Additional file 2: Figure S2. of FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine

FRAX597 and gemcitabine decreased Ki67 staining on orthotopic pancreatic tail tumours. Pan02 murine pancreatic tumours from the orthotopic pancreatic tail tumour model treated with saline (control; CT), FRAX597 (FRAX), gemcitabine (Gem), or FRAX597 and gemcitabine (Gem + FRAX) at the doses given in the Materials and Methods section, were fixed and stained for the proliferative marker, Ki67. Three representative images were taken from each treatment group. (PPTX 2275 kb

Additional file 1: Figure S1. of FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine

PAK1 Knock-down (KD) effects on survival and ERK expression. PAK1 KD cells were measured in the presence (darker bars) and absence (lighter bars) of FBS to measure survival, using thymidine-withdrawal. Survival in PANC-1 PAK1 KD clones (A) was significantly lower but no difference was observed in MiaPaCa-2 PAK1 KD clones (B). No reduction in the expression of either phospho-ERK (pERK1/2) or total ERK (ERK1/2) was detected in either PANC-1 (C) or MiaPaCa-2 (D) PAK1 KD cells, as assessed by western blot. The data represent mean ± SEM, summarised from three independent experiments. *** p < 0.001, compared to the corresponding clone with FBS. (PPTX 433 kb

Glaucarubinone Combined with Gemcitabine Improves Pancreatic Cancer Survival in an Immunocompetent Orthotopic Murine Model

<p><i>Background</i>: Pancreatic cancer continues to have a poor survival rate with an urgent need for improved treatments. Glaucarubinone, a natural product first isolated from the seeds of the tree <i>Simarouba glauca</i>, has recently been recognized as having anti-cancer properties that may be particularly applicable to pancreatic cancer. <i>Methods</i>: The effect of glaucarubinone on the growth and migration of murine pancreatic cancer cells was assessed by ³H-thymidine incorporation assay. The survival impact of glaucarubinone alone and in combination with gemcitabine chemotherapy was assessed using an immunocompetent orthotopic murine model of pancreatic cancer. <i>Results</i>: Glaucarubinone inhibited the growth of the murine pancreatic cancer cell lines LM-P and PAN02. Treatment with either glaucarubinone or gemcitabine reduced proliferation <i>in vitro</i> and the combination was synergistic. The combination treatment improved survival two-fold compared to gemcitabine treatment alone (<i>p</i> = 0.046) in PAN02 cells. <i>Conclusions</i>: The synergistic inhibition by glaucarubinone and gemcitabine observed <i>in vitro</i> and the improved survival <i>in vivo</i> suggest that glaucarubinone may be a useful adjunct to current chemotherapy regimens.</p

Additional file 1: Figure S1. of Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis

PF-3758309 increased the numbers of white blood cells, and splenic weight and white pulp area, in SCID mice. HCT116 human CRC cells were grown as xenografted tumours in SCID mice for 2 weeks. The mice (n = 6) were then treated with PF-3758309 by peritoneal injection (25 mg/Kg) for a further 2 weeks. The mice were then culled, the blood taken for blood cell count and the spleens weighed, fixed in formalin, sectioned and stained with H&E. Control mice (n = 4) were treated with 5% DMSO in saline. Cont: control; WCC: white blood cell; neut: neutrophil; lym: lymphocyte; mono: monocytes. *, p < 0.05, **, p < 0.01, compared to control (PPTX 566 kb

Restrictive intraoperative fluid optimisation algorithm improves outcomes in patients undergoing pancreaticoduodenectomy: A prospective multicentre randomized controlled trial

<div><p>We aimed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy with or without a cardiac output goal directed therapy (GDT) algorithm. We conducted a multicentre randomised controlled trial in four high volume hepatobiliary-pancreatic surgery centres. We evaluated whether the additional impact of a intraoperative fluid optimisation algorithm would influence the amount of fluid delivered, reduce fluid related complications, and improve length of hospital stay. Fifty-two consecutive adult patients were recruited. The median (IQR) duration of surgery was 8.6 hours (7.1:9.6) in the GDT group vs. 7.8 hours (6.8:9.0) in the usual care group (p = 0.2). Intraoperative fluid balance was 1005mL (475:1873) in the GDT group vs. 3300mL (2474:3874) in the usual care group (p<0.0001). Total volume of fluid administered intraoperatively was also lower in the GDT group: 2050mL (1313:2700) vs. 4088mL (3400:4525), p<0.0001 and vasoactive medications were used more frequently. There were no significant differences in proportions of patients experiencing overall complications (p = 0.179); however, fewer complications occurred in the GDT group: 44 vs. 92 (Incidence Rate Ratio: 0.41; 95%CI 0.24 to 0.69, p = 0.001). Median (IQR) length of hospital stay was 9.5 days (IQR: 7.0, 14.3) in the GDT vs. 12.5 days in the usual care group (IQR: 9.0, 22.3) for an Incidence Rate Ratio 0.64 (95% CI 0.48 to 0.85, p = 0.002). In conclusion, using a surgery-specific, patient-specific goal directed restrictive fluid therapy algorithm in this cohort of patients, can justify using enough fluid without causing oedema, yet as little fluid as possible without causing hypovolaemia i.e. “precision” fluid therapy. Our findings support the use of a perioperative haemodynamic optimization plan that prioritizes preservation of cardiac output and organ perfusion pressure by judicious use of fluid therapy, rational use of vasoactive drugs and timely application of inotropic drugs. They also suggest the need for further larger studies to confirm its findings.</p></div

Postoperative fluid intervention in patients undergoing pancreaticoduodenectomy with and without goal directed therapy (GDT).

<p>Data presented as median (interquartile range) or number (proportion).</p

Modified Rankin scale showing the proportion of participants in the usual care and goal directed therapy (GDT) groups with complications.

<p>Modified Rankin scale showing the proportion of participants in the usual care and goal directed therapy (GDT) groups with complications.</p

Surgery-specific cardiac output algorithm.

<p>Surgery-specific cardiac output algorithm.</p

Consort diagram.

<p>Consort diagram.</p

Summary of complications in patients undergoing pancreaticoduodenectomy with and without goal directed therapy.

<p>Data presented as number (proportion).</p