Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors.

Purpose:To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods:In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m2). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results:A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3-4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were recorded in 38 patients (70%). In part 1, no maximum tolerated dose was achieved and 1600 mg/day was determined to be the RP2D. Of 38 patients evaluable for efficacy, 1 (3%) had complete response, 5 (13%) partial response, 13 (34%) stable disease, and 17 (45%) progressive disease. No drug-drug interactions were found. Plasma CSF-1 levels increased 1.6- to 53-fold, and CD14dim/CD16+ monocyte levels decreased by 57-100%. Conclusions:The combination of pexidartinib and paclitaxel was generally well tolerated. RP2D for pexidartinib was 1600 mg/day. Pexidartinib blocked CSF-1R signaling, indicating potential for mitigating macrophage tumor infiltration

Manual / Issue 8 / Give and Take

Manual, a journal about art and its making. Give and Take. The eigth issue. Manual 8 (Give and Take) explores interaction, transaction, and social exchange and indebtedness. The earliest known use of the expression “give and take” can be traced to horse racing. It referred to races in which larger, stronger horses carried more weight, and smaller ones, less. Implied therein is an accounting for relative capacities. In such a race, the goal remains the same—crossing the finish line first—but introducing this variable highlights the relationship between the competing horses. A win is only meaningful if each horse can be considered in relation to the others. We . . . find ourselves in a historical moment that makes our interconnectedness both more visible and more complex. Boundaries—physical, geographical, ideological—have become more porous, and the institutions that have provided structure—while always deeply flawed—have shown themselves to be more vulnerable than some of us would have liked to believe. Old systems are breaking down, giving way. New ones will take hold. —Mary-Kim Arnold, from the introduction to Issue 8: Give and Takehttps://digitalcommons.risd.edu/risdmuseum_journals/1034/thumbnail.jp

Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosinebinding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237. Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation

Median raphe region stimulation alone generates remote, but not recent fear memory traces

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Vital rates of sardine and anchovy larvae: trying to shed new light on early life history dynamics

36th Annual Larval Fish Conference, 2-6 July 2012, Os, NorwayLaboratory experiments to study the vital rates of sardine (Sardina pilchardus) and anchovy (Engraulis encrasicolus) larvae in relation to differences in several key physical and biological factors considered most important for regulating their growth and survival, are being carried out in the framework of the project VITAL, financed by the Portuguese Foundation for Science and Technology (PTDC/MAR/111304/2009). The experiments aim at obtaining parameters such as the physiological tolerance limits of temperature, salinity and food availability for larvae survival and their influence on larval growth and ingestion rates. The nutritional condition of larvae reared in the laboratory is being monitored and compared with larvae collected in the wild, validating combined techniques (fatty acids and RNA/DNA). The quantitative estimates of the vital rates for the larvae of these fish species under controlled laboratory conditions will be used for parameterize an individual-based model to couple to a hydrodynamic model developed for the western Portuguese coast. Efforts to build models describing environmental regulation of small pelagic fish species (e.g., to examine links between climate and recruitment) are currently hampered by a lack of data such as the vital rates of the larval phase, to which we hope to contribute with our research. In this talk, we will present a synopsis of the results obtained so far for sardines, from adult fish collection and spawning initiation to the experiments of growth rates of sardine larvae under different prey regimes. Nearly 300 adult sardines were acclimated to a tank of the Oceanrio de Lisboa and since 2010 have spawned viable eggs for more than 200 days. Although there were no significant differences in egg size, the mean size of sardine larvae at hatch was significantly different amongst experiments (2.8 - 4.8 mm). Interestingly, in those experiments which had, on average, smaller larvae at hatch, the growth during the first week of life appeared to be higher than in experiments with larger larvae; early growth was significantly related to size-at-hatch until 9 dph, 5 days beyond the exogenous feeding initiation. The growth and survival for the remaining period of exogenous feeding was affected by food type and concentration. Highest growth and nutritional condition (RNA/DNA) of sardine larvae, growing up to 75 dph, were obtained using high concentrations of a mixed diet, combining Gymnodinium sp., rotifers and Acartia grani nauplii. This diet guaranteed higher growth and survival than a diet based on wild planktonPeer reviewe

Effector proteins of the bacterial pathogen pseudomonas syringae alter the extracellular proteome of the host plant, Arabidopsis thaliana

In plants, potential pathogenic bacteria do not enter the host cell. Therefore, a large portion of the molecular interaction between microbial pathogen and host occurs in the extracellular space. To investigate potential mechanisms of disease resistance and susceptibility, we analyzed changes in the extracellular proteome, or secretome, using the Arabidopsis-Pseudomonas syringae pathosystem. This system provides the possibility to directly compare interactions resulting in basal resistance, susceptibility, and gene-specific resistance by using different genotypes of Pseudomonas on the same host. After infecting suspension-cultured cells of Arabidopsis with the Pseudomonas strain of interest, we isolated protein from the cell culture medium representing the secretome. After one-dimensional gel separation and in-gel digestion of proteins, we used iTRAQ (isobaric tags for relative and absolute quantitation) labeling in conjunction with LC-MS/MS to perform relative quantitative comparisons of the secretomes from each of these interactions. We obtained quantitative information from 45 Arabidopsis proteins that were present in all three biological experiments. We observed complex patterns of accumulation, ranging from proteins that decreased in abundance in the presence of all three bacterial strains to proteins that specifically increased or decreased during only one of the interactions. A particularly intriguing result was that the virulent bacteria (e.g. a susceptible interaction) caused the extracellular accumulation of a specific subset of host proteins lacking traditional signal peptides. These results indicate that the pathogen may manipulate host secretion to promote the successful invasion of plants