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Article: The dark side of immunotherapy: challenges facing the new hope in cancer treatment.

Teixidor, Eduard / Bosch-Barrera, Joaquim

2019 Volume 7, Issue Suppl 6, Page(s) S183

Language	English
Publishing date	2019-09-05
Publishing country	China
Document type	Editorial ; Comment
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2019.07.69
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: STAR-121: A Phase III Randomized Study of Domvanalimab and Zimberelimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Untreated Metastatic Non-Small Cell Lung Cancer With No Actionable Gene Alterations.

Rodriguez-Abreu, Delvys / Bosch-Barrera, Joaquim / Gray, Jhanelle E / Ahn, Myung-Ju / Johnson, Melissa / Yu, Xinwei / Mohammad, Saad / Chen, Xueying / Todd, Trever / Kim, Jongseok / Reck, Martin

Clinical lung cancer

2024

Abstract: Introduction: Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non-small cell lung ... ...

Abstract	Introduction: Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non-small cell lung cancer (mNSCLC). The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti-PD-1) plus chemotherapy versus pembrolizumab plus chemotherapy in mNSCLC with no actionable gene alterations. Participants and methods: Approximately 720 participants (≥18 years old) with untreated mNSCLC and no EGFR and ALK mutations will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 expression (tumor cells <50% vs. ≥50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Group A will receive domvanalimab 1200 mg plus zimberelimab 360 mg plus platinum-doublet chemotherapy (PT), group B will receive pembrolizumab 200 mg plus PT, and group C will receive zimberelimab 360 mg plus PT, every 3 weeks. Treatment will be administered until disease progression or intolerable toxicity. Dual primary endpoints are progression-free survival (by blinded independent central review [BICR]) and overall survival for group A versus B. Key secondary endpoints comprise overall response rate (by BICR), safety, and quality of life. Exploratory endpoints include efficacy and safety between groups A and C, pharmacokinetics, patient-reported outcomes, and biomarkers. Conclusion: Enrollment in the STAR-121 study commenced on October 12, 2022, and is currently ongoing with completion planned by September 2024. The study completion is expected by December 2027.
Language	English
Publishing date	2024-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2145146-1
ISSN	1938-0690 ; 1525-7304
ISSN (online)	1938-0690
ISSN	1525-7304
DOI	10.1016/j.cllc.2023.12.010
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Zs.A 5893: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Silibinin is a suppressor of the metastasis-promoting transcription factor ID3.

Verdura, Sara / Encinar, José Antonio / Gratchev, Alexei / Llop-Hernández, Àngela / López, Júlia / Serrano-Hervás, Eila / Teixidor, Eduard / López-Bonet, Eugeni / Martin-Castillo, Begoña / Micol, Vicente / Bosch-Barrera, Joaquim / Cuyàs, Elisabet / Menendez, Javier A

Phytomedicine : international journal of phytotherapy and phytopharmacology

2024 Volume 128, Page(s) 155493

Abstract: Background: ID3 (inhibitor of DNA binding/differentiation-3) is a transcription factor that enables metastasis by promoting stem cell-like properties in endothelial and tumor cells. The milk thistle flavonolignan silibinin is a phytochemical with anti- ... ...

Abstract	Background: ID3 (inhibitor of DNA binding/differentiation-3) is a transcription factor that enables metastasis by promoting stem cell-like properties in endothelial and tumor cells. The milk thistle flavonolignan silibinin is a phytochemical with anti-metastatic potential through largely unknown mechanisms. Hypothesis/purpose: We have mechanistically investigated the ability of silibinin to inhibit the aberrant activation of ID3 in brain endothelium and non-small cell lung cancer (NSCLC) models. Methods: Bioinformatic analyses were performed to investigate the co-expression correlation between ID3 and bone morphogenic protein (BMP) ligands/BMP receptors (BMPRs) genes in NSCLC patient datasets. ID3 expression was assessed by immunoblotting and qRT-PCR. Luciferase reporter assays were used to evaluate the gene sequences targeted by silibinin to regulate ID3 transcription. In silico computational modeling and LanthaScreen TR-FRET kinase assays were used to characterize and validate the BMPR inhibitory activity of silibinin. Tumor tissues from NSCLC xenograft models treated with oral silibinin were used to evaluate the in vivo anti-ID3 effects of silibinin. Results: Analysis of lung cancer patient datasets revealed a top-ranked positive association of ID3 with the BMP9 endothelial receptor ACVRL1/ALK1 and the BMP ligand BMP6. Silibinin treatment blocked the BMP9-induced activation of the ALK1-phospho-SMAD1/5-ID3 axis in brain endothelial cells. Constitutive, acquired, and adaptive expression of ID3 in NSCLC cells were all significantly downregulated in response to silibinin. Silibinin blocked ID3 transcription via BMP-responsive elements in ID3 gene enhancers. Silibinin inhibited the kinase activities of BMPRs in the micromolar range, with the lower IC Conclusions: ID3 is a largely undruggable metastasis-promoting transcription factor. Silibinin is a novel suppressor of ID3 that may be explored as a novel therapeutic approach to interfere with the metastatic dissemination capacity of NSCLC.
Language	English
Publishing date	2024-03-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2024.155493
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Article ; Online: AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models.

Polonio-Alcalá, Emma / Porta, Rut / Ruiz-Martínez, Santiago / Vásquez-Dongo, Carmen / Relat, Joana / Bosch-Barrera, Joaquim / Ciurana, Joaquim / Puig, Teresa

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 156, Page(s) 113942

Abstract: Different EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients harboring sensitizing mutations in the EGFR gene. Apart from acquired secondary mutations, multiple resistance ... ...

Abstract	Different EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients harboring sensitizing mutations in the EGFR gene. Apart from acquired secondary mutations, multiple resistance mechanisms have been reported, such as the overexpression of fatty acid synthase (FASN), a multi-functional enzyme essential for the de novo lipogenesis, or the increase of cancer stem cells, a small subpopulation within the tumor responsible for relapse, metastasis, and resistance to therapies. Hence, the purpose of this work is to evaluate the novel FASN inhibitor AZ12756122, both alone and in combination with gefitinib and osimertinib, in EGFR-mutated (EGFRm) lung adenocarcinoma cell models sensitive and resistant to EGFR-TKIs. The molecular effect of AZ12756122 (alone and in combination with EGFR-TKI) on FASN, EGFR/STAT3, Akt/mTOR, and MAPK signaling pathways was analyzed using RT-qPCR and Western blot. FASN expression was also evaluated in samples from patients with EGFRm NSCLC through immunohistochemistry. Our findings revealed that AZ12756122 caused cytotoxic effects inducing apoptosis, downregulated FASN expression and activity, decreased the activation of EGFR and Akt/mTOR pathway, and reduced cancer stem-like cells. Furthermore, the combination of AZ12756122 and osimertinib sensitized cells to EGFR-TKI, showing a synergistic effect that resulted in a reduction in the activation of EGFR, Akt/mTOR, and MAPK signaling pathways. Our study also showed that FASN+ EGFRm NSCLC patients exhibited a longer mPFS in patients who responded to EGFR-TKI treatment. In conclusion, FASN inhibition should be further studied for the treatment, alone or in combination with EGFR-TKIs, for EGFRm NSCLC patients.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Drug Resistance, Neoplasm ; Neoplasm Recurrence, Local ; ErbB Receptors/genetics ; Protein Kinase Inhibitors/pharmacology ; Fatty Acid Synthases ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	osimertinib (3C06JJ0Z2O) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; ErbB Receptors (EC 2.7.10.1) ; Protein Kinase Inhibitors ; Fatty Acid Synthases (EC 2.3.1.85) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2022-10-28
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.113942
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Article: Challenges and Novel Opportunities of Radiation Therapy for Brain Metastases in Non-Small Cell Lung Cancer.

Jablonska, Paola Anna / Bosch-Barrera, Joaquim / Serrano, Diego / Valiente, Manuel / Calvo, Alfonso / Aristu, Javier

Cancers

2021 Volume 13, Issue 9

Abstract: Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25-50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and ... ...

Abstract	Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25-50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier. Some of the new targeted therapies, especially the group of tyrosine kinase inhibitors (TKIs) have shown durable CNS response. However, the use of ionizing radiation remains vital in the management of metastatic brain disease. Although a decrease in CNS-related deaths has been achieved over the past decade, many challenges arise from the need of multiple and repeated brain radiation treatments, which carry along not insignificant risks and toxicity. The combination of stereotactic radiotherapy and systemic treatments in terms of effectiveness and adverse effects, such as radionecrosis, remains a subject of ongoing investigation. This review discusses the challenges of the use of radiation therapy in NSCLC BMs in view of different systemic treatments such as chemotherapy, TKIs and immunotherapy. It also outlines the future perspectives and strategies for personalized BMs management.
Language	English
Publishing date	2021-04-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13092141
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Article ; Online: Addendum: Immune-related adverse events and atypical radiological response with checkpoint inhibitor immunotherapy in an elderly patient with high PD-L1 expressing lung adenocarcinoma.

Teixidor, Eduard / Sais, Elia / Vásquez, Carmen Amalia / Carbajal, Walter / Hernández, Alejandro / Sánchez, Gloria / Izquierdo, Angel / Verdura, Sara / Menéndez, Javier A / Bosch-Barrera, Joaquim

Oncotarget

2023 Volume 14, Page(s) 668

Language	English
Publishing date	2023-07-01
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.28471
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Article: Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors.

Verdura, Sara / Encinar, Jose Antonio / Teixidor, Eduard / Segura-Carretero, Antonio / Micol, Vicente / Cuyàs, Elisabet / Bosch-Barrera, Joaquim / Menendez, Javier A

Cancers

2022 Volume 14, Issue 24

Abstract: Epithelial-to-mesenchymal transition (EMT) may drive the escape of ALK-rearranged non-small-cell lung cancer (NSCLC) tumors from ALK-tyrosine kinase inhibitors (TKIs). We investigated whether first-generation ALK-TKI therapy-induced EMT promotes cross- ... ...

Abstract	Epithelial-to-mesenchymal transition (EMT) may drive the escape of ALK-rearranged non-small-cell lung cancer (NSCLC) tumors from ALK-tyrosine kinase inhibitors (TKIs). We investigated whether first-generation ALK-TKI therapy-induced EMT promotes cross-resistance to new-generation ALK-TKIs and whether this could be circumvented by the flavonolignan silibinin, an EMT inhibitor. ALK-rearranged NSCLC cells acquiring a bona fide EMT phenotype upon chronic exposure to the first-generation ALK-TKI crizotinib exhibited increased resistance to second-generation brigatinib and were fully refractory to third-generation lorlatinib. Such cross-resistance to new-generation ALK-TKIs, which was partially recapitulated upon chronic TGFβ stimulation, was less pronounced in ALK-rearranged NSCLC cells solely acquiring a partial/hybrid E/M transition state. Silibinin overcame EMT-induced resistance to brigatinib and lorlatinib and restored their efficacy involving the transforming growth factor-beta (TGFβ)/SMAD signaling pathway. Silibinin deactivated TGFβ-regulated SMAD2/3 phosphorylation and suppressed the transcriptional activation of genes under the control of SMAD binding elements. Computational modeling studies and kinase binding assays predicted a targeted inhibitory binding of silibinin to the ATP-binding pocket of TGFβ type-1 receptor 1 (TGFBR1) and TGFBR2 but solely at the two-digit micromolar range. A secretome profiling confirmed the ability of silibinin to normalize the augmented release of TGFβ into the extracellular fluid of ALK-TKIs-resistant NSCLC cells and reduce constitutive and inducible SMAD2/3 phosphorylation occurring in the presence of ALK-TKIs. In summary, the ab initio plasticity along the EMT spectrum may explain the propensity of ALK-rearranged NSCLC cells to acquire resistance to new-generation ALK-TKIs, a phenomenon that could be abrogated by the silibinin-driven attenuation of the TGFβ/SMAD signaling axis in mesenchymal ALK-rearranged NSCLC cells.
Language	English
Publishing date	2022-12-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14246101
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Article ; Online: Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells.

Verdura, Sara / Encinar, José Antonio / Fernández-Arroyo, Salvador / Joven, Jorge / Cuyàs, Elisabet / Bosch-Barrera, Joaquim / Menendez, Javier A

International journal of molecular sciences

2022 Volume 23, Issue 17

Abstract: The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that ... ...

Abstract	The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug−drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.
MeSH term(s)	Aminopyridines/pharmacology ; Aminopyridines/therapeutic use ; Anaplastic Lymphoma Kinase ; Carcinoma, Non-Small-Cell Lung/pathology ; Cytochrome P-450 CYP3A ; Hepatocytes ; Humans ; Lactams ; Lactams, Macrocyclic/pharmacology ; Lipids/therapeutic use ; Lung Neoplasms/pathology ; Protein Kinase Inhibitors/therapeutic use ; Pyrazoles ; Silybin ; Tandem Mass Spectrometry ; Triglycerides/therapeutic use
Chemical Substances	Aminopyridines ; Lactams ; Lactams, Macrocyclic ; Lipids ; Protein Kinase Inhibitors ; Pyrazoles ; Triglycerides ; Silybin (4RKY41TBTF) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; lorlatinib (OSP71S83EU)
Language	English
Publishing date	2022-09-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23179986
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Article: Lung Cancer Management with Silibinin: A Historical and Translational Perspective.

Verdura, Sara / Cuyàs, Elisabet / Ruiz-Torres, Verónica / Micol, Vicente / Joven, Jorge / Bosch-Barrera, Joaquim / Menendez, Javier A

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 6

Abstract: The flavonolignan silibinin, the major bioactive component of the silymarin extract ... ...

Abstract	The flavonolignan silibinin, the major bioactive component of the silymarin extract of
Language	English
Publishing date	2021-06-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14060559
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Article: Dilemas éticos en la práctica médica en 2010: reflexiones en torno a los resultados de una encuesta a más de 10.000 facultativos.

Bosch-Barrera, Joaquim

Cuadernos de bioetica : revista oficial de la Asociacion Espanola de Bioetica y Etica Medica

2011 Volume 22, Issue 74, Page(s) 113–118

Title translation	Ethical dilemmas in the medical practice in 2010: reflexions around the results of a survey to 10,000 physicians.
MeSH term(s)	Attitude of Health Personnel ; Bioethical Issues ; Data Collection/statistics & numerical data ; Ethics, Medical ; Global Health ; Humans ; Internet ; Medicine ; Physician-Patient Relations/ethics ; Physicians/statistics & numerical data ; Professional Practice/ethics ; United States
Language	Spanish
Publishing date	2011-01
Publishing country	Spain
Document type	Journal Article
ZDB-ID	2546303-2
ISSN	1132-1989
ISSN	1132-1989
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