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1.
Blood Cancer J ; 10(2): 14, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029700

RESUMO

Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361-0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137-0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.

3.
Cureus ; 11(9): e5649, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31700751

RESUMO

Implementing an electronic health record (EHR) can be a difficult task to take on and planning the process is of utmost importance to minimize errors. Evaluating the selection criteria and implementation plan of an EHR system, intending interoperability, confidentiality, availability, and integrity of the patient health information data, while ensuring timely, accurate, and regulatory compliant generation of reports is a critical task. This article discusses the selection and implementation plan that will primarily consist of assessing existing institutional workflows for each department, and it outlines the necessities and inclinations of the institution to include in the EHR system for the organization to function properly. Resources and tools are included to assist in the selection of the product as well as ideas on how to train staff and evaluate staff readiness. Regulatory requirements are also included for consideration during the initial process. EHR increases the logistic productivity of workflows and offers a safer way to care for patients. To ensure efficiency, there is a series of steps the provider's staff must follow to ensure proper implementation and handling of the EHR system. Before using the implemented EHR, it is recommended to have a testing protocol in place to ensure areas of possible staff confusion are identified and controlled. Using a proper implementation strategy for a new EHR system can facilitate success, minimize delays, and increase health care worker's satisfaction and decrease the chances of usability being compromised.

4.
Eur J Haematol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31724208

RESUMO

OBJECTIVE: The obesity/overweight may have an influence on APL outcomes. METHODS: This is the biggest multicentre analysis on 1320 APL patients treated with AIDA-induction and risk-adapted consolidation between 1996 and 2012. Patients body mass index (BMI) was classified as underweight (<18.5 kg/m2 ), normal (18.5-25 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥30 kg/m2 ) according to the World Health Organization (WHO) criteria. RESULTS AND CONCLUSIONS: Relationship between male gender, older age, and other known laboratory abnormalities in overweight/obese patients was significant. The induction mortality rate was significantly higher in APL with BMI ≥25 vs BMI <25 (10% vs 6%; P = .04). APL patients with BMI ≥25 had a trend to lower OS (74% vs 80%; P = .06). However, in the multivariate analysis, BMI did not retain the independent predictive value (P = .46). There was no higher incidence of differentiation syndrome with BMI ≥25, but there was a trend in obese. There was no difference in relapse rate according to the BMI. In summary, overweight/obesity does not represent an independent risk factor for APL outcomes. The influence of obesity in APL patients treated with chemotherapy-free regimens remains to be established.

5.
Blood Cancer J ; 9(7): 52, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209206

RESUMO

Follicular lymphoma (FL) is a heterogeneous disease whose pathogenesis remains partially unknown. Around 20% of FL patients experience early progression or treatment-refractory disease and 2-3% of patients per year experience histological transformation (HT) into a more aggressive lymphoma (tFL). Here, we evaluate the immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in 187 FL cases to assess its impact on clinical outcome and histological transformation. The IGHV gene repertoire was remarkably biased in FL. The IGHV4-34 (14%), IGHV3-23 (14%), IGHV3-48 (10%), IGHV3-30 (9%) and IGHV3-21 (7%) genes accounted for more than half of the whole cohort. IGHV3-48 was overrepresented in cases of tFL (19%) compared with non-transformed FL at 5 years (5%, P = 0.05). Patients with the IGHV3-48 gene were significantly more likely to have had HT after 10 years than those who used other genes (71% vs. 25%, P < 0.05), irrespective of the therapy they received. Moreover, IGHV3-30 was also overrepresented in cases of FL (9%) and tFL (13%) compared with diffuse large B-cell lymphoma in which it was nearly absent. In conclusion, our results indicate a role for antigen selection in the development of FL, while the use of IGHV3-48 could help predict histological transformation.

6.
Rev. bras. orientac. prof ; 20(1): 31-44, jan.-jun. 2019. tab
Artigo em Espanhol | LILACS, Index Psicologia - Periódicos técnico-científicos | ID: biblio-1042395

RESUMO

Este artículo expone los resultados de un estudio centrado en el desarrollo de competencias prácticas autopercibidas por los estudiantes de pedagogía. El objetivo es conocer si el nivel de autopercepción en la adquisición de competencias generales y específicas para el ejercicio de la profesión pedagógica, varía tras la realización de las prácticas y verificar la existencia de diferencias significativas en la autopercepción del estudiante en función de las variables: año de finalización de estudios, rendimiento académico, mención cursada y titularidad del centro de prácticas. La metodología utilizada es cuantitativa, el diseño de investigación de tipo pre-experimental, con aplicación de pre-test y post-test. Se empleó un método descriptivo-inferencial, por medio del estudio de encuesta electrónica. Los resultados muestran que la valoración de los futuros pedagogos sobre la adquisición de diferentes competencias del Grado de Pedagogía, es muy positiva tanto antes como después del periodo de prácticas externas; así como la existencia de diferencias significativas en función de las variables estudiadas.


Este artigo expõe os resultados de um estudo centrado no desenvolvimento de competências práticas autopercebidas pelos estudantes de Pedagogia. O objetivo é saber se o nível de autopercepção na aquisição de competências gerais e específicas para o exercício da profissão pedagógica varia após a realização das práticas e verificar a existência de diferenças significativas na autopercepção do aluno de acordo com as variáveis: ano de conclusão dos estudos, desempenho acadêmico, especialização matriculada e tipo de instituição de estágio. A metodologia empregada é quantitativa, o desenho de investigação de tipo pre-experimental, com aplicação de pré-teste e pós-teste. Utilizou-se um método descritivo-inferencial, por meio do estudo de pesquisas eletrônicas de opinião. Os resultados mostram que a valoração dos futuros pedagogos sobre a aquisição de diferentes competências do curso de Pedagogia, é muito positiva antes e depois do período de práticas externas; assim como a existência de diferenças significativas em função das variáveis estudadas.


This article presents the results of a study focused on the development of self - perceived practical skills by Pedagogy majors. The objective is to know if the level of self-perception in the acquisition of general and specific competences for the exercise of the pedagogical profession varies after the accomplishment of the teacher training period and verify the existence of significant differences in the student´s self-perception according to the variables: year of studies completion, academic performance, specialization enrollment and type of internship institution. The methodology used is quantitative, the research design is of the pre-experimental type, with application of pre-test and post-test. A descriptive-inferential method was used, through the study of electronic opinion surveys. The results reveal that the future teachers´ evaluation of the acquisition of different competences in the Degree Program in Pedagogy is very positive, both before and after the period of external teaching training; as well as the existence of significant differences according to the studied variables.


Assuntos
Competência Profissional , Estudantes , Ensino , Mobilidade Ocupacional
7.
Pharmaceuticals (Basel) ; 12(2)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934879

RESUMO

Here, the synthesis and glycosidase inhibition properties of the two first known 3-ethyloctahydro-1H-indole-4,5,6-triols are reported. This study shows the transformation of d-glucose into polyhydroxylated 1-(2-nitrocyclohexane) acetaldehydes, followed by a protocol involving the formation of the azacyclopentane ring. Results of inhibitory potency assays and docking calculations show that at least one of them could be a lead for optimization in the search for compounds that behave like folding chaperones in lysosomal storage diseases.

8.
Br J Haematol ; 185(3): 480-491, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30793290

RESUMO

The use of immunochemotherapy has improved the outcome of follicular lymphoma (FL). Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. This study aimed to analyse the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). The training series comprised 263 patients consecutively diagnosed with FL in a 10-year period who needed therapy and were treated with rituximab-containing regimens. An independent cohort of 693 FL patients from the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) group was used for validation. In the training cohort, 188 patients were in CR30, with a 10-year overall survival (OS) of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Multivariate analysis indicated that the FL International Prognostic Index was the most important variable predicting OS in the CR30 group. The impact of CR30 status on RS was validated in the independent GELTAMO series. In conclusion, FL patients treated with immunochemotherapy who were in CR at 30 months showed similar survival to a sex- and age-matched Spanish general population.

9.
J Affect Disord ; 247: 161-167, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30669075

RESUMO

BACKGROUND: The potential effect of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) to prevent depression remains largely unknown, in spite of the implication of inflammation in depression. This study aimed to investigate whether the habitual intake of aspirin and other NSAIDs was prospectively associated with a reduction in the observed incidence of depression. METHODS: A dynamic cohort including 22,564 Spanish university graduates (mean age: 37 years) initially free of depression was followed during an average of 8.7 years. Exposure to NSAIDs was assessed with specific repeated questionnaires throughout follow-up, starting in the 2-year follow-up questionnaire. Incident cases of depression were defined as either a new validated medical diagnosis of depression or reporting the initiation of habitual use of antidepressants. RESULTS: We identified 772 incident cases of depression. Regular intake of aspirin and other NSAIDs was not associated with depression risk. Only in secondary sensitivity analyses using a definition of the outcome with higher specificity (a validated medical diagnosis of depression), an inverse association of aspirin with depression was found [HR (95%CI): 0.20 (0.04-0.87)]. However, these results were non-significant after adjustment for multiple testing. LIMITATIONS: A possible underestimation of incident depression and a limited ability to detect all possible residual confounding. CONCLUSIONS: Regular use of NSAIDs was not associated with the incidence of depression. Further longitudinal controlled studies are necessary to clarify a potential role of aspirin use in depression risk.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Depressão/epidemiologia , Adulto , Estudos de Coortes , Depressão/induzido quimicamente , Feminino , Humanos , Incidência , Masculino , Estudos Prospectivos , Fatores de Risco , Espanha/epidemiologia , Inquéritos e Questionários , Universidades
10.
Stress ; 22(1): 1-8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30345850

RESUMO

With the detrimental relationship between school burnout and physiological and cognitive functioning now well documented, interventions to ameliorate school burnout symptomology are needed. This study examined the effectiveness of a self-regulatory biofeedback intervention program (Heart Rate Variability Coherence Biofeedback Training [HRVCB]) in contrast to a protocol demonstrated to produce cognitive and physiological improvements (a high intensity interval training protocol [HIIT]) as well as a wait-list control condition at decreasing school burnout in an American collegiate sample (N = 90). Intervention training was conducted over a 4-week span (three sessions per week) with accompanying baseline and post-intervention assessments. In addition to measurements of school burnout and negative affect (depression and anxiety), intervention influences on cognition (via a serial subtraction task) and physiology (hemodynamics, electrocardiography, and a submaximal cardiorespiratory fitness test) were explored. Findings indicate HRVCB training significantly decreased school burnout and increased mathematical performance from pre- to post-intervention measurement. These changes did not occur for HIIT or waitlist participants. Brachial and aortic systolic blood pressure decreased pre to post-intervention for HRVCB but not HIIT or waitlist participants. Cardiovascular fitness (VO2max) improved pre to post-intervention for HIIT but not HRVCB or waitlist participants. Also, both HRVCB and HIIT training participants decreased heart rate from pre to post-intervention but not waitlist participants. Finally, all participants decreased cardiac sympathovagal tone from pre to post-intervention. These findings provide evidence that HRVCB training programs can decrease school burnout as well as improve components associated with cardiac health. Study limitations and directions for future research are discussed.


Assuntos
Biorretroalimentação Psicológica/métodos , Esgotamento Psicológico/fisiopatologia , Esgotamento Psicológico/terapia , Coração/fisiopatologia , Adolescente , Esgotamento Psicológico/psicologia , Cognição , Eletrocardiografia , Feminino , Frequência Cardíaca/fisiologia , Hemodinâmica , Humanos , Masculino , Autorrelato , Estudantes/psicologia , Universidades , Adulto Jovem
13.
Haematologica ; 104(3): 576-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30262568

RESUMO

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.

14.
Materials (Basel) ; 11(11)2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30469421

RESUMO

The purpose of this work was to analyse the compaction of a cohesive material using different Discrete Element Method (DEM) simulators to determine the equivalent contact models and to identify how some simulation parameters affect the compaction results (maximum force and compact appearance) and computational costs. For this purpose, three cohesion contact models were tested: linear cohesion in EDEM, and simplified Johnson-Kendall-Roberts (SJKR) and modified SJKR (SJKR2) in LIGGGHTS. The influence of the particle size distribution (PSD) on the results was also investigated. Further assessments were performed on the effect of (1) selecting different timesteps, (2) using distinct conversion tolerances to export the three-dimensional models to standard triangle language (STL) files, and (3) moving the punch with different speeds. Consequently, we determined that a timestep equal to a 10% Rayleigh timestep, a conversion tolerance of 0.01 mm, and a punch speed of 0.1 m/s is adequate for simulating the compaction process using the materials and the contact models in this work. The results showed that the maximum force was influenced by the PSD due to the rearrangement of the particles. The PSD was also related to the computational cost because of the number of simulated particles and their sizes. Finally, an equivalence was found between the linear cohesion and SJKR2 contact models.

15.
Pediatr Exerc Sci ; 30(4): 480-486, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30193554

RESUMO

PURPOSE: Childhood and adolescent obesity is a major international public health crisis. It is crucial to prevent the negative effects of obesity at an early age by implementing appropriate lifestyle interventions, such as exercise training. We evaluated the effects of a combined resistance and aerobic exercise training (CET) regimen on arterial stiffness, vasoactive substances, inflammatory markers, metabolic profile, and body composition in obese adolescent girls. METHODS: A total of 30 obese adolescent girls were randomly assigned to a CET (n = 15) or a control group (n = 15). The CET group trained for 3 days per week. Plasma nitric oxide, endothelin-1, C-reactive protein, arterial stiffness, glucose, insulin, the adiponectin/leptin ratio, and body fat were measured before and after 12 weeks. RESULTS: There were significant increases (P < .05) in nitric oxide (4.0 µM) and adiponectin/leptin ratio (0.33); and decreases (P < .05) in arterial stiffness (-1.0 m/s), C-reactive protein (-0.5 mg/L), glucose (-1.2 mmol/L), insulin (-17.1 µU/mL), and body fat (-3.6%) following CET compared with control. There were no significant changes in endothelin-1 after CET or control. CONCLUSIONS: The findings of this study indicate that CET improves arterial stiffness, nitric oxide, and inflammatory and metabolic markers in obese adolescent girls. CET may have important health implications for the prevention of atherosclerosis at an early age.


Assuntos
Composição Corporal , Exercício , Inflamação/sangue , Metaboloma , Obesidade/sangue , Rigidez Vascular , Adiponectina/sangue , Adolescente , Biomarcadores/sangue , Glicemia/análise , Proteína C-Reativa/análise , Endotelina-1/sangue , Feminino , Humanos , Insulina/sangue , Leptina/sangue , Óxido Nítrico/sangue , Obesidade/fisiopatologia , Treinamento de Resistência
16.
Ann Hematol ; 97(11): 2217-2224, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30019128

RESUMO

Programmed death 1 (PD-1) activation triggers an immune checkpoint resulting in inhibition of T cells that leads to peripheral tolerance. Some PD-1 polymorphisms have been described and associated with the development of autoimmune diseases or cancer predisposition, but there are few data concerning the relevance of such polymorphisms on the clinical outcome after allogeneic hematopoietic stem cell transplant (alloHSCT). We analyzed the distribution of the SNPs PD-1.1G/A (rs36084323) and PD-1.3G/A (rs11568821) genotypes of the donor in a cohort of 1485 alloHSCT from HLA-identical sibling donors. We found an increased risk of grades II to IV graft-versus-host disease (GvHD) in patients receiving grafts from donors homozygous for the G allele at the rs36084323 SNP (P = 0.033; hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.1 to 4.8) and also from donors homozygous for the A allele at the rs11568821 position (P < 0.001; HR 4.5, 95%CI 2.0 to 10.1). In contrast, the PD-1 genotype of the donor did not show association with overall survival or relapse incidence. These results suggest that the PD-1 genotype of the donor plays an important role for the development of acute GvHD after alloHSCT from HLA-identical sibling donors.


Assuntos
Genótipo , Doença Enxerto-Hospedeiro , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Polimorfismo Genético , Receptor de Morte Celular Programada 1/genética , Irmãos , Doença Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Taxa de Sobrevida
17.
Blood Adv ; 2(14): 1719-1737, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-30030270

RESUMO

Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients. Data were analyzed using a linear regression model and the least absolute shrinkage and selection operator (LASSO). The statistical model was constructed by randomly selecting 85% of cases (training set), and the predictive ability was confirmed based on the remaining 15% of cases (test set). Models including clinical and genetic variables (CG-M) predicted severe aGVHD significantly better than models including only clinical variables (C-M) or only genetic variables (G-M). For grades 3-4 aGVHD, the correct classification rates (CCR1) were: 100% for CG-M, 88% for G-M, and 50% for C-M. On the other hand, CG-M and G-M predicted extensive cGVHD better than C-M (CCR1: 80% vs. 66.7%, respectively). A risk score was calculated based on LASSO multivariate analyses. It was able to correctly stratify patients who developed grades 3-4 aGVHD (P < .001) and extensive cGVHD (P < .001). The novel predictive models proposed here improve the prediction of severe GVHD after allo-SCT. This approach could facilitate personalized risk-adapted clinical management of patients undergoing allo-SCT.


Assuntos
Citocinas/genética , Doença Enxerto-Hospedeiro/genética , Neoplasias Hematológicas/genética , Modelos Genéticos , Polimorfismo Genético , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Feminino , Seguimentos , Neoplasias Hematológicas/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
Oncotarget ; 9(40): 26019-26031, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29899839

RESUMO

PI3Kδ (idelalisib) and BTK (ibrutinib) inhibitors have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) interfering with the cross-talk between CLL cells and the lymph node microenviroment, yet their mechanism of action remains to be fully elucidated. Here, we developed an ex vivo model with the aim of reproducing the effects of the microenvironment that would help shed light on the in vivo mechanism of action of idelalisib and ibrutinib and predict their clinical efficacy in individual patients. First we explored the effects of various cell-extrinsic elements on CLL apoptosis and proliferation and found that the combination of CpG+IL2+HS5 stromal cell line + human serum +CLL plasma and erythrocyte fractions represented the best co-culture conditions to test the effects of the novel inhibitors. Then, using this assay, we investigated the impact of idelalisib and ibrutinib on both survival and proliferation in 30 CLL patients. While both drugs had a limited direct pro-apoptotic activity, a potent inhibition of proliferation was achieved at clinically achievable concentrations. Notably, up to 10% of CLL cells still proliferated even at the highest concentrations, likely mirroring the known difficulty to achieve complete responses in vivo. Altogether, this novel assay represents an appropriate ex vivo drug testing system to potentially predict the clinical response to novel inhibitors in particular by quantifying the antiproliferative effect.

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