This hypothesis-generating trial evaluated neoadjuvant ipatasertib–paclitaxel for early triple-negative breast cancer (TNBC).
In this randomized phase II trial, patients with early TNBC (T≥1.5cm, ...N0–2) were randomized 1:1 to receive weekly paclitaxel 80mg/m2 with ipatasertib 400mg or placebo (days 1–21 every 28days) for 12weeks before surgery. Co-primary end points were pathologic complete response (pCR) rate (ypT0/TisN0) in the intention-to-treat (ITT) and immunohistochemistry phosphatase and tensin homolog (PTEN)-low populations. Secondary end points included pCR rate in patients with PIK3CA/AKT1/PTEN-altered tumors and pre-surgery response rates by magnetic resonance imaging (MRI).
pCR rates with ipatasertib versus placebo were 17% versus 13%, respectively, in the ITT population (N=151), 16% versus 13% in the immunohistochemistry PTEN-low population (N=35), and 18% versus 12% in the PIK3CA/AKT1/PTEN-altered subgroup (N=62). Rates of overall and complete response (CR) by MRI favored ipatasertib in all three populations (CR rate 39% versus 9% in the PIK3CA/AKT1/PTEN-altered subgroup). Ipatasertib was associated with more grade ≥3 adverse events (32% versus 16% with placebo), especially diarrhea (17% versus 1%). Higher cycle 1 day 8 (C1D8) immune score was significantly associated with better response only in placebo-treated patients. All ipatasertib-treated patients with low immune scores and a CR had PIK3CA/AKT1/PTEN-altered tumors.
Adding ipatasertib to 12weeks of paclitaxel for early TNBC did not clinically or statistically significantly increase pCR rate, although overall response rate by MRI was numerically higher with ipatasertib. The antitumor effect of ipatasertib was most pronounced in biomarker-selected patients. Safety was consistent with prior experience of ipatasertib–paclitaxel. A T-cell-rich environment at C1D8 had a stronger association with improved outcomes in paclitaxel-treated patients than seen for baseline tumor-infiltrating lymphocytes. This dependency may be overcome with the addition of AKT inhibition, especially in patients with PIK3CA/AKT1/PTEN-altered tumors.
NCT02301988.
Summary
Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality ...traits in the species. We performed a functional genome‐wide association study (GWAS) of 17 wood traits in Norway spruce using 178 101 single nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings. We applied a Least Absolute Shrinkage and Selection Operator (LASSO‐based) association mapping method using a functional multilocus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine a significant quantitative trait locus. The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multilocus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.
Significance Statement
Wood provides both structural support and a transport route for water and solutes in trees. Our work provides a framework to dissect the genetic nature of wood formation and adds to our understanding of tree growth and development. With the current research focus on wood cell wall biosynthesis in general, and lignocellulose feedstock for biorefineries, we believe that this contribution will be of wide interest for the plant science community.
Confidence judgments are a central example of metacognition-knowledge about one's own cognitive processes. According to this metacognitive view, confidence reports are generated by a second-order ...monitoring process based on the quality of internal representations about beliefs. Although neural correlates of decision confidence have been recently identified in humans and other animals, it is not well understood whether there are brain areas specifically important for confidence monitoring. To address this issue, we designed a postdecision temporal wagering task in which rats expressed choice confidence by the amount of time they were willing to wait for reward. We found that orbitofrontal cortex inactivation disrupts waiting-based confidence reports without affecting decision accuracy. Furthermore, we show that a normative model can quantitatively account for waiting times based on the computation of decision confidence. These results establish an anatomical locus for a metacognitive report, confidence judgment, distinct from the processes required for perceptual decisions.
Plants optimize carbon assimilation while limiting water loss by adjusting stomatal aperture. In grasses, a developmental innovation—the addition of subsidiary cells (SCs) flanking two ...dumbbell-shaped guard cells (GCs)—is linked to improved stomatal physiology. Here, we identify a transcription factor necessary and sufficient for SC formation in the wheat relative Brachypodium distachyon. Unexpectedly, the transcription factor is an ortholog of the stomatal regulator AtMUTE, which defines GC precursor fate in Arabidopsis. The novel role of BdMUTE in specifying lateral SCs appears linked to its acquisition of cell-to-cell mobility in Brachypodium. Physiological analyses on SC-less plants experimentally support classic hypotheses that SCs permit greater stomatal responsiveness and larger range of pore apertures. Manipulation of SC formation and function in crops, therefore, may be an effective approach to enhance plant performance.
In situ forming chitosan hydrogels have been prepared via coupled ionic and covalent cross-linking. Thus, different amounts of genipin (0.05, 0.10, 0.15, and 0.20% (w/w)), used as a chemical ...cross-linker, were added to a solution of chitosan that was previously neutralized with a glycerol–phosphate complex (ionic cross-linker). In this way, it was possible to overcome the pH barrier of the chitosan solution, to preserve its thermosensitive character, and to enhance the extent of cross-linking in the matrix simultaneously. To investigate the contributions of the ionic cross-linking and the chemical cross-linking, separately, we prepared the hydrogels without the addition of either genipin or the glycerol–phosphate complex. The addition of genipin to the neutralized solution disturbs the ionic cross-linking process and the chemical cross-linking becomes the dominant process. Moreover, the genipin concentration was used to modulate the network structure and performance. The more promising formulations were fully characterized, in a hydrated state, with respect to any equilibrium swelling, the development of internal structure, the occurrence of in vitro degradability and cytotoxicity, and the creation of in vivo injectability. Each of the hydrogel systems exhibited a notably high equilibrium water content, arising from the fact that their internal structure (examined by conventional SEM, and environmental SEM) was highly porous with interconnecting pores. The porosity and the pore size distribution were quantified by mercury intrusion porosimetry. Although all gels became degraded in the presence of lysozyme, their degradation rate greatly depended on the genipin load. Through in vitro viability tests, the hydrogel-based formulations were shown to be nontoxic. The in vivo injection of a co-cross-linking formulation revealed that the gel was rapidly formed and localized at the injection site, remaining in position for at least 1 week.
Summary
Inhibition of coagulation greatly limits cancer metastasis in many experimental models. Cancer cells trigger coagulation, through expression of tissue factor or P‐selectin ligands that have ...correlated with worse prognosis in human clinical studies. Cancer cells also affect coagulation through expression of thrombin and release of microparticles that augment coagulation. In the cancer‐bearing host, coagulation facilitates tumour progression through release of platelet granule contents, inhibition of Natural Killer cells and recruitment of macrophages. We are revisiting this literature in the light of recent studies in which treatment of clinical cohorts with anticoagulant drugs led to diminished metastasis.
Dynamic cell identities underlie flexible developmental programs. The stomatal lineage in the Arabidopsis leaf epidermis features asynchronous and indeterminate divisions that can be modulated by ...environmental cues. The products of the lineage, stomatal guard cells and pavement cells, regulate plant-atmosphere exchanges, and the epidermis as a whole influences overall leaf growth. How flexibility is encoded in development of the stomatal lineage and how cell fates are coordinated in the leaf are open questions. Here, by leveraging single-cell transcriptomics and molecular genetics, we uncovered models of cell differentiation within Arabidopsis leaf tissue. Profiles across leaf tissues identified points of regulatory congruence. In the stomatal lineage, single-cell resolution resolved underlying cell heterogeneity within early stages and provided a fine-grained profile of guard cell differentiation. Through integration of genome-scale datasets and spatiotemporally precise functional manipulations, we also identified an extended role for the transcriptional regulator SPEECHLESS in reinforcing cell fate commitment.
Display omitted
•Distinct models of cell differentiation and lineage trajectories define leaf tissue•Cell-cycle regulators exhibit distinct, yet overlapping, expression profiles•Flexible stomatal lineage cell states exist along a continuum•Single-cell resolution refines cell fate commitment decisions that yield stomata
How do cells build developmentally flexible organs? Lopez-Anido et al. employed single-cell transcriptomics to uncover distinct models of cell differentiation within Arabidopsis leaf tissue. Along with revealing dynamics of cellular programs, they identified underlying cell heterogeneity within the epidermal lineage and interrogated new roles for a core transcriptional regulator.
PDF
