Extracellular Adenosine Triphosphate Affects the Response of Human Macrophages Infected With Mycobacterium tuberculosis

International audienceGranulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular adenosine triphosphate (ATP) indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into adenosine monophosphate (AMP), and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage but may also favor bacterial immune escape

Multimodal In Vivo Imaging of Tumorigenesis and Response to Chemotherapy in a Transgenic Mouse Model of Mammary Cancer

International audiencePurpose: Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy.Procedures: Positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) and 3'-deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT), single photon emission tomography (SPECT) with [ 99m Tc]TcO 4 ([ 99m Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [ 18 F]FDG and [ 99m Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed. Results: All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [ 99m Tc]TEC and [ 18 F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [ 18 F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [ 18 F]FDG and [ 99m Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week−1 in untreated, doxorubicin, and docetaxel groups, respectively.Conclusions: Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [18F]FDG-PET and [99mTc]TEC SPECT monitor tumor response to chemotherapy

Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide-1

<p><b>Copyright information:</b></p><p>Taken from "Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide"</p><p>http://www.biomedcentral.com/1471-2210/7/13</p><p>BMC Pharmacology 2007;7():13-13.</p><p>Published online 27 Oct 2007</p><p>PMCID:PMC2180168.</p><p></p>ase time (0) and 3 hours after administration of etoposide alone or etoposide plus fluconazole or etoposide plus imatinib or etoposide with imatinib and fluconazole. . After administration of etoposide (VP16) with STI571, concentrations of VP16 peaked at 30.9 ± 2.1 ng/mL, followed by a bi-exponential decline.

Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide-3

<p><b>Copyright information:</b></p><p>Taken from "Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide"</p><p>http://www.biomedcentral.com/1471-2210/7/13</p><p>BMC Pharmacology 2007;7():13-13.</p><p>Published online 27 Oct 2007</p><p>PMCID:PMC2180168.</p><p></p> alone (E) at a dosage of 12 mg/kg in one daily intraperitoneal injection on days 1 to 3 (▲), etoposide (VP16) and STI571 (E + S) administered by one daily intraperitoneal injection at a dose of 70 mg/kg on days 1 to 3 (■), etoposide (VP16) and fluconazole (E + F) at a dosage of 40 mg/kg in one daily intraperitoneal injection on days 1 to 3 (○), or etoposide (VP16) with STI571 and fluconazole (E + S + F)(◇). All other groups included STI571 alone (S)(□), fluconazole alone (F)(△), and STI571 + fluconazole (S + F)(◆) and 0.9% NaCl (●). (B) Mice bearing LY-3 tumors were treated by one (□) daily intraperitoneal injection of STI571 (S) at a dose of 70 mg/kg from day 1 until sacrifice of the animals. (D) Xenografted LY-3 tumors were treated by gemcitabine at a dosage of 60 mg/kg by one weekly intraperitoneal injection, with (G + S)(■) or without (G)(▲) STI571 administered by one daily intraperitoneal injection at a dose of 70 mg/kg from day 1 until sacrifice of the animals. Mice treated by STI571 alone (S) are indicated by (□). All control groups received injections of 0.9% NaCl (Control)(●). Tumor growth was evaluated by measuring the relative tumor volume (RTV), as described in "Materials and Methods". A Mann-Whitney test was used to assess the effects of treatments on xenografted tumor growth

Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide-0

<p><b>Copyright information:</b></p><p>Taken from "Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide"</p><p>http://www.biomedcentral.com/1471-2210/7/13</p><p>BMC Pharmacology 2007;7():13-13.</p><p>Published online 27 Oct 2007</p><p>PMCID:PMC2180168.</p><p></p> alone (E) at a dosage of 12 mg/kg in one daily intraperitoneal injection on days 1 to 3 (▲), etoposide (VP16) and STI571 (E + S) administered by one daily intraperitoneal injection at a dose of 70 mg/kg on days 1 to 3 (■), etoposide (VP16) and fluconazole (E + F) at a dosage of 40 mg/kg in one daily intraperitoneal injection on days 1 to 3 (○), or etoposide (VP16) with STI571 and fluconazole (E + S + F)(◇). All other groups included STI571 alone (S)(□), fluconazole alone (F)(△), and STI571 + fluconazole (S + F)(◆) and 0.9% NaCl (●). (B) Mice bearing LY-3 tumors were treated by one (□) daily intraperitoneal injection of STI571 (S) at a dose of 70 mg/kg from day 1 until sacrifice of the animals. (D) Xenografted LY-3 tumors were treated by gemcitabine at a dosage of 60 mg/kg by one weekly intraperitoneal injection, with (G + S)(■) or without (G)(▲) STI571 administered by one daily intraperitoneal injection at a dose of 70 mg/kg from day 1 until sacrifice of the animals. Mice treated by STI571 alone (S) are indicated by (□). All control groups received injections of 0.9% NaCl (Control)(●). Tumor growth was evaluated by measuring the relative tumor volume (RTV), as described in "Materials and Methods". A Mann-Whitney test was used to assess the effects of treatments on xenografted tumor growth