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1.
Cancer Med ; 13(13): e7440, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38989639

RESUMO

Cancer genomic services (CGS) can support genetic risk-stratified cancer prevention and treatment. Racial/ethnic minority groups are less likely to access and utilize CGS compared with non-Hispanic Whites. Little research has described characteristics of interventions targeted at CGS among Latinos. This scoping review aimed to (1) describe interventions promoting uptake of CGS among Latinos in the United States and Latin America, (2) describe intervention adaptations for Latino participants, and (3) summarize intervention implementation factors suggested by reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework. We conducted a search in English and Spanish of literature published between 2005 and 2022 across PubMed and Latin American and Caribbean Health Sciences Literature databases. Sixteen of 2344 papers met the inclusion criteria of the analysis. Efforts to promote CGS among Latino communities were limited in the US and lower in Latin America. This review highlights the need for in-depth exploration of acculturation-informed interventions and better reporting on implementation factors to enhance their scalability across diverse settings.


Assuntos
Genômica , Hispânico ou Latino , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/etnologia , Genômica/métodos , Estados Unidos , América Latina
2.
PLoS One ; 19(7): e0306717, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38990836

RESUMO

BACKGROUND: Studies of prognostication in advanced cancer use a wide range of outcomes and outcome measures, making it difficult to compare these studies and their findings. Core Outcome Sets facilitate comparability and standardisation between studies and would benefit future prognostic research. This qualitative study, the second step in a wider study developing such a Core Outcome Set, aimed to explore the perceptions and experiences of patients with advanced cancer, informal caregivers, and clinicians regarding the potential outcomes to assess the impact of prognostication. METHODS: We conducted semi-structured interviews with patients living with advanced cancer (n = 8), informal caregivers (n = 10), and clinicians (n = 10) recruited from palliative care services across three sites in London, United Kingdom. Interviews were conducted in-person, via telephone, or video conferencing, and were audio-recorded. Data were analysed using framework analysis. Findings were compared with outcomes identified in a previously published systematic review. RESULTS: We identified 33 outcomes, 16 of which were not previously reported in the literature. We grouped these outcomes into 10 domains, nine from the COMET taxonomy, plus a tenth domain (spiritual/religious/existential functioning/wellbeing) which we added further to the previous systematic review. These findings highlighted discrepancies between the priorities of existing research and those of stakeholders. Novel outcomes highlight the more personal and emotional impacts of prognostication, whilst other outcomes confirm the relevance of survival length, depression, anxiety, pain, hope dynamics, emotional distress, and the quality of patient-clinician relationships for assessing the impact of prognostication. CONCLUSIONS: This study offers valuable insights into outcomes which matter to key stakeholders, particularly patients and informal caregivers, highlights discrepancies between their priorities and those identified in previous studies, and underscores the need for a patient-centred approach in research and clinical practice in prognostication in advanced cancer. This work will contribute to developing a Core Outcome Set for assessing the impact of prognostication in advanced cancer.


Assuntos
Cuidadores , Neoplasias , Pesquisa Qualitativa , Humanos , Neoplasias/psicologia , Feminino , Masculino , Prognóstico , Pessoa de Meia-Idade , Idoso , Cuidadores/psicologia , Cuidados Paliativos , Avaliação de Resultados em Cuidados de Saúde/métodos , Adulto , Idoso de 80 Anos ou mais , Qualidade de Vida
3.
Proc Natl Acad Sci U S A ; 121(29): e2404551121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38990945

RESUMO

Confined cell migration hampers genome integrity and activates the ATR and ATM mechano-transduction pathways. We investigated whether the mechanical stress generated by metastatic interstitial migration contributes to the enhanced chromosomal instability observed in metastatic tumor cells. We employed live cell imaging, micro-fluidic approaches, and scRNA-seq to follow the fate of tumor cells experiencing confined migration. We found that, despite functional ATR, ATM, and spindle assembly checkpoint (SAC) pathways, tumor cells dividing across constriction frequently exhibited altered spindle pole organization, chromosome mis-segregations, micronuclei formation, chromosome fragility, high gene copy number variation, and transcriptional de-regulation and up-regulation of c-MYC oncogenic transcriptional signature via c-MYC locus amplifications. In vivo tumor settings showed that malignant cells populating metastatic foci or infiltrating the interstitial stroma gave rise to cells expressing high levels of c-MYC. Altogether, our data suggest that mechanical stress during metastatic migration contributes to override the checkpoint controls and boosts genotoxic and oncogenic events. Our findings may explain why cancer aneuploidy often does not correlate with mutations in SAC genes and why c-MYC amplification is strongly linked to metastatic tumors.


Assuntos
Movimento Celular , Amplificação de Genes , Proteínas Proto-Oncogênicas c-myc , Estresse Mecânico , Humanos , Movimento Celular/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Linhagem Celular Tumoral , Camundongos , Mitose/genética , Instabilidade Cromossômica , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo
4.
PLoS One ; 19(7): e0306035, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38990967

RESUMO

PURPOSE: The COVID-19 pandemic posed unique challenges to cancer-related care as health systems balanced competing risks of timely delivery of care and minimizing exposure to infection in a high-risk, immunocompromised patient population. This study aimed to better understand how pandemic-related factors affected the patient experience of cancer care during this time. METHODS: We conducted fifteen semi-structured interviews with adults from rural counties in Maryland who were diagnosed with and/or actively treated for cancer at the TidalHealth healthcare network between January 2020 and October 2022. RESULTS: Interviews from fifteen participants were analyzed. Two major themes emerged including COVID Impact on Care, and COVID Impact on Mental Health. Subthemes under COVID Impact on Care include Staffing Shortages, Hospital Regulations, Visitation, Importance of Advocacy, and Telehealth Utilization, and subthemes under COVID Impact on Mental Health include Loneliness, Support Networks, and Perceptions of COVID and Personal Protection. Overall, participants described positive care experiences despite notable delays, disruptions to continuity of care, difficult transitions to telemedicine, visitation policies that limited patient support, increased mental health struggles related to social distancing measures, and greater desire for patient advocacy. CONCLUSION: Our findings reveal significant impacts of the COVID-19 pandemic on experiences of cancer treatment and survivorship in a more vulnerable, rural patient population with lower healthcare access and income level. Our findings suggest areas for targeted interventions to limit disruptions to quality care in future public health emergencies.


Assuntos
COVID-19 , Neoplasias , Pesquisa Qualitativa , Telemedicina , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Feminino , Masculino , Neoplasias/terapia , Neoplasias/psicologia , Pessoa de Meia-Idade , Idoso , Adulto , SARS-CoV-2 , Pandemias , Saúde Mental , Maryland/epidemiologia , População Rural
5.
Science ; 385(6705): eadl6173, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38991060

RESUMO

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.


Assuntos
Imunidade Inata , Isocitrato Desidrogenase , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Animais , Camundongos , Humanos , Elementos de DNA Transponíveis , Metilação de DNA , Mutação , Neoplasias/imunologia , Neoplasias/genética , Epigênese Genética , Evasão Tumoral , Linhagem Celular Tumoral , DNA/metabolismo , Glutaratos/metabolismo , Desmetilação do DNA , Nucleotidiltransferases
6.
Science ; 385(6705): 140-142, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38991086
7.
JCO Precis Oncol ; 8: e2300715, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38991178

RESUMO

PURPOSE: African American/Black (AA/B) individuals are under-represented in genomic databases and thus less likely to receive definitive information from germline genetic testing (GGT) than non-Hispanic White (NHW) individuals. With nearly 500,000 AA/B and NHW individuals having undergone multigene panel testing (MGPT) for hereditary cancer risk at a single commercial laboratory, to our knowledge, we present the largest study to date investigating cancer GGT results in AA/B and NHW individuals. METHODS: MGPT results from a retrospective cohort of AA/B (n = 48,684) and NHW (n = 444,831) patients were evaluated. Frequencies of pathogenic germline variants (PGVs) and variants of uncertain significance (VUS) were compared between AA/B and NHW individuals. Changes in frequency of VUS over time were determined. Pearson's chi-squared test was used to compare categorical variables among groups. All significance tests were two-tailed, and P < .05 was considered statistically significant. RESULTS: Between 2015 and 2022, rates of VUS decreased 2.3-fold in AA/B and 1.8-fold in NHW individuals; however, frequencies of VUS and PGV remained significantly higher (46% v 32%; P < .0001) and lower (9% v 13%; P < .0001) in AA/B compared with NHW individuals. Rates of VUS in ATM, BRCA1, BRCA2, PALB2, and PMS2 were significantly higher in AA/B compared with NHW individuals, whereas rates of PGV in BRCA1, BRCA2, and PALB2 were higher in AA/B compared with NHW individuals (P < .001). CONCLUSION: Despite reductions in VUS frequencies over time, disparities in definitive GGT results persist. Increasing inclusion of AA/B populations in both testing and research will further increase knowledge of genetic variants across these racial groups.


Assuntos
Negro ou Afro-Americano , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , População Branca , Humanos , População Branca/genética , Estudos Retrospectivos , Negro ou Afro-Americano/genética , Masculino , Feminino , Neoplasias/genética , Neoplasias/etnologia , Testes Genéticos/métodos , Pessoa de Meia-Idade , Adulto
9.
JCO Glob Oncol ; 10: e2400063, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38991187

RESUMO

PURPOSE: Most patients with cancer will be hospitalized throughout the disease course. However, most evidence on the causes and outcomes of these hospitalizations comes from administrative data or small retrospective studies from high-income countries. METHODS: This study is a retrospective cohort of patients with solid tumors hospitalized from February 1, 2021, to December 31, 2021, in a tertiary cancer center in São Paulo, Brazil. We collected data on cancer diagnosis, symptoms at admission, hospitalization diagnosis, and survival clinical outcomes during in-hospital stay (in-hospital mortality) and after discharge (readmission rates and overall survival [OS]). Progressive disease (PD) diagnosis during admission was retrieved from manual chart review if explicitly stated by the attending physician. We modeled in-hospital mortality and postdischarge OS with logistic regression and Cox proportional hazards models, respectively. RESULTS: A total of 3,726 unique unplanned admissions were identified. The most common symptoms at admission were pain (40.6%), nausea (16.8%), and dyspnea (16.1%). PD (34.0%), infection (31.1%), and cancer pain (13.4%) were the most frequent reasons for admission. The in-hospital mortality rate was 18.9%. Patients with PD had a high in-hospital mortality rate across all tumor groups and higher odds of in-hospital death (odds ratio, 3.5 [95% CI, 3.0 to 4.2]). The 7-, 30-, and 90-day readmission rates were 11.9%, 33.5%, and 54%, respectively. The postdischarge median OS (mOS) was 12.6 months (95% CI, 11.6 to 13.7). Poorer postdischarge survival was observed among patients with PD (mOS, 5 months v 18 months; P < .001; hazard ratio, 2.4 [95% CI, 2.1 to 2.6]). CONCLUSION: PD is a common diagnosis during unplanned hospitalizations and is associated with higher in-hospital mortality rates and poorer OS after discharge. Oncologists should be aware of the prognostic implications of PD during admission and align goals of care with their patients.


Assuntos
Mortalidade Hospitalar , Hospitalização , Neoplasias , Humanos , Neoplasias/mortalidade , Neoplasias/terapia , Neoplasias/epidemiologia , Brasil/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Hospitalização/estatística & dados numéricos , Progressão da Doença , Adulto , Readmissão do Paciente/estatística & dados numéricos
10.
Cell Host Microbe ; 32(7): 1045-1047, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38991501

RESUMO

The microbiota can impact antitumor immunity, but whether the microbiota regulates omental antitumor immunity remains elusive. In this issue of Cell Host & Microbe, Meza-Perez et al. demonstrated that Proteobacteria consume arginine to increase Treg cell suppressive capacity and inhibit antitumor immune responses, promoting tumor growth in the omentum.


Assuntos
Arginina , Omento , Proteobactérias , Arginina/metabolismo , Animais , Omento/imunologia , Omento/microbiologia , Humanos , Camundongos , Microbioma Gastrointestinal/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias/imunologia , Neoplasias/microbiologia
11.
BMJ Open ; 14(7): e081823, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38991689

RESUMO

OBJECTIVES: In our study, we aimed to characterise adult childhood cancer survivors (ACCS), assess their health issues, gauge health-related quality of life (HRQOL) and evaluate visit satisfaction. DESIGN: Prospective cohort study using data from clinical visits and questionnaires. SETTING: Interdisciplinary follow-up programme for ACCS based on the long-term follow-up (LTFU) guidelines of the Children's Oncology Group and overseen by internists in two Swiss hospitals. PARTICIPANTS: ACCS attending our LTFU clinics between April 2017 and January 2022 were eligible. INTERVENTIONS: We documented medical history, current health status and assessed HRQOL using Short Form-36 V.2, comparing it with Swiss general population (SGP) norms (T mean=50, SD=10; age stratified). 3 months post visit, a feedback questionnaire was distributed. MAIN RESULTS: Among 102 ACCS (mean age: 32 years (range: 18-62 years), 68% women), 43 had no prior follow-up (36 ACCS>28 years, 7 ACCS≤28 years). A notable 94% had health issues, affecting an average of 6.1 (SD=3.3) organ systems. HRQOL was lower in ACCS>28 years than the SGP>28 years (physical: 44.8 (SD=11.65) vs 49.3 (SD=10.29), p=0.016; mental: 44.4 (SD=13.78) vs 50.53 (SD=9.92), p=0.004). Older ACCS (>28 years) reported inferior physical (44.8 vs 50.1 (SD=9.30), p=0.017) and mental HRQOL (44.4 vs 50.3 (SD=7.20), p=0.009) than younger ACCS. The majority of respondents reported high levels of satisfaction with the consultation, exceeding 90%. CONCLUSION: ACCS attending LTFU clinics face diverse health issues impacting multiple organ systems and exhibit lower HRQOL compared with the SGP. Thus, internist-led LTFU clinics are crucial for optimising follow-up care.


Assuntos
Sobreviventes de Câncer , Neoplasias , Qualidade de Vida , Humanos , Feminino , Masculino , Sobreviventes de Câncer/psicologia , Estudos Prospectivos , Adulto , Suíça , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Neoplasias/psicologia , Neoplasias/terapia , Inquéritos e Questionários , Satisfação do Paciente , Seguimentos , Nível de Saúde
12.
J Immunother Cancer ; 12(7)2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38991727

RESUMO

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.


Assuntos
Pesquisa Biomédica , COVID-19 , Imunoterapia , Neoplasias , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , SARS-CoV-2/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Pandemias
13.
Pharmacogenomics J ; 24(4): 22, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992025

RESUMO

Bevacizumab-induced hypertension poses a therapeutic challenge and identifying biomarkers for hypertension can enhance therapy safety. Lower plasma levels of VEGF-A, angiopoietin-2, and rs6770663 in KCNAB1 were previously associated with increased risk of bevacizumab-induced hypertension. This study investigated whether these factors independently contribute to grade 2-3 bevacizumab-induced hypertension risk in 277 cancer patients (CALGB/Alliance 90401). Multivariable analyses assessed the independent association of each factor and hypertension. Likelihood ratio test (LRT) evaluated the explanatory significance of combining protein levels and rs6770663 in predicting hypertension. Boostrap was employed to assess the mediation effect of protein levels on the rs6770663 association with hypertension. Lower protein levels and rs6770663 were independently associated with increased hypertension risk. Adding rs6770663 to protein levels improved the prediction of hypertension (LRT p = 0.0002), with no mediation effect observed. Protein levels of VEGF-A, angiopoietin-2 and rs6770663 in KCNAB1 are independent risk factors and, when combined, may improve prediction of bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00110214.


Assuntos
Angiopoietina-2 , Bevacizumab , Hipertensão , Fator A de Crescimento do Endotélio Vascular , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Angiogênese/efeitos adversos , Angiopoietina-2/sangue , Angiopoietina-2/genética , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Hipertensão/genética , Hipertensão/induzido quimicamente , Hipertensão/sangue , Neoplasias/tratamento farmacológico , Neoplasias/sangue , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Canais de Potássio Shab/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética
14.
Nat Commun ; 15(1): 5842, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992037

RESUMO

Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.


Assuntos
Imunidade Inata , Imunoconjugados , Interferons , Proteínas de Membrana , Animais , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Imunidade Inata/efeitos dos fármacos , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Imunoconjugados/farmacologia , Imunoconjugados/administração & dosagem , Interferons/metabolismo , Interferon lambda , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Interferon Tipo I/imunologia , Citocinas/metabolismo , Células Mieloides/imunologia , Células Mieloides/efeitos dos fármacos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Receptores de IgG/agonistas , Receptores de IgG/metabolismo , Receptores de IgG/imunologia
15.
Nat Commun ; 15(1): 5837, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992034

RESUMO

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children's Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Disseminação de Informação , Neoplasias , Medicina de Precisão , Humanos , Neoplasias/genética , Neoplasias/tratamento farmacológico , Criança , Medicina de Precisão/métodos , Masculino , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adolescente , Lactente , Mutação , Ensaios Clínicos como Assunto , Terapia de Alvo Molecular/métodos , Genômica/métodos , Recém-Nascido
16.
Signal Transduct Target Ther ; 9(1): 181, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992067

RESUMO

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.


Assuntos
Bortezomib , Proteínas de Ciclo Celular , Mitose , Complexo de Endopeptidases do Proteassoma , Proteínas Tirosina Quinases , Piroptose , Piroptose/efeitos dos fármacos , Humanos , Camundongos , Animais , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Mitose/efeitos dos fármacos , Mitose/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Inibidores de Proteassoma/farmacologia , Pirimidinas/farmacologia , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Gasderminas , Pirimidinonas
17.
Support Care Cancer ; 32(8): 509, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992238

RESUMO

PURPOSE: Exercise and physical activity (PA) during oncological treatment have many benefits. However, PA levels and adherence are often low. This systematic review of qualitative literature aims to explore the experience and the perceived barriers and facilitators to exercise and physical activity during treatment. METHODS: A systematic search of the published literature was carried out in the Embase and Medline databases; full details for the protocol can be found in the Prospero database (CRD42022371206). Studies eligible for inclusion were qualitative and included participants that were either currently undergoing oncological treatment or had finished treatment within the last 6 months. The findings from each study were tabulated and synthesised into analytical themes. RESULTS: Eighteen full texts from 309 studies met inclusion criteria with a total of 420 participants including both curative and palliative treatment intents. Four overarching themes were generated: (1) Facilitators; (2) Barriers; (3) Experience of PA/exercise and (4) Transforming attitudes. Sub-themes that showed perceptions of PA or exercise during treatment were positive, and seeing personal positive change was highly motivating, especially in a group class setting. Barriers included lack of support or guidance from healthcare professionals (HCPs), environmental challenges and disease burden/fear or worsening symptoms. CONCLUSIONS: Despite having positive perceptions of exercise and PA during oncological treatment, there are significant barriers impacting participation. Lack of support from HCPs and fear of worsening symptoms were significant barriers. Future research should focus on impacting these barriers to ultimately improve PA and exercise levels in those undergoing oncological treatment.


Assuntos
Exercício Físico , Neoplasias , Pesquisa Qualitativa , Humanos , Neoplasias/psicologia , Neoplasias/terapia , Exercício Físico/psicologia , Atitude Frente a Saúde , Terapia por Exercício/métodos , Terapia por Exercício/psicologia , Motivação
18.
BMC Health Serv Res ; 24(1): 802, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992687

RESUMO

PURPOSE: To evaluate the availability, cost, affordability of anti-cancer medicines in Nanjing, Jiangsu. METHODS: A longitudinal tracking investigation study was performed to collect information about 24 essential anti-cancer medicines (EAMs) and 17 innovative anti-cancer medicines (IAMs) in 26 healthcare institutions in Nanjing from 2016 to 2020. The availability, cost, drug utilization and affordability of EAMs and IAMs were investigated. RESULTS: The availability of EAMs showed no significant changes in Nanjing, but the availability of IAMs showed a significant increase in 2018 and 2019 and tended to stabilize in 2020. For EAMs, the DDDc(Defined Daily Dose cost) of LPGs (Lowest-Priced Generics) showed no significant changes, and the DDDc of OBs (Originator Brands) and IAMs significantly decreased. The DDDs(Defined Daily Doses) of EAMs (LPGs) showed a decreasing trend since 2016 and rose again in 2019. Overall, the DDDs of EAMs (LPGs) decreased by 25.18% between 2016 and 2020, but the proportion selected for clinical treatment remained at 67.35% in 2020. The DDDs of EAMs (OBs) and IAMs both showed an increasing trend year by year, with a proportional increase of 207.72% and 652.68%, respectively; but the proportion selected for clinical treatment was only 16.09% and 16.56% respectively in 2020. EAMs (LPGs) had good affordability for urban residents but poor affordability for rural residents; the affordability of EAMs (OBs) and IAMs was poor for both urban and rural residents. CONCLUSIONS: There were no significant changes in the availability and cost of EAMs (LPGs), whose lower prices showed better affordability. Although their relative change in drug utilization showed a decreasing trend, they still dominated clinical treatment. Driven by the national drug price negotiation (NDPN) policy, the availability of IAMs was on the rise. It is necessary to further develop and strengthen policies for essential medicines procurement assessment to improve the accessibility of EAMs.


Assuntos
Antineoplásicos , Custos de Medicamentos , Medicamentos Essenciais , Acessibilidade aos Serviços de Saúde , Estudos Longitudinais , Humanos , China , Antineoplásicos/uso terapêutico , Antineoplásicos/economia , Antineoplásicos/provisão & distribuição , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Medicamentos Essenciais/provisão & distribuição , Medicamentos Essenciais/economia , Custos de Medicamentos/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Drogas em Investigação/economia
19.
J Biomed Sci ; 31(1): 67, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992695

RESUMO

Exosomes are extracellular vesicles generated by all cells and they carry nucleic acids, proteins, lipids, and metabolites. They mediate the exchange of substances between cells,thereby affecting biological properties and activities of recipient cells. In this review, we briefly discuss the composition of exocomes and exosome isolation. We also review the clinical applications of exosomes in cancer biology as well as strategies in exosome-mediated targeted drug delivery systems. Finally, the application of exosomes in the context of cancer therapeutics both in practice and literature are discussed.


Assuntos
Exossomos , Neoplasias , Exossomos/metabolismo , Humanos , Neoplasias/terapia , Sistemas de Liberação de Medicamentos/métodos , Ensaios Clínicos como Assunto
20.
Pharmacol Res Perspect ; 12(4): e1241, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38992911

RESUMO

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6ß-hydroxycortisol, deoxycholic acid, and 1ß-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.


Assuntos
Biomarcadores , Citocromo P-450 CYP3A , Monitoramento de Medicamentos , Compostos de Fenilureia , Quinolinas , Humanos , Compostos de Fenilureia/urina , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/sangue , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Feminino , Quinolinas/urina , Quinolinas/uso terapêutico , Quinolinas/sangue , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Idoso , Pessoa de Meia-Idade , Masculino , Biomarcadores/urina , Biomarcadores/sangue , Monitoramento de Medicamentos/métodos , Adulto , Idoso de 80 Anos ou mais , Antineoplásicos/urina , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Inibidores de Proteínas Quinases/urina , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/sangue , Neoplasias/urina , Espectrometria de Massas em Tandem/métodos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/urina , Neoplasias do Endométrio/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/urina , Cromatografia Líquida/métodos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/urina , Neoplasias da Glândula Tireoide/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/urina , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/urina , Carcinoma de Células Renais/sangue
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