Health Utility Analysis of Tepotinib in Patients with Non-small Cell Lung Cancer Harboring MET Exon 14 Skipping

OBJECTIVES: The VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC). We analyzed health state utilities using patient-reported outcomes from VISION. METHODS: EQ-5D-5L and European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6-12 weeks during treatment, and at end-of-treatment and safety follow-up. EQ-5D-5L and EORTC Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using US, Canada, UK and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD). RESULTS: Utilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± standard deviation) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post-progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre- versus post-progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, UK and Taiwan showed comparable trends. CONCLUSIONS: In this first analysis of health state utilities in patients with METex14 skipping NSCLC, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment

Regulation of MMP-9 by p53 in first trimester cytotrophoblastic cells

BACKGROUND: The matrix metalloproteinase (MMP) family is known to play a key role in tissue remodelling during embryonic development and in pathological conditions, such as cardiovascular disease, arthritis and cancer metastasis. It has been shown previously that p53 regulates positively or negatively the expression of different MMPs. Because of p53 overexpression in trophoblastic cells, and its potential role in regulating MMP-2 and MMP-9 expression in different cell lines, we hypothesized that the expression of MMP-9 could also be regulated by p53 in first trimester cytotrophoblasts (CTB). METHODS and RESULTS: Transfection experiments in CTB demonstrated that wild-type p53 down-regulates the -670 (P < 0.001) but not the -531 and -90 human MMP-9 promoter/CAT reporter plasmid activity, whereas p53 mutants partially lost this repressive activity. However, endogenous p53 is not able to regulate MMP-9 expression in CTB. The presence of high molecular weight complexes of p53 in CTB suggests a potential mechanism of inactivation of p53 transcriptional activity towards MMPs in these cells. CONCLUSIONS: Although p53 is mutated in trophoblast, it is functionally incompetent towards MMPs in these cells

Identification and phylogenetic comparison of p53 in two distinct mussel species (Mytilus)

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Elsevier B. V. for personal use, not for redistribution. The definitive version was published in Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 140 (2005): 237-250, doi:10.1016/j.cca.2005.02.011.The extent to which humans and wildlife are exposed to anthropogenic challenges is an important focus of environmental research. Potential use of p53 gene family marker(s) for aquatic environmental effects monitoring is the long-term goal of this research. The p53 gene is a tumor suppressor gene that is fundamental in cell cycle control and apoptosis. It is mutated or differentially expressed in about 50% of all human cancers and p53 family members are differentially expressed in leukemic clams. Here, we report the identification and characterization of the p53 gene in two species of Mytilus, Mytilus edulis and Mytilus trossulus, using RT-PCR with degenerate and specific primers to conserved regions of the gene. The Mytilus p53 proteins are 99.8% identical and closely related to clam (Mya) p53. In particular, the 3′ untranslated regions were examined to gain understanding of potential post-transcriptional regulatory pathways of p53 expression. We found nuclear and cytoplasmic polyadenylation elements, adenylate/uridylate-rich elements, and a K-box motif previously identified in other, unrelated genes. We also identified a new motif in the p53 3′UTR which is highly conserved across vertebrate and invertebrate species. Differences between the p53 genes of the two Mytilus species may be part of genetic determinants underlying variation in leukemia prevalence and/or development, but this requires further investigation. In conclusion, the conserved regions in these p53 paralogues may represent potential control points in gene expression. This information provides a critical first step in the evaluation of p53 expression as a potential marker for environmental assessment.AFM was supported by the Greater Vancouver Regional District, BC, Canada, and RLC was supported by STAR grant R82935901 from the Environmental Protection Agency (USA)

Microtubule disruption targets HIF-1α mRNA to cytoplasmic P-bodies for translational repression

Active translation of HIF-1α requires association and trafficking of HIF mRNA on dynamic microtubules, whereas microtubule disruption represses HIF-1α translation by releasing its mRNA from polysomes and sequestering it to P-bodies

hMSH5 is a nucleocytoplasmic shuttling protein whose stability depends on its subcellular localization

MSH5 is a MutS-homologous protein required for meiotic DNA recombination. In addition, recent studies suggest that the human MSH5 protein (hMSH5) participates to mitotic recombination and to the cellular response to DNA damage and thus raise the possibility that a tight control of hMSH5 function(s) may be important for genomic stability. With the aim to characterize mechanisms potentially involved in the regulation of hMSH5 activity, we investigated its intracellular trafficking properties. We demonstrate that hMSH5 possesses a CRM1-dependent nuclear export signal (NES) and a nuclear localization signal that participates to its nuclear targeting. Localization analysis of various mutated forms of hMSH5 by confocal microscopy indicates that hMSH5 shuttles between the nucleus and the cytoplasm. We also provide evidence suggesting that hMSH5 stability depends on its subcellular compartmentalization, hMSH5 being much less stable in the nucleus than in the cytoplasm. Together, these data suggest that hMSH5 activity may be regulated by nucleocytoplasmic shuttling and nuclear proteasomal degradation, both of these mechanisms contributing to the control of nuclear hMSH5 content. Moreover, data herein also support that in tissues where both hMSH5 and hMSH4 proteins are expressed, hMSH5 might be retained in the nucleus through masking of its NES by binding of hMSH4

Tepotinib treatment in patients with MET exon 14-skipping non-small cell lung cancer: long-term follow-up of the VISION phase 2 nonrandomized clinical trial

IMPORTANCE MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches.OBJECTIVE To assess the long-term efficacy and safety of tepotinib, a potent and highly selective MET inhibitor, in patients with METex14-skipping NSCLC in the VISION study.DESIGN, SETTING, AND PARTICIPANTS The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C) from September 2016 to May 2021. Cohort C (>18 months' follow-up) was an independent cohort, designed to confirm findings from cohort A (>35 months' follow-up). Data cutoff was November 20, 2022.INTERVENTION Patients received tepotinib, 500mg (450mg active moiety), once daily.MAIN OUTCOMES AND MEASURES The primary end point was objective response by independent review committee (RECIST v1.1). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.RESULTS Cohorts A and C included 313 patients (50.8% female, 33.9% Asian; median [range] age, 72 [41-94] years). The objective response rate (ORR) was 51.4%(95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9%(95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines, comparable to cohort A (n = 152). In treatment-naive patients (cohorts A and C; n = 164), ORR was 57.3%(95% CI, 49.4%-65.0%) and mDOR was 46.4 (95% CI, 13.8-NE) months. In previously treated patients (n = 149), ORR was 45.0% (95% CI, 36.8%-53.3%) and mDOR was 12.6 (95% CI, 9.5-18.5) months. Peripheral edema, the most common treatment-related adverse event, occurred in 210 patients (67.1%) (35 [11.2%] experienced grade >= 3 events).CONCLUSIONS AND RELEVANCE The findings from cohort C in this nonrandomized clinical trial supported the results from original cohort A. Overall, the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC, supporting the global approvals of tepotinib and enabling clinicians to implement this therapeutic approach for such patients.Pathogenesis and treatment of chronic pulmonary disease

Anti-Microtube Agents: Mechanismes of Action and Resistance / Agents anti-microtubulars: mecanismes d'acció i resistència

[eng] The focus of this thesis has been four-fold. On one hand it has been to decipher, understand and manipulate the role of microtubule-trafficking in the cell. Secondly we have concentrated on the mechanism of action of agents that target the microtubules, and thirdly we have developed a model to explain acquired drug resistance to these microtubule-targeting agents. Lastly, we tested new microtubule-targeting agents that overcome acquired and intrinsic drug resistance to microtubule-targeting agents. Microtubules (microtubules) are major dynamic structural components in cells that are essential for the development and maintenance of cell shape, cell signaling, movement, and division. We sought to understand the role microtubules play within the cellular context. Microtubules act as "active highways" within the cells and are essential for the correct operation of the cell by controlling the delivery, location, and function of a plethora of proteins. We have focused on the p53 and the HIF1-α proteins. Both these proteins are crucial players in tumor progression and angiogenesis. p53 is a tumor suppressor gene commonly referred to as the guardian of the genome and HIF1-α is a transcriptional factor that plays a key role in adaptation to hypoxia. Upon DNA damage or hypoxia, p53 or HIF1-α respectively are induced and quickly localize to the cell nucleus; whereas upon DNA repair or normoxia they must quickly concentrate in the cytoplasm for degradation. Their fast movement rate is not random and is directed by a microtubule-driven motor. Furthermore, we have shown that HIF1-α mRNA also uses the microtubule network to travel from the nucleus to the site of translation. Drugs that bind to either tubulin or microtubules form one of the most effective classes of anticancer agents. The so-called anti-mitotic drugs usually arrest cells in mitosis leading to apoptosis. We analyzed the differential effects of taxol treatment on parental and taxol-resistant cells. Survivin is a protein that senses mitotic arrest and leading to apoptotic cell death. Despite the clinical success of microtubule-targeting agents, the emergence of acquired resistance to the drug is a limiting factor for curing cancer. Acquired drug resistance is the most common reason for the failure of drug treatment in cancer patients with initially sensitive tumors, and as such, is presently responsible for the majority of deaths from cancer. We sought to understand the timeline of events that takes place during the development of drug resistance to microtubule-targeting agents. While it has been widely published that a major mechanism of resistance to anti-mitotic drugs is due to acquired β-tubulin mutations, we have shown loss of heterozygosity of the wild type allele of β-tubulin must occur to confer higher levels of resistance. To overcome drug resistance to microtubule-targeting agents we have focused on alternate drug regimens that are active in anti-mitotic drug-resistant cells. The synergistic interaction of farnesyltransferase inhibitors (FTI) and taxol has recently been introduced in the clinic and surprisingly overcomes taxol resistance. We have shown that FTIs increase the binding of taxol to β-tubulin tubulin, even in taxol-resistant cells. In an effort to dissect the molecular mechanism underlying the synergistic interaction of FTIs with taxanes, we have recently discovered that FTIs affect microtubule acetylation and stability, partly due to inhibition of the tubulin deacetylase HDAC6. The inhibition of HDAC6 by the FTI lonafarnib leads to increased tubulin acetylation and that this is the molecular basis for the synergy of FTIs with Taxol.[spa] La tesis titulada "Anti-microtubule drugs: Mechanisms of Action and Resistance. Agents anti-microtubulars: Mecanismes d'Acció i Resistència" tiene cuatro objetivos principales. El primer objetivo ha sido descifrar, entender y manipular el papel del tráfico microtubular. El segundo objetivo se ha centrado en el mecanismo de acción de los agentes que tienen como diana los microtúbulos. En el tercer objetivo se ha desarrollado un modelo para explicar la quimioresistencia adquirida a estos agentes anti-microtubulares. En el cuarto y ultimo objetivo se han probado nuevos agentes anti-microtubulares que son activos en casos de quimioresistencia adquirida o endógena a agentes anti-microtubulares. Los microtúbulos, componentes dinámicos y estructurales de las células, son esenciales para el desarrollo y mantenimiento de la forma celular, el movimiento y división celulares. Se ha intentado entender el papel que juegan los microtúbulos en el contexto celular. Los microtúbulos actúan como "autopistas activas" dentro de las células y son esenciales para la correcta operación celular ya que controlan la entrega, localización y función de una multitud de proteínas. El primer objetivo de la tesis se ha centrado en las proteínas p53 y HIF1-α. Estas dos proteínas son principales protagonistas en la progresión tumoral y la angiogenesis. La p53 es un gen supresor de tumor comúnmente llamado el guardián del genoma y el HIF1-α es un factor de trascripción que tiene un papel crucial en la adaptación celular a la hipoxia (la baja concentración de oxigeno). En los casos de el daño al ADN o hipoxia, la p53 o el HIF1-α, respectivamente, son inducidos y se translocan rápidamente al núcleo celular, mientras que cuando el ADN ha sido reparado o el regreso al estado de normoxia, las proteínas se deben concentrar en el citoplasma para su degradación por el proteosoma. El rápido movimiento de estas proteínas no es aleatorio y esta dirigido por un motor microtubular. Además, se ha demostrado que el ARN mensajero del HIF1-α también usa la red de microtúbulos para llegar del núcleo al sitio de translación a proteína. Las drogas que se unen a la tubulina forman parte de una de las clases más efectivas de agentes anticáncer. Estas drogas comúnmente referidas como antimitóticas arrestan las células en mitosis conllevando a la apoptosis celular. Se han analizados los diferentes efectos del tratamiento del taxol en líneas celulares sensibles al taxol y en líneas celulares resistentes al taxol derivadas de las líneas sensibles. La survivina es una proteína clave en el pase del arresto mitótico en la célula a la muerte por apoptosis. A pesar del éxito clínico de las drogas antimicrotubulares, un factor que limita su aplicación universal es la apariencia de focos resistentes. La quimioresistencia adquirida es la razón más común del fracaso de la quimioterapia en pacientes con cáncer que inicialmente responden al tratamiento. En el tercer objetivo de la tesis se ha descrito un modelo temporal para explicar el desarrollo de la quimioresistencia en líneas celulares tratadas continuamente con drogas antimicrotubulares. Aunque se ha publicado extensamente que el principal mecanismo de quimioresistencia a los agentes antimicrotubulares es debido a la apariencia de mutaciones en el gen de la beta-tubulina, en este objetivo se ha demostrado que es necesario que también haya perdida de heterocigosidad en el alelo wt para que las células tengan unos altos niveles de resistencia. En el cuarto objetivo se han estudiado nuevos regimenes de quimioterapia que son activos en las células resistentes. La interacción sinergística entre los inhibidores de la farnesiltransferasa (FTI) y los taxanos se introdujo recientemente en la clínica y es muy activa contra la resistencia al taxol. Se ha demostrado que los FTIs intensifican la unión del taxol a la beta-tubulina, incluso en células resistentes al taxol. Los FTIs afectan la acetilación microtubular, a través de la inhibición de la HDAC6, la tubulina deacetilasa. La mayor acetilación de la tubulina, conlleva a una tubulina más estable y más propensa a la unión del taxol

Changes in fan gratifications and sports media dependency after the postponement of sports due to the COVID-19 pandemic

Master of ScienceDepartment of Journalism and Mass CommunicationsRaluca CozmaThroughout most of written history, there has been a fascination for sports, from gladiator fights to the first Olympic Games, which has turned into a form of dependence worldwide. Today, a bevy of professional sports and a plethora of professional teams fill stadiums, television slots, and streaming sites. With every sport comes fans, and with every fan comes an assortment of reasons as to why they are fans of certain sports, teams or athletes. Most of these fans use sports as an escape from under-stimulation (i.e., boredom, apathy) as well as over-stimulation (i.e., stress and anxiety) in their daily lives (Wann, Allen & Rochelle, 2004). Some fans, especially those heavily dedicated to specific teams, may even consider their sport or team a religion of sorts (Price, 2005). What would a typical fan do if all sports were taken away from them quickly and without warning? How would fans react if their favorite team was suddenly unable to participate in playoffs or championship? That is exactly what happened in March of 2020 because of growing concern about COVID-19. This thesis explores how the average sports fans and fantasy sports fans spent their time quarantining without their beloved sports, and it examines how dependent the common fans are on sports and sports media before, during, and after being forced to remain at home without any new games or matches for months on end

Health Utility Analysis of Tepotinib in Patients With Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping.

OBJECTIVES: The VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer. We analyzed health state utilities using patient-reported outcomes from VISION. METHODS: 5-level version of EQ-5D (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6 to 12 weeks during treatment, and at the end of treatment and safety follow-up. EQ-5D-5L and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using United States, Canada, United Kingdom, and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD). RESULTS: Utilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± SD) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre versus post progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, United Kingdom, and Taiwan showed comparable trends. CONCLUSIONS: In this first analysis of health state utilities in patients with METex14 skipping non-small cell lung cancer, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment