Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin.

Aspergillus flavus is an opportunistic pathogen of plants such as maize and peanut under conducive conditions such as drought stress resulting in significant aflatoxin production. Drought-associated oxidative stress also exacerbates aflatoxin production by A. flavus. The objectives of this study were to use proteomics to provide insights into the pathogen responses to H2O2-derived oxidative stress, and to identify potential biomarkers and targets for host resistance breeding. Three isolates, AF13, NRRL3357, and K54A with high, moderate, and no aflatoxin production, were cultured in medium supplemented with varying levels of H2O2, and examined using an iTRAQ (Isobaric Tags for Relative and Absolute Quantification) approach. Overall, 1,173 proteins were identified and 220 were differentially expressed (DEPs). Observed DEPs encompassed metabolic pathways including antioxidants, carbohydrates, pathogenicity, and secondary metabolism. Increased lytic enzyme, secondary metabolite, and developmental pathway expression in AF13 was correlated with oxidative stress tolerance, likely assisting in plant infection and microbial competition. Elevated expression of energy and cellular component production in NRRL3357 and K54A implies a focus on oxidative damage remediation. These trends explain isolate-to-isolate variation in oxidative stress tolerance and provide insights into mechanisms relevant to host plant interactions under drought stress allowing for more targeted efforts in host resistance research.

Minimal residual disease (MRD) after initial therapy is integral to risk stratification in B-and Tprecursor acute lymphoblastic leukemia (B-ALL, T-ALL). While MRD determines depth of remission, remission remains defined by morphology. We determined the outcomes of children with discordant assessments of remission by morphology vs. flow cytometry using patients age 1-30.99 years enrolled on Children's Oncology Group ALL trials who underwent bone marrow assessment at the end of induction (N=9 350). Morphologic response was assessed locally as M1 (<5% lymphoblasts; remission), M2 (5-25%), or M3 (>25%). MRD was centrally measured by flow cytometry. 19.8% of patients with M2/M3 morphology had MRD<5%. M1 with MRD≥5% was less common in B-ALL (0.9%) than T-ALL (6.9%; p<0.0001). In B-ALL, M1/MRD≥5% was associated with superior 5-year event-free survival (EFS) than M2/MRD≥5% (59.1%±6.5% vs. 39.1%±7.9%; p=0.009), but was inferior to M1/MRD<5% (87.1%±0.4%; p<0.0001). MRD levels were higher in M2/MRD≥5% than M1/MRD≥5% patients. In T-ALL, EFS was not significantly different between M1/MRD≥5% and M2/MRD ≥5%. Patients with morphologic remission but MRD ≥5% have outcomes similar to those who fail to achieve morphological remission, and significantly inferior to those with M1 marrows and concordant MRD, suggesting that flow cytometry should augment the definition of remission in ALL.

Mitogen-activated protein kinase (MPK) cascades play important roles in plant development, immune signaling and stress responses. MPK4 was initially identified as a negative regulator in systemic acquired resistance (SAR) because the levels of salicylic acid (SA) and reactive oxygen species (ROS) were higher in the Arabidopsis mpk4 mutant. MPK4 is highly expressed in guard cells, specialized epidermal cells forming stomatal pores on leaf surface that function at the frontline of bacterial pathogen invasion. In addition to biotic stresses, stomatal guard cells also mediate cellular responses to abiotic stimuli such as drought and CO changes. MPK4 appears to play different roles in different plant systems. In this review, we briefly discuss the protein kinase MPK4 functions and focus on its signaling roles in different plant systems, especially in stomatal guard cells.