Search results for "XL"
showing 10 items of 104 documents
BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer
2022
The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3 mimetics can induce apoptosis. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads …
Myelodysplastic syndromes with 20q deletion: incidence, prognostic value and impact on response to azacitidine of ASXL1 chromosomal deletion and gene…
2021
In myelodysplastic syndromes (MDS), the 20q deletion [del(20q)] may cause deletion of the ASXL1 gene. We studied 153 patients with MDS and del(20q) to assess the incidence, prognostic value and impact on response to azacitidine (AZA) of ASXL1 chromosomal alterations and genetic mutations. Additionally, in vitro assay of the response to AZA in HAP1 (HAP1(WT)) and HAP1 ASXL1 knockout (HAP1(KN)) cells was performed. ASXL1 chromosomal alterations were detected in 44 patients (28 center dot 5%): 34 patients (22%) with a gene deletion (ASXL1(DEL)) and 10 patients (6 center dot 5%) with additional gene copies. ASXL1(DEL) was associated with a lower platelet count. The most frequently mutated genes…
Effects of fluvastatin slow-release (XL 80 mg) versus simvastatin (20 mg) on the lipid triad in patients with type 2 diabetes.
2005
The lipid triad is the association of small, dense (sd) low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and hypertriglyceridemia, all of which play a role in coronary artery disease in patients with type 2 diabetes. Although statins have demonstrated clear positive effects on cardiovascular morbidity/mortality in patients with diabetes and on single components of the lipid triad, it remains controversial whether they affect all components of the triad in these patients. Therefore, we performed a single-center, parallel-group, prospective, randomized, open-label, blinded-endpoint (PROBE)-type comparison of fluvastatin extended-release (XL) 80 mg (n=48) and simvastatin 20 m…
Mujeres directivas, espacio de poder y relaciones de género
2003
This study has two main aims, both of which are related to gender segregation in the labour market and to the "glass ceiling phenomen on". The first is to establish why women with high educational qualifications and management capabilities tend not to reach the top of the organisational pyramid. The second is to investigate whether traditional management models, that is, masculine models, are able to respond effectively to the challenges of the current labour situation. To answer these two questions we will study the obstacles that women encounter in their attempts to build professional careers, and will also analyse gender diversity and the transformational management style. The starting p…
Numerical study for a new methodology of flaws detection in train axles
2013
Train loads and travel speeds have increased over time, requiring more efficient non-destructive inspection methods. Railway axles are critical elements; despite being designed to last more than 20 years several cases of premature failure have been recorded. Train axles are inspected regularly, but the limits associated to the traditional inspection technologies create a growing interest towards new solutions. Here a novel non-destructive inspection method of in-service axles based on non-contact data collection is presented. The propagation of surface waves, generated by a thermo-elastic laser source, is investigated using a finite element method based on dynamic explicit integration. Coup…
Laser ultrasonics for defect evaluation on coated railway axles
2020
Abstract This scientific paper focuses on the application of an advanced non-destructive technique for an effective inspection of railway axles. The method pertains to ultrasonic techniques, which are widely used in the railway field. The experimental investigation was carried out on simulated defects tooled near the cross section reduction of the axle, in order to simulate fatigue cracks which, due to notch effect, can trigger crack propagation and axle failure. The aim of this research activity is to evaluate how efficiently the proposed technique detects defects and to verify its applicability to axles with a black coating for protection. In view of the experimental setup, comprising a p…
The Partial Discharge Behavior of Different Materials under DC Periodic Stress
2019
The aim of the present work is to evaluate the PDs behavior by stressing a specimen with a new type of waveform named DCP. This waveform was proposed by the authors in a previous work with the aim to overcome the main issues of PDs under DC stress. In the previous work PDs test on Kapton specimen was performed. In this paper, we propose a new DCP test on a different insulating material, such as the XLPE. The obtained patterns and the acquired data have been evaluated in order to validate the DCP approach as a new method for PDs measure under constant stress. The behavior of the XLPE material has been reported and compared with the former measures obtained for Kapton material.
O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells
2006
Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X(L). We found that the levels of MGMT expression were a major predictor of T…
In-silico screening of new potential Bcl-2/Bcl-xl inhibitors as apoptosis modulators
2008
One of the major problems in the fight against cancer is drug-resistance, which, at a molecular level, can be acquired through mutations able to deactivate apoptosis. In particular, proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-xl and Bcl-2, are overexpressed in many tumours. The development of new inhibitors of these proteins as potential anticancer therapeutics represents a new frontier. In this work, we carried out an in-silico screening of compounds from a free database of more than 2 million structures (ZINC database), which allowed us to identify 17 sulfonamide derivatives as new potential inhibitors; thes…
On two topological cardinal invariants of an order-theoretic flavour
2012
Noetherian type and Noetherian $\pi$-type are two cardinal functions which were introduced by Peregudov in 1997, capturing some properties studied earlier by the Russian School. Their behavior has been shown to be akin to that of the \emph{cellularity}, that is the supremum of the sizes of pairwise disjoint non-empty open sets in a topological space. Building on that analogy, we study the Noetherian $\pi$-type of $\kappa$-Suslin Lines, and we are able to determine it for every $\kappa$ up to the first singular cardinal. We then prove a consequence of Chang's Conjecture for $\aleph_\omega$ regarding the Noetherian type of countably supported box products which generalizes a result of Lajos S…