A Method to Create Directed Acyclic Graphs from Cycles of Transmission of Zoonotic and Vector-Borne Infectious Agents.

The life cycles of zoonotic and vector-borne diseases can be complex. This complexity makes it challenging to identify factors that confound the association between an exposure of interest and infection in one of the susceptible hosts. In epidemiology, directed acyclic graphs (DAGs) can be used to visualize the relationships between exposures and outcomes and also to identify which factors confound the association between exposure and the outcome of interest.

Imaging correlates of serum enzyme-linked immunoelectrotransfer blot (EITB) positivity in patients with parenchymal neurocysticercosis: results from 521 patients.

Background: The presence of perilesional edema among patients with parenchymal neurocysticercosis (pNCC) of various lesion subtypes has not been correlated with results of serum enzyme-linked immunotransfer blot (EITB) for cysticercal antibodies.

Methods: In total, 521 patients with pNCC were classified into solitary cysticercus granuloma (SCG), multiple lesions, at least one of which was an enhancing granuloma (GMNCC), solitary calcified cysticercal lesion (SCC) and multiple calcified cysticercal lesions (CMNCC). The proportion of EITB positivity among each lesion subtype and its association with perilesional edema were determined.

Breaking through the glioblastoma micro-environment via extracellular vesicles.

Glioblastoma (GBM) is the most common and most aggressive brain tumour. Prognosis remains poor, despite the combined treatment of radio- and chemotherapy following surgical removal. GBM cells coexist with normal non-neoplastic cells, including endothelial cells, astrocytes and immune cells, constituting a complex and dynamic tumour micro-environment (TME).

Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.

Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements.

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.

Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels.

Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML.

The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation.

Studying the right cell in acute myelogenous leukemia: dynamic changes of apoptosis and signal transduction pathway protein expression in chemotherapy resistant ex-vivo selected "survivor cells".

We hypothesized that studying protein expression in cells surviving in vitro chemotherapy ("survivor cells", SV), could provide more important insight into the biology of drug-resistant AML cells than analysis of the bulk population of leukemic cells. Leukemia-enriched samples from 79 patients with new or relapsed AML were cultured for four days +/- cytarabine (5-10 microM). Early apoptotic cells were removed to yield purified SV.

Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study.

Following exposure to cytotoxic agents, acute myeloid leukemia (AML) blasts elevate cellular cholesterol in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/ (M2 x day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M2 x day) by CI, days 4-7] in 15 newly diagnosed and 22 salvage patients with unfavorable (n = 26) or intermediate (n = 10) prognosis cytogenetics.

Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia.

Deregulation of signal transduction pathways (STPs) may promote leukemogenesis by conferring cell proliferation and survival advantages in acute myelogenous leukemia (AML). Several agents targeting STPs are under development; however, redundancy and cross-talk between STPs could activate multiple downstream effectors and this could negate the effect of single-target inhibition. The frequency of concurrent activation of multiple STPs in AML and the prognostic relevance of STP activation in AML are unknown.

2-Chlorodeoxyadenosine and cytarabine combination therapy for idiopathic hypereosinophilic syndrome.

Background: Hypereosinophilic syndrome (HES) is a rare, disabling, and incurable disease. In this study, a combination of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (ara-C) chemotherapy was evaluated in patients with HES.

Methods: Nine patients with HES were treated with ara-C (1 g/m(2)) given intravenously over 2 hours at 0 hours, 48 hours, 72 hours, 96 hours, and 120 hours; and 2-CdA (12 mg/m(2) per day) was given as a continuous intravenous infusion over 5 days starting at 24 hours.

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia.

In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells.

Engraftment of acute myeloid leukemia in NOD/SCID mice is independent of CXCR4 and predicts poor patient survival.

The aim of this study was to investigate factors influencing the engraftment potential of acute myeloid leukemia (AML) CD34+ cells in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We examined the relationship between engraftment, CXCR4 expression on CD34+ and CD34+CD38- cells, and patient (Pt) clinical/laboratory characteristics in 44 samples from 11 Pts. Engraftment, evaluated by Southern blot and CD45 flow cytometric analyses, was observed in murine bone marrow of 6 of 11 Pt samples, ranging from 0.

The anti-apoptotic genes Bcl-X(L) and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells.

In acute myeloid leukaemia (AML), cell kinetic quiescence has been postulated to contribute to drug resistance. As the anti-apoptotic genes Bcl-2 and Bcl-X(L) have been implicated in cell cycle regulation, we investigated the expression of these genes in non-proliferating (Q) and proliferating (P) AML and normal CD34+ progenitor cells. Using reverse transcription polymerase chain reaction, Bcl-X(L) and Bcl-2 were overexpressed in Q versus P AML cells, whereas no difference in Bcl-XS and Bax expression was found.

Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia.

It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1-overexpressing, p53(null) HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO.