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LOW-ORDER MODELING OF IGNITION IN ANNULAR COMBUSTORS
The SPINTHIR model, which is a Lagrangian stochastic low-order model for ignition validated and applied to several premixed and non-premixed cases, is modified in this paper to improve the numerical prediction of the flame light-round process in premixed annular combustors. This work proposes to take into account Flame Generated Turbulent Intensity (FGTI) and to impose the tubulent flame speed to the flame particles using expressions from the literature to address the current limitations in SPINTHIR. For this, using RANS CFD results as an input, the model was applied to simulate the ignition transient in a premixed, swirled bluff body stabilized annular combustor to characterize the light-round time, both in stable conditions and close to the stability limits. Several cases were analyzed, where flame speed and fuel are varied and light-round times are compared to experimental results. The proposed modifications increased the precision of the light-round time predictions, suggesting that FGTI may be an essential phenomenon to be modeled. The SPINTHIR model coupled with the Bray turbulent flame speed expression resulted in an average error of , a maximum error of and minimum error of for the explored range of parameters. This is an attractive feature considering the low computational cost of these simulations, which take on average 75\,\si{min} per simulation in a single core of a local workstation.RC has been supported by funding from the European Union’s
Horizon 2020 Research and Innovation Programme under the
Marie Skłodowska-Curie Grant Agreement No. 765998, project ANNULIGHT. LCCM has been supported by funding from the Clean Sky 2 Joint Undertaking (JU) under project PROTEUS, Grant Agreement No 785349. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and the Clean Sky 2 JU members other than the Union
Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies
Accumulating evidence suggests that cancer can be envisioned as a "signaling disease", in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to "targeted" agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in hematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects. Originally published Drug Resistance Updates, Vol. 10, No. 3, June 200
Case report of unusual synchronous anal and rectal squamous cell carcinoma: clinical and therapeutic lesson
Synchronous tumors of the rectum and anus are sporadic. Most cases in the literature are rectal adenocarcinomas with concomitant anal squamous cell carcinoma. To date, only two cases of concomitant squamous cell carcinomas of the rectum and anus are reported, and both were treated with up-front surgery and received abdominoperineal resection with colostomy. Here, we report the first case in the literature of a patient with synchronous HPV-positive squamous cell carcinoma of the rectum and anus treated with definitive chemoradiotherapy with curative intent. The clinical-radiological evaluation demonstrated complete tumor regression. After 2 years of follow-up, no evidence of recurrence was observed
AXL is an oncotarget in human colorectal cancer
AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC
Rationale and design of MILES-3 and MILES-4 studies: two randomized phase III trials comparing single-agent chemotherapy versus cisplatin-based doublets in elderly patients with advanced non-small cell lung cancer
BACKGROUND:
Platinum-based chemotherapy is the cornerstone of treatment of advanced non-small-cell lung cancer (NSCLC) patients, but the efficacy of adding cisplatin to single-agent chemotherapy remains to be demonstrated in prospective phase III trials dedicated to elderly patients. Furthermore, the superiority of cisplatin/pemetrexed over cisplatin/gemcitabine in non-squamous NSCLC has not been confirmed prospectively. We present the rationale and design of two open-label, multicenter, randomized phase III trials for elderly patients with advanced NSCLC∶ Multicenter Italian Lung cancer in the Elderly Study (MILES)-3 and MILES-4. The aim is to evaluate the efficacy of adding cisplatin to single-agent chemotherapy (both trials) and the efficacy of pemetrexed versus gemcitabine in non-squamous tumors (MILES-4).
PATIENTS AND METHODS:
Both trials are dedicated to first-line therapy of patients older than 70 years with advanced NSCLC, ECOG performance status 0-1. In the MILES-3 trial, patients are randomized in a 1∶1 ratio to gemcitabine or cisplatin/gemcitabine. In the MILES-4 study patients with non-squamous histology are randomized, in a factorial design with 1∶1∶1∶1 ratio, to four arms: gemcitabine (A), cisplatin/gemcitabine (B), pemetrexed (C), cisplatin/pemetrexed (D). Two comparisons are planned∶ A+C vs B+D to test the role of cisplatin; A+B vs C+D to test the role of pemetrexed. Primary endpoint of both trials is overall survival. Secondary and exploratory endpoints include progression-free survival, response rate, toxicity, and quality of life.
CONCLUSIONS:
MILES-3 and MILES-4 results will add important evidence about the role of cisplatin-based doublets and pemetrexed in the first-line therapy of elderly patients with advanced NSCLC
Exploratory findings from a prematurely closed international, multicentre, academic trial: RAVELLO, a phase III study of regorafenib versus placebo as maintenance therapy after first-line treatment in RAS wild-type metastatic colorectal cancer
Background In patients with RAS wild-type (WT)
metastatic colorectal cancer (mCRC), the role of
maintenance therapy after first-line treatment with
chemotherapy plus antiepidermal growth factor receptor
(EGFR) monoclonal antibodies (MoAb) is still an object of
debate.
Methods We assessed the efficacy and safety of
regorafenib as a switch maintenance strategy after
upfront 5-fluorouracil-based chemotherapy plus an anti-
EGFR MoAb in patients with RAS WT mCRC. RAVELLO
was a phase III, international, double-blind, placebocontrolled,
academic trial. The primary endpoint was
progression-free survival (PFS). Secondary endpoints
included overall survival and toxicity. Regorafenib or
placebo were administered daily for 3 weeks of 4-week
cycle until disease progression or unacceptable toxicity,
up to 24 months.
Results The study was stopped prematurely due to
slow accrual and lack of funding after the randomisation
of 21 patients: 11 in the regorafenib arm and 10 in
the placebo arm. The small sample size precludes
any statistical analysis. Toxicity was acceptable and
consistent with the known regorafenib safety profile.
Median PFS was similar in the two arms. However,
a subgroup of patients treated with regorafenib
experienced a remarkably long PFS. Three patients
were progression free at 9 months in the regorafenib
arm versus one patient in the placebo arm, whereas at
12 months two regorafenib-treated patients were still
progression free versus none in the placebo arm.
Conclusion RAVELLO trial demonstrated that
growing financial and bureaucratic hurdles affect the
feasibility of independent academic research. Although
stopped prematurely and within the limited sample
size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront
chemotherapy and anti-EGFR MoAb. However, a
subgroup of patients experienced a remarkable long
PFS, indicating that a better refinement of the patient
population would help to identify subjects that might
benefit from a regorafenib personalised approach in the
switch maintenance settin
SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer
Potent Cardioprotective Effect of the 4-Anilinoquinazoline Derivative PD153035: Involvement of Mitochondrial KATP Channel Activation
Background: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function. Methodology/Principal Findings: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation. Conclusions/Significance: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation
High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs
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