13 research outputs found
A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer
Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC50s under the Cmax in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients
Lawson criterion for ignition exceeded in an inertial fusion experiment
For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion
Tunneled superficial inferior epigastric artery (SIEA) myocutaneous/vascularized femur chimeric flaps: A model to study the role of vascularized bone marrow in composite allografts
Hereditary Neuropathy with Liability to Pressure Palsy: A Brief Review with a Case Report
The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine
SNS-032 (BMS-387032) is a selective cyclin-dependent kinase (CDK) inhibitor. In this study, we evaluated its effects on primary acute myeloid leukemia (AML) samples (n=87). In vitro exposure to SNS-032 for 48 h resulted in a mean LD50 of 139±203 nM; Cytarabine (Ara-C) was more than 35 times less potent in the same cohort. SNS-032-induced a dose-dependent increase in annexin V staining and caspase-3 activation. At the molecular level, SNS-032 induced a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and inhibited the expression of CDK2 and CDK9 and dephosphorylated CDK7. Furthermore, the combination of SNS-032 and Ara-C showed remarkable synergy that was associated with reduced mRNA levels of the antiapoptotic genes XIAP, BCL2 and MCL1. In conclusion, SNS-032 is effective as a single agent and in combination with Ara-C in primary AML blasts. Treatment with Ara-C alone significantly induced the transcription of the antiapoptotic genes BCL2 and XIAP. In contrast, the combination of SNS-032 and Ara-C suppressed the transcription of BCL2, XIAP and MCL1. Therefore, the combination of SNS-032 and Ara-C may increase the sensitivity of AML cells to the cytotoxic effects of Ara-C by inhibiting the transcription of antiapoptotic genes