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Plant-parasitic nematodes cause severe economic losses to agriculture. As important biocontrol agents, nematophagous fungi evolved the ability to obtain nitrogen sources from nematodes. However, the impact of nitrogen sources on the growth and development of these fungi is largely unknown. In this study, we aimed to better understand how nitrogen sources could influence vegetative growth and conidiation through epigenetic regulation in the nematophagous fungus, Purpureocillium lavendulum. Through nutrition screening, we found a phenomenon of the fungus, limited colony extension with a large amount of conidia production when cultured on PDA media, can be altered by adding ammonia nitrate. Characterized by site-directed mutagenesis, the histone H3K14 acetylation was found to be involved in the alternation. Furthermore, the acetyltransferase PlGCN5 was responsible for H3K14 acetylation. Knockout of Plgcn5 severely diminished conidiation in P. lavendulum. Chip-seq showed that H3K14ac distributed in conidiation regulating genes, and genes in the MAPK pathway which may be the downstream targets in the regulation. These findings suggest that histone modification and nitrogen sources coordinated lifestyle regulation in P. lavendulum, providing new insight into the mechanism of growth regulation by nutritional signals for the carnivorous fungus. [ABSTRACT FROM AUTHOR]

Aim. To investigate the expressions of glutathione peroxidase 1 (GPX1) and caudal-related homeodomain transcription factor (CDX2) in GAC and their correlation with clinicopathological features and tumor cell proliferation. Methods. The expressions of GPX1, CDX2, and Ki67 were immunohistochemically evaluated in 172 GAC specimens. The association of GPX1 and CDX2 with patient's clinicopathological features and Ki67 positive rate was analyzed statistically. Results. In 172 cases of GAC, the expression of GPX1 was weaker than that in adjacent normal mucosa, and the expression of CDX2 was higher than that in adjacent normal mucosa. High expression GPX1 strong-expression was associated with differentiation, Lauren type,WHOtype and extensive lymph node metastasis of GAC. High expression of CDX2 was associated with differentiation, Lauren type, WHO type, extensive lymph node metastasis, and TNM of GAC. Survival curves showed that expressions of GPX1 and CDX2 were factors of good outcome (P = .03 and .02, resp.). According to multivariate analysis, only lymph node metastasis, TNM stage, and CDX2 expression were independently associated with survival. In addition, a strong association of GPX1 expression was noted with Ki67 and CDX2. Conclusions. The expression of GPX1 and CDX2 may play a role in the carcinogenesis, differentiation, and progression of GAC, and CDX2 may be an independent prognostic factor. [ABSTRACT FROM AUTHOR]

Cytokines are deregulated in cancers and can contribute to tumor growth. In patients with diffuse large-cell lymphoma (DLBCL), we observed higher levels of JAK/STAT pathway-related serum cytokines (ie, IL-6, IL-10, epidermal growth factor, and IL-2) compared with controls. Of these, only IL-10 activated the JAK2 pathway in lymphoma cells in vitro. Patients with high serum IL-10 had shorter event-free survival (EFS) than patients with low levels (P > .01) and high IL-10 was correlated with high lactase dehydrogenase (p = .0085) and higher International Prognostic Index scores (P = .01). To explore the mechanism by which IL-10 may contribute to an inferior EFS, we investigated the effect of IL-10 on the JAK2 pathway and found that the IL-10/IL-10 receptor complex upregulated JAK2 signaling. Neutralizing Ab to IL-10 inhibited constitutive and IL-10-induced JAK2/STAT3 phosphorylation. JAK2 inhibition dephosphorylated JAK2 and STAT3 and caused an inhibitory effect on phospho-JAK2-positive DLBCL cells; there was a minimal effect on phospho-JAK2-negative cells. Apoptosis induced by JAK2 inhibition was dependent on inhibition of autocrine IL-10 and c-myc expression and independent of Bcl-2 family expression. These results provide the rationale for testing JAK2 inhibitors in DLBCL patients, and indicate that serum IL-10 may be a biomarker to identify patients more likely to respond to JAK2-targeted therapy. [ABSTRACT FROM AUTHOR]

The plant metabolite 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME, compound 6) was synthesized, and its potential effect on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby canine kidney cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule (MT) model were investigated. Membrane, cytosolic, and total annexin A1 (AxA1), α-enolase, and heat shock protein 90 (HSP90) amounts were examined by Western blot analysis after subcellular fractionation, then confirmed by immunofluorescence staining of cultured cells. Pretreatment of MDCKI cells with TGAME for up to 6 h significantly diminished COM crystal binding in a concentration-dependent manner. TGAME significantly inhibited AxA1 surface expression by immunofluorescence microscopy, whereas intracellular AxA1 increased. Western blot analysis confirmed AxA1 expression changes in the membrane and cytosolic fractions of compound-treated cells, whereas whole cell AxA1 remained unchanged. TGAME also significantly decreased the size, number, and growth of calcium oxalate (CaOx) crystals induced in a Drosophila melanogaster MT model and possessed a potent antioxidant activity in a DPPH assay. [ABSTRACT FROM AUTHOR]

Everolimus is an oral agent that targets the mTOR pathway. This study investigated mTOR pathway activation in T cell lymphoma (TCL) cell lines and assessed anti-tumor activity in patients with relapsed/refractory TCL in a Phase II trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T cell proliferation with minimal cytotoxic effects. Everolimus completely inhibited phosphorylation of ribosomal S6, a raptor/mTORC1 target, without a compensatory activation of the rictor/mTORC2 target Akt (S475). In the clinical trial, 16 patients with relapsed TCL were enrolled and received everolimus 10 mg PO daily. Seven (44%) patients had cutaneous (all mycosis fungoides); 4 (25%) peripheral T-cell NOS; 2 (13%) anaplastic large cell; and 1 each of extranodal NK/T-cell, angioimmunoblastic, and precursor T lymphoblastic leukemia/lymphoma types. The overall response rate was 44% (7/16; 95% CI: 20-70%). The median PFS was 4.1 months (95% CI: 1.5-6.5); and, the median OS 10.2 months (95% CI: 2.6-44.3). The median duration of response for the 7 responders was 8.5 months (95% CI: 1.0-not reached). These studies indicate that everolimus has anti-tumor activity and provide proof-of-concept that targeting the mTORC1 pathway in TCL is clinically relevant. [ABSTRACT FROM AUTHOR]

Self-assembly of Cd(II) ions with five positional isomeric flexible bipyridyl benzene and 2,2'-azodibenzoic acid ligands yielded five interesting coordination polymers: [Cd2L2(3-pbpmb)3]n (1), [Cd2L2(2-pbpmb)]n (2), {[CdL(4-mbpmb)2]·MeOH}n (3), {[Cd2L2(3-mbpmb)3]·2.5H2O}n (4) and [Cd2Cl2L(3-obpmb)2]n (5) where H2L = 2,2'-azodibenzoic acid, 3-pbpmb = 1,4-bis(pyridine-3-ylmethoxy)benzene, 2-pbpmb = 1,4-bis(pyridine-2-ylmethoxy)benzene, 4-mbpmb = 1,3-bis(pyridine-4-ylmethoxy)benzene, 3-mbpmb = 1,3-bis(pyridine-3-ylmethoxy)benzene and 3-obpmb = 1,2-bis(pyridine-3-ylmethoxy)benzene. Their structures have been determined by single-crystal X-ray diffraction analyses, elemental analyses, IR spectroscopy, powder X-ray diffraction (PXRD) and thermogravimetric analyses (TGA). Compound 1 has a 3D architecture constructed by 1D ladder-like [Cd4(3-pbpmb)4]n chains as well as L linkers and displays an interesting 5-connected net with a 4664 topology. Compound 2 comprises a 3D framework built from 2D wrinkled [Cd2L4]n networks and 2-pbpmb bridges with a 6-connected pcu net. Compound 3 bears a 2D network based on [Cd2(4-mbpmb)2] building units and 1D [CdL]n chains. Compound 4 features a 2D network in which the helical [Cd(3-mbpmb)]n chains are alternately arranged in a right- and left-handed sequence. Compound 5 exhibits a 2D network constructed by 1D [Cd2Cl2(3-obpmb)2]n chains and L linkers. The results reveal that the diverse coordination networks of 1-5 can be adjusted by the positional isomeric effect of flexible bipyridyl benzene building blocks. Moreover, the luminescence properties of compounds 1-5 in the solid state have also been investigated. [ABSTRACT FROM AUTHOR]

STAT3 regulates cell growth by upregulating downstream targets, such as Myc. The frequency of phosphorylated STAT3 (pSTAT3) and Myc expression and their prognostic relevance is unknown within diffuse large B-cell lymphoma (DLBCL) germinal center B-cell (GCB) and non-GCB subtypes. pSTAT3 and Myc were studied by immunohistochemistry (IHC) on tumors from 40 DLBCL patients uniformly treated on a clinical trial of epratuzumab/rituximab-CHOP. A total of 35% of cases were pSTAT3-positive, and pSTAT3 positivity was more frequent in the non-GCB (P = .06) type but did not correlate with event-free survival (EFS). Myc expression was observed In 50% of cases and was more frequent in non-GCB type (P = .07). Myc-positive cases had inferior EFS in all patients, including the GCB and pSTAT3-positive cases, were more likely to express Myc (P = .06). Myc translocations Involving the major breakpoint regions were found in 10% (3 of 29) of cases, and all 3 cases were GCB and had an inferior EFS (P = .09). pSTAT3, but not Myc expression, was correlated with elevated pretreatment serum cytokines, such as IL-b (P = .05), G-CSF (P = .03), and TNF-α (P = .04). pSTAT3 IHC in DLBCL tumors has the potential to identify patients for STAT3 pathway-directed therapy; Myc IHC is a potential marker for inferior EFS in GCB patients. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and anti-apoptotic signaling in various lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are typically partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing a variety of lymphoid malignancies. OSI-027, but not rapamycin, inhibited phosphorylation of Akt at Ser473, a direct target of mTORC2, in multiple lymphoid lines. In further contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended upon transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Consistent with these results, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, upregulated Puma, and induced regressions in Jeko xenografts, derived from a patient with mantle cell lymphoma. Collectively, these studies not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo. [ABSTRACT FROM AUTHOR]