant to cell-cell junction disassembly, but also accelerates the kinetics of adherens junction assembly. Mtss1 drives enhanced junction formation specifically by elevating Rac-GTP. Lastly, we show that Mtss1 depletion reduces recruitment of F-actin at cell-cell junctions. We thus propose that Mtss1 promotes Rac1 activation and actin recruitment driving junction maintenance. We suggest that the observed loss of Mtss1 in cancers may compromise junction stability and thus promote EMT and metastasis

Brain Source Correlates of Speech Perception and Reading Processes in Children With and Without Reading Difficulties

Neural correlates in reading and speech processing have been addressed extensively in the literature. While reading skills and speech perception have been shown to be associated with each other, their relationship remains debatable. In this study, we investigated reading skills, speech perception, reading, and their correlates with brain source activity in auditory and visual modalities. We used high-density event-related potentials (ERPs), fixation-related potentials (FRPs), and the source reconstruction method. The analysis was conducted on 12–13-year-old schoolchildren who had different reading levels. Brain ERP source indices were computed from frequently repeated Finnish speech stimuli presented in an auditory oddball paradigm. Brain FRP source indices were also computed for words within sentences presented in a reading task. The results showed significant correlations between speech ERP sources and reading scores at the P100 (P1) time range in the left hemisphere and the N250 time range in both hemispheres, and a weaker correlation for visual word processing N170 FRP source(s) in the posterior occipital areas, in the vicinity of the visual word form areas (VWFA). Furthermore, significant brain-to-brain correlations were found between the two modalities, where the speech brain sources of the P1 and N250 responses correlated with the reading N170 response. The results suggest that speech processes are linked to reading fluency and that brain activations to speech are linked to visual brain processes of reading. These results indicate that a relationship between language and reading systems is present even after several years of exposure to print