Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.

Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease

Effect of Systemic Matrix Metalloproteinase Inhibition on Periodontal Wound Repair: A Proof of Concept Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141196/1/jper0441.pd

Modelowanie turbinowych silników odrzutowych w środowisku GasTurb na przykładzie silnika K-15

W artykule dokonano oceny możliwości modelowania silników turbinowych przy użyciu programu GasTurb na przykładzie jednoprzepływowego turbinowego silnika odrzutowego K-15. Uzyskane wyniki porównano z danymi zamieszczonymi wopisie technicznym silnika K-15 oraz opublikowanymi w literaturze wynikami badań silników tego typu. Wyznaczono rozkład podstawowych parametrów termogazodynamicznych wzdłuż kanału przepływowego silnika oraz wybrane charakterystyki. Wskazano zalety i wady oprogramowania GasTurb wynikające z przeprowadzonych obliczeń oraz analiz

Phase IV study of first-line bevacizumab plus irinotecan and infusional 5-FU/LV in patients with metastatic colorectal cancer: AVIRI

4068 Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF. In a phase III trial (AVF2107g), BEV significantly improved overall (OS) and progression-free survival (PFS) when combined with first-line irinotecan plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (IFL) in patients with metastatic colorectal cancer (mCRC). A multicentre, open-label trial is being conducted to evaluate the efficacy and safety of first-line BEV in combination with irinotecan and infusional 5-FU (FOLFIRI), a widely used first-line chemotherapy (CT) regimen. Methods: Patients had to have: mCRC; no surgery within 28 days; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function; no CNS metastases. CT consisted of a minimum of six cycles of irinotecan plus infusional 5-FU/LV according to the classical FOLFIRI regimen; variations like the simplified FOLFIRI and the weekly regimen were also allowed. BEV 5mg/kg was given on day 1 with CT and then every 2 weeks until disease progression. Tumour assessments were performed every 3 months during the first 12 months and every 4 months thereafter. Safety was assessed at the time of CT administration and every 4 weeks thereafter. The primary objective was PFS; secondary objectives included safety, overall response rate, time to response, duration of response and OS. Results: A total of 209 patients were enrolled at 31 centres worldwide, between April and November 2005. An interim analysis showed that the safety profile of BEV plus FOLFIRI appeared to be similar to that reported for Avastin plus IFL. The 44% overall response rate and 90% disease control rate are at least equivalent to that reported in comparable trials. Additionally, the 6 months PFS estimate of 82% was superior to that reported in AVF2107. Mature PFS data will be presented. Conclusions: AVIRI is the largest clinical trial, to date, to report data for BEV in combination with FOLFIRI in first-line patients with mCRC. The safety profile appears consistent with that observed in other BEV trials in mCRC, while the preliminary efficacy data suggest that this regimen is as active as the bolus regimen. No significant financial relationships to disclose. </jats:p