Noelia Paco - Academia.edu (original) (raw)

Papers by Noelia Paco

Research paper thumbnail of Determining The Value of Selexipag For The Treatment of Pulmonary Arterial Hypertension (PAH) In Spain By Multi-Criteria Decision Analysis (MCDA)

Value in Health

health technology appraisals in different European countries have been reported previously. For o... more health technology appraisals in different European countries have been reported previously. For orphan medicines the level of variation may be even more marked than for non specialised medicines. In 2015 the National Institute for Health and Care Excellence (NICE) introduced an appraisal process for highly specialised medicines, the HST process; to date four HST appraisals have been published and ten are in development. The fourteen orphan drugs with published technology appraisals or appraisals in development via the NICE HST process were assessed for availability in Scotland, France and Germany. Of the four HST appraisals published by NICE all were positive recommendations with some restrictions. However outcomes were delayed by over a year for three out of four medicines when compared with recommendations by the Haute Autorité de Santé (HAS) in France. For two medicines where an HST is in development, the HAS issued positive guidance over a year previously. The Scottish Medicines Consortium (SMC) has issued restrictive guidance for one out of the four drugs approved by NICE and a "not recommended" for the remaining three. In Germany the added medical benefit of orphan drugs is deemed as proven by the fact that they have been approved. These drugs are therefore approved for use in Germany at marketing authorisation. ConClusions: Despite the introduction of the HST process by NICE, access to some orphan drugs is delayed in England and restricted in Scotland when compared with France and Germany.

Research paper thumbnail of Supplementary Figure 2 from Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

PDF file - 25K, Fig. S2. Quantitation of apoptosis by cleaved caspase-3 measurement.

Research paper thumbnail of Early Access to Medicines: Use of Multicriteria Decision Analysis (MCDA) as a Decision Tool in Catalonia (Spain)

Journal of Clinical Medicine, Mar 1, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Detection of Phospho-KRAS by Electrophoretic Mobility Change in Human Cell Lines and in Tumor Samples from Nude Mice Grafts

BIO-PROTOCOL, 2015

[Abstract] KRAS is the oncogene most frequently mutated in human solid tumors especially in pancr... more [Abstract] KRAS is the oncogene most frequently mutated in human solid tumors especially in pancreas, colon, small intestine, biliary tract and lung. We have recently demonstrated that oncogenic KRAS needs S181 phosphorylation to fully display its oncogenic features suggesting its inhibition as a therapeutic treatment against KRAS-driven tumors. Due to the importance to detect KRAS phosphorylation in human tumors and the absence of specific antibodies against phosphorylated KRAS, we developed a new protocol based on the Phos-tag SDS methodology to detect this post-translational modification for KRAS. Phos-tag is a molecule that binds specifically to phosphorylated proteins, decreasing their migration speed in SDS-PAGE and allowing its separation from the non-phosphorylated forms.

Research paper thumbnail of Patient involvement in reflective multicriteria decision analysis to assist decision making in oncology

International Journal of Technology Assessment in Health Care, 2019

Objectives Patient involvement in drug evaluation decision making is increasing. The aim of the c... more Objectives Patient involvement in drug evaluation decision making is increasing. The aim of the current study was to develop a multi-criteria decision analysis (MCDA) framework that would enable the inclusion of the patient perspective in the selection of appropriate criteria for MCDAs being used in the value assessments of oncologic drugs. Methods A literature review was conducted to identify and define criteria used in drug assessments from patient perspectives. The Evidence and Value: Impact on Decision Making methodology was used to develop a MCDA framework. Identified criteria were discussed by a sample of oncology patient association representatives who decided which criteria were important from patient perspectives. Selected criteria were rated by importance. The preliminary MCDA framework was tested through the assessment of a hypothetical oncology treatment. A discussion was carried out to agree on a final pilot MCDA framework. Results Twenty-two criteria were extracted fro...

Research paper thumbnail of Tumor Growth Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein i... more KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showe...

Research paper thumbnail of KRAS phosphorylation regulates cell polarization and tumorigenic properties in colorectal cancer

Research paper thumbnail of Oncogenic K-ras segregates at spatially distinct plasma membrane signaling platforms according to its phosphorylation status

Journal of Cell Science, 2013

Activating mutations in the K-Ras small GTPase are extensively found in human tumors. Although th... more Activating mutations in the K-Ras small GTPase are extensively found in human tumors. Although these mutations induce the generation of a constitutively GTP-loaded, active form of K-Ras, phosphorylation at Ser181 within the C-terminal hypervariable region can modulate oncogenic K-Ras function without affecting the in vitro affinity for its effector Raf-1. In striking contrast, K-Ras phosphorylated at Ser181 shows increased interaction in cells with the active form of Raf-1 and with p110a, the catalytic subunit of PI 3-kinase. Because the majority of phosphorylated K-Ras is located at the plasma membrane, different localization within this membrane according to the phosphorylation status was explored. Density-gradient fractionation of the plasma membrane in the absence of detergents showed segregation of K-Ras mutants that carry a phosphomimetic or unphosphorylatable serine residue (S181D or S181A, respectively). Moreover, statistical analysis of immunoelectron microscopy showed that both phosphorylation mutants form distinct nanoclusters that do not overlap. Finally, induction of oncogenic K-Ras phosphorylation -by activation of protein kinase C (PKC) -increased its co-clustering with the phosphomimetic K-Ras mutant, whereas (when PKC is inhibited) non-phosphorylated oncogenic K-Ras clusters with the non-phosphorylatable K-Ras mutant. Most interestingly, PI 3-kinase (p110a) was found in phosphorylated K-Ras nanoclusters but not in non-phosphorylated K-Ras nanoclusters. In conclusion, our data provide -for the first time -evidence that PKC-dependent phosphorylation of oncogenic K-Ras induced its segregation in spatially distinct nanoclusters at the plasma membrane that, in turn, favor activation of Raf-1 and PI 3-kinase. Supplementary material Fig S1. Fractionation of ectopic wild-type K-Ras. To study the possible effect of K-Ras mutants overexpression on its distribution, HEK293 cells were co-transfected with wild-type K-Ras (either with mCh-or YFP-taggs) and fractions obtained as in were analyzed by western blotting. mCh-tagged K-Ras was detected with anti-RFP and YFP-tagged with anti-GFP.

Research paper thumbnail of Determining The Value of Selexipag For The Treatment of Pulmonary Arterial Hypertension (PAH) In Spain By Multi-Criteria Decision Analysis (MCDA)

Value in Health

health technology appraisals in different European countries have been reported previously. For o... more health technology appraisals in different European countries have been reported previously. For orphan medicines the level of variation may be even more marked than for non specialised medicines. In 2015 the National Institute for Health and Care Excellence (NICE) introduced an appraisal process for highly specialised medicines, the HST process; to date four HST appraisals have been published and ten are in development. The fourteen orphan drugs with published technology appraisals or appraisals in development via the NICE HST process were assessed for availability in Scotland, France and Germany. Of the four HST appraisals published by NICE all were positive recommendations with some restrictions. However outcomes were delayed by over a year for three out of four medicines when compared with recommendations by the Haute Autorité de Santé (HAS) in France. For two medicines where an HST is in development, the HAS issued positive guidance over a year previously. The Scottish Medicines Consortium (SMC) has issued restrictive guidance for one out of the four drugs approved by NICE and a "not recommended" for the remaining three. In Germany the added medical benefit of orphan drugs is deemed as proven by the fact that they have been approved. These drugs are therefore approved for use in Germany at marketing authorisation. ConClusions: Despite the introduction of the HST process by NICE, access to some orphan drugs is delayed in England and restricted in Scotland when compared with France and Germany.

Research paper thumbnail of Supplementary Figure 2 from Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

PDF file - 25K, Fig. S2. Quantitation of apoptosis by cleaved caspase-3 measurement.

Research paper thumbnail of Early Access to Medicines: Use of Multicriteria Decision Analysis (MCDA) as a Decision Tool in Catalonia (Spain)

Journal of Clinical Medicine, Mar 1, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Detection of Phospho-KRAS by Electrophoretic Mobility Change in Human Cell Lines and in Tumor Samples from Nude Mice Grafts

BIO-PROTOCOL, 2015

[Abstract] KRAS is the oncogene most frequently mutated in human solid tumors especially in pancr... more [Abstract] KRAS is the oncogene most frequently mutated in human solid tumors especially in pancreas, colon, small intestine, biliary tract and lung. We have recently demonstrated that oncogenic KRAS needs S181 phosphorylation to fully display its oncogenic features suggesting its inhibition as a therapeutic treatment against KRAS-driven tumors. Due to the importance to detect KRAS phosphorylation in human tumors and the absence of specific antibodies against phosphorylated KRAS, we developed a new protocol based on the Phos-tag SDS methodology to detect this post-translational modification for KRAS. Phos-tag is a molecule that binds specifically to phosphorylated proteins, decreasing their migration speed in SDS-PAGE and allowing its separation from the non-phosphorylated forms.

Research paper thumbnail of Patient involvement in reflective multicriteria decision analysis to assist decision making in oncology

International Journal of Technology Assessment in Health Care, 2019

Objectives Patient involvement in drug evaluation decision making is increasing. The aim of the c... more Objectives Patient involvement in drug evaluation decision making is increasing. The aim of the current study was to develop a multi-criteria decision analysis (MCDA) framework that would enable the inclusion of the patient perspective in the selection of appropriate criteria for MCDAs being used in the value assessments of oncologic drugs. Methods A literature review was conducted to identify and define criteria used in drug assessments from patient perspectives. The Evidence and Value: Impact on Decision Making methodology was used to develop a MCDA framework. Identified criteria were discussed by a sample of oncology patient association representatives who decided which criteria were important from patient perspectives. Selected criteria were rated by importance. The preliminary MCDA framework was tested through the assessment of a hypothetical oncology treatment. A discussion was carried out to agree on a final pilot MCDA framework. Results Twenty-two criteria were extracted fro...

Research paper thumbnail of Tumor Growth Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein i... more KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showe...

Research paper thumbnail of KRAS phosphorylation regulates cell polarization and tumorigenic properties in colorectal cancer

Research paper thumbnail of Oncogenic K-ras segregates at spatially distinct plasma membrane signaling platforms according to its phosphorylation status

Journal of Cell Science, 2013

Activating mutations in the K-Ras small GTPase are extensively found in human tumors. Although th... more Activating mutations in the K-Ras small GTPase are extensively found in human tumors. Although these mutations induce the generation of a constitutively GTP-loaded, active form of K-Ras, phosphorylation at Ser181 within the C-terminal hypervariable region can modulate oncogenic K-Ras function without affecting the in vitro affinity for its effector Raf-1. In striking contrast, K-Ras phosphorylated at Ser181 shows increased interaction in cells with the active form of Raf-1 and with p110a, the catalytic subunit of PI 3-kinase. Because the majority of phosphorylated K-Ras is located at the plasma membrane, different localization within this membrane according to the phosphorylation status was explored. Density-gradient fractionation of the plasma membrane in the absence of detergents showed segregation of K-Ras mutants that carry a phosphomimetic or unphosphorylatable serine residue (S181D or S181A, respectively). Moreover, statistical analysis of immunoelectron microscopy showed that both phosphorylation mutants form distinct nanoclusters that do not overlap. Finally, induction of oncogenic K-Ras phosphorylation -by activation of protein kinase C (PKC) -increased its co-clustering with the phosphomimetic K-Ras mutant, whereas (when PKC is inhibited) non-phosphorylated oncogenic K-Ras clusters with the non-phosphorylatable K-Ras mutant. Most interestingly, PI 3-kinase (p110a) was found in phosphorylated K-Ras nanoclusters but not in non-phosphorylated K-Ras nanoclusters. In conclusion, our data provide -for the first time -evidence that PKC-dependent phosphorylation of oncogenic K-Ras induced its segregation in spatially distinct nanoclusters at the plasma membrane that, in turn, favor activation of Raf-1 and PI 3-kinase. Supplementary material Fig S1. Fractionation of ectopic wild-type K-Ras. To study the possible effect of K-Ras mutants overexpression on its distribution, HEK293 cells were co-transfected with wild-type K-Ras (either with mCh-or YFP-taggs) and fractions obtained as in were analyzed by western blotting. mCh-tagged K-Ras was detected with anti-RFP and YFP-tagged with anti-GFP.