Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.649
Filtrar
1.
Front Immunol ; 12: 716361, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34491250

RESUMO

Background: COVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients. Objective: This study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation. Methods: Markers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 µg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response. Results: Increases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU. Conclusion: Complement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.


Assuntos
COVID-19/imunologia , Ativação do Complemento/imunologia , Inflamação/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Trombose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/sangue , COVID-19/virologia , Inativadores do Complemento/sangue , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Ativação Plaquetária/imunologia , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Trombose/sangue , Adulto Jovem
2.
Mayo Clin Proc ; 96(8): 2157-2167, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34353470

RESUMO

OBJECTIVE: To determine the relationship between 25-hydroxyvitamin D (25[OH]D) values and subsequent cancer incidence and mortality. PATIENTS AND METHODS: We identified all adult patients living in Olmsted County, Minnesota, between January 1, 2005, and December 31, 2011, who had at least 1 25(OH)D measurement and no prior diagnosis of cancer. Cancer outcomes were retrieved starting 30 days after 25(OH)D measurement and until patients' final clinical visit as an Olmsted County resident; December 31, 2014; or death. Cox proportional hazards regression was used to analyze data. RESULTS: A total of 8700 individuals had a 25(OH)D measurement and no history of cancer, with a mean ± SD 25(OH)D value of 29.7±12.8 ng/mL (to convert to nmol/L, multiply by 2.496). The mean ± SD age was 51.5±16.4 years, and most were women (78.1%; n=6796) and White (85.7%; n=7460). A total of 761 individuals developed cancer (skin cancer, n=360; nonskin cancer, n=401) during a median follow-up of 4.6 (interquartile range, 3.4-6.1) years. Compared with participants with 25(OH)D values of 20 to 50 ng/mL (reference group), those with 25(OH)D values less than 12 ng/mL had a greater nonskin cancer incidence (hazard ratio [HR], 1.56; 95% CI, 1.03 to 2.36; P=.04) after adjustment. There was no association between 25(OH)D values and total cancer or skin cancer incidence. Compared with individuals from the reference group, 25(OH)D levels less than 12 ng/mL (HR, 2.35; 95% CI, 1.01 to 5.48; P=.047) and 12 to 19 ng/mL (HR, 2.10; 95% CI, 1.05 to 4.22; P=.04) were associated with increased cancer mortality. CONCLUSION: Low 25(OH)D levels were associated with increased risk for incident nonskin cancer and cancer-related mortality.


Assuntos
Neoplasias/epidemiologia , Vigilância da População , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Causas de Morte/tendências , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Adulto Jovem
3.
Nat Commun ; 12(1): 4172, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234141

RESUMO

Cell-free DNA (cfDNA) is attractive for many applications, including detecting cancer, identifying the tissue of origin, and monitoring. A fundamental task underlying these applications is SNV calling from cfDNA, which is hindered by the very low tumor content. Thus sensitive and accurate detection of low-frequency mutations (<5%) remains challenging for existing SNV callers. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this challenge. Furthermore, by leveraging cfDNA's comprehensive coverage of tumor clonal landscape, cfSNV can profile mutations in subclones. In both simulated and real patient data, cfSNV outperforms existing tools in sensitivity while maintaining high precision. cfSNV enhances the clinical utilities of cfDNA by improving mutation detection performance in medium-depth sequencing data, therefore making Whole-Exome Sequencing a viable option. As an example, we demonstrate that the tumor mutation profile from cfDNA WES data can provide an effective biomarker to predict immunotherapy outcomes.


Assuntos
DNA Tumoral Circulante/genética , Análise Mutacional de DNA/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biópsia , DNA Tumoral Circulante/sangue , Simulação por Computador , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Sensibilidade e Especificidade
4.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298989

RESUMO

Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.


Assuntos
Heteroplasmia/genética , Mitocôndrias/genética , Neoplasias/sangue , Neoplasias/genética , Alelos , Biomarcadores/sangue , Enzimas de Restrição do DNA/uso terapêutico , Progressão da Doença , Epigênese Genética , Terapia Genética/métodos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/genética
5.
J Hematol Oncol ; 14(1): 86, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059088

RESUMO

Vaccination for SARS-CoV-2 provides significant protection against the infection in the general population. However, only limited data exist for patients with cancer under systemic therapy. Based on this, our site has initiated a study evaluating safety and efficacy of SARS-CoV-2 vaccination in patients with solid and hematological malignancies under several systemic therapies. The initial results of the cohort of 59 patients receiving Immune Checkpoint Inhibitors are presented here. Despite no new safety issues have been noticed, the levels of SARS-CoV-2 neutralizing antibodies are significantly lower in comparison to matched healthy volunteers up to day 22 post the first dose. These results should be taken into consideration for the patients under treatment.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , SARS-CoV-2/imunologia , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Vacinação
6.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064383

RESUMO

Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Receptores Purinérgicos P2Y/metabolismo , Estresse Fisiológico/imunologia , Animais , COVID-19/sangue , COVID-19/tratamento farmacológico , COVID-19/imunologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Vigilância Imunológica/imunologia , Inflamação/sangue , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Camundongos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Agonistas do Receptor Purinérgico P2Y/farmacologia , Agonistas do Receptor Purinérgico P2Y/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073560

RESUMO

There exist many different human cancers, but regardless of the cancer type, an early diagnosis is a necessary condition for further optimal outcomes from the disease. Therefore, efficient specific and sensitive cancer biomarkers are urgently needed. This is especially true for the cancers depicting a silent progression, and those only diagnosed in an already metastatic state with a poor survival prognostic. After a rapid overview of the previous methods for cancer diagnosis, the outstanding characteristics of extracellular vesicles (EVs) will be presented, as new interesting candidates for early cancer diagnosis in human biofluid non-invasive liquid biopsy. The present review aims to give the state-of-the-art of the numerous searches of efficient EV-mediated cancer diagnosis. The corresponding literature quest was performed by means of an original approach, using a powerful Expernova Questel big data platform, which was specifically adapted for a literature search on EVs. The chosen collected scientific papers are presented in two parts, the first one drawing up a picture of the current general status of EV-mediated cancer diagnosis and the second one showing recent applications of such EV-mediated diagnosis for six important human-specific cancers, i.e., lung, breast, prostate, colorectal, ovary and pancreatic cancers. However, the promising perspective of finally succeeding in the worldwide quest for the much-needed early cancer diagnosis has to be moderated by the many remaining challenges left to solve before achieving the efficient clinical translation of the constantly increasing scientific knowledge.


Assuntos
Biomarcadores Tumorais/sangue , Micropartículas Derivadas de Células , Detecção Precoce de Câncer , Vesículas Extracelulares , Neoplasias , Micropartículas Derivadas de Células/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Humanos , Biópsia Líquida , Neoplasias/sangue , Neoplasias/diagnóstico , Neoplasias/patologia
8.
Cancer Sci ; 112(9): 3911-3917, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34128569

RESUMO

Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue-based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer-related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.


Assuntos
DNA Tumoral Circulante/genética , Perfilação da Expressão Gênica/normas , Guias como Assunto , Neoplasias/sangue , Neoplasias/genética , Biomarcadores Tumorais/genética , Coleta de Amostras Sanguíneas/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Japão , Biópsia Líquida , Mutação , Transcriptoma
9.
Front Immunol ; 12: 641879, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093531

RESUMO

Objectives: Febrile neutropenia (FN) causes treatment disruption and unplanned hospitalization in children with cancer. Serum biomarkers are infrequently used to stratify these patients into high or low risk for serious infection. This study investigated plasma abundance of cytokines in children with FN and their ability to predict bacteraemia. Methods: Thirty-three plasma cytokines, C-reactive protein (CRP) and procalcitonin (PCT) were measured using ELISA assays in samples taken at FN presentation (n = 79) and within 8-24 h (Day 2; n = 31). Optimal thresholds for prediction of bacteraemia were identified and the predictive ability of biomarkers in addition to routinely available clinical variables was assessed. Results: The median age of included FN episodes was 6.0 years and eight (10%) had a bacteraemia. On presentation, elevated PCT, IL-10 and Mip1-beta were significantly associated with bacteraemia, while CRP, IL-6 and IL-8 were not. The combination of PCT (≥0.425 ng/ml) and IL-10 (≥4.37 pg/ml) had a sensitivity of 100% (95% CI 68.8-100%) and specificity of 89% (95% CI 80.0-95.0%) for prediction of bacteraemia, correctly identifying all eight bacteraemia episodes and classifying 16 FN episodes as high-risk. There was limited additive benefit of incorporating clinical variables to this model. On Day 2, there was an 11-fold increase in PCT in episodes with a bacteraemia which was significantly higher than that observed in the non-bacteraemia episodes. Conclusion: Elevated PCT and IL-10 accurately identified all bacteraemia episodes in our FN cohort and may enhance the early risk stratification process in this population. Prospective validation and implementation is required to determine the impact on health service utilisation.


Assuntos
Bacteriemia/sangue , Neutropenia Febril/sangue , Interleucina-10/sangue , Neoplasias/sangue , Pró-Calcitonina/sangue , Bacteriemia/imunologia , Bacteriemia/microbiologia , Criança , Pré-Escolar , Neutropenia Febril/imunologia , Neutropenia Febril/microbiologia , Feminino , Humanos , Interleucina-10/imunologia , Masculino , Neoplasias/imunologia , Neoplasias/microbiologia , Valor Preditivo dos Testes , Pró-Calcitonina/imunologia
10.
Biomed Res Int ; 2021: 5585206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124248

RESUMO

Background: We aimed to examine the differences of clinical characteristics between patients with ischemic stroke with active cancer and those without cancer to develop a clinical score for predicting the presence of occult cancer in patients with ischemic stroke. Methods: This retrospective study enrolled consecutive adult patients with acute ischemic stroke who were admitted to our department between December 2017 and January 2019. The demographic, clinical, laboratory, and neuroimaging characteristics were compared between patients with ischemic stroke with active cancer and those without cancer. Multivariate analysis was performed to identify independent factors associated with active cancer. Subsequently, a predictive score was developed using the areas under the receiver operating characteristic curves based on these independent factors. Finally, Bayesian decision theory was applied to calculate the posterior probability of active cancer for finding the best scoring system. Results: Fifty-three (6.63%) of 799 patients with ischemic stroke had active cancer. The absence of a history of hyperlipidemia (odds ratio (OR) = 0.17, 95% confidence interval (CI): 0.06-0.48, P < 0.01), elevated serum fibrinogen (OR = 1.72, 95% CI: 1.33-2.22, P < 0.01) and D-dimer levels (OR = 1.43, 95% CI: 1.24-1.64, P <0.01), and stroke of undetermined etiology (OR = 22.87, 95% CI: 9.91-52.78, P < 0.01) were independently associated with active cancer. A clinical score based on the absence of hyperlipidemia, serum fibrinogen level of ≥4.00 g/L, and D-dimer level of ≥2.00 µg/mL predicted active cancer with an area under the curve of 0.83 (95% CI: 0.77-0.89, P < 0.01). The probability of active cancer was 59% at a supposed prevalence of 6.63%, if all three independent factors were present in a patient with ischemic stroke. Conclusions: We devised a clinical score to predict active cancer in patients with ischemic stroke based on the absence of a history of hyperlipidemia and elevated serum D-dimer and fibrinogen levels. The use of this score may allow for early intervention. Further research is needed to confirm the implementation of this score in clinical settings.


Assuntos
Biomarcadores Tumorais/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , AVC Isquêmico , Neoplasias , Idoso , Feminino , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , AVC Isquêmico/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/complicações , Neoplasias/diagnóstico , Estudos Retrospectivos
11.
Nutrients ; 13(5)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067632

RESUMO

Coenzyme Q10 (CoQ10) is an essential cofactor in oxidative phosphorylation (OXPHOS), present in mitochondria and cell membranes in reduced and oxidized forms. Acting as an energy transfer molecule, it occurs in particularly high levels in the liver, heart, and kidneys. CoQ10 is also an anti-inflammatory and antioxidant agent able to prevent the damage induced by free radicals and the activation of inflammatory signaling pathways. In this context, several studies have shown the possible inverse correlation between the blood levels of CoQ10 and some disease conditions. Interestingly, beyond cardiovascular diseases, CoQ10 is involved also in neuronal and muscular degenerative diseases, in migraine and in cancer; therefore, the supplementation with CoQ10 could represent a viable option to prevent these and in some cases might be used as an adjuvant to conventional treatments. This review is aimed to summarize the clinical applications regarding the use of CoQ10 in migraine, neurodegenerative diseases (including Parkinson and Alzheimer diseases), cancer, or degenerative muscle disorders (such as multiple sclerosis and chronic fatigue syndrome), analyzing its effect on patients' health and quality of life.


Assuntos
Suplementos Nutricionais , Ubiquinona/análogos & derivados , Disponibilidade Biológica , Humanos , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/terapia , Neoplasias/sangue , Neoplasias/terapia , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/terapia , Doenças Neuromusculares/sangue , Doenças Neuromusculares/terapia , Qualidade de Vida , Ubiquinona/uso terapêutico
12.
Nat Commun ; 12(1): 3770, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145282

RESUMO

Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Marcadores Genéticos/genética , Neoplasias/genética , Análise Mutacional de DNA/métodos , Frequência do Gene/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/genética , Neoplasias/sangue , Neoplasias/patologia
13.
Anticancer Res ; 41(5): 2591-2596, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952488

RESUMO

BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.


Assuntos
Administração Intravenosa/métodos , Administração Oral , Neoplasias/tratamento farmacológico , Tacrolimo/administração & dosagem , Adolescente , Adulto , Idoso , Fenômenos Fisiológicos Sanguíneos/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Pediatria , Tacrolimo/efeitos adversos , Adulto Jovem
14.
Nat Commun ; 12(1): 2965, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34017005

RESUMO

Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity. However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that "deviate" from the reference. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species.


Assuntos
Neoplasias/imunologia , RNA-Seq/métodos , Análise de Célula Única/métodos , Linfócitos T/imunologia , Viroses/imunologia , Animais , Diferenciação Celular/imunologia , Estudos de Coortes , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias/sangue , Neoplasias/patologia , Valores de Referência , Software , Especificidade da Espécie , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Viroses/sangue
15.
Nat Commun ; 12(1): 3199, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045463

RESUMO

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.


Assuntos
Autopsia/métodos , DNA Tumoral Circulante/genética , Análise Mutacional de DNA/métodos , Neoplasias/diagnóstico , Microambiente Tumoral/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Quimiorradioterapia Adjuvante , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Heterogeneidade Genética , Humanos , Masculino , Terapia Neoadjuvante , Neoplasias/sangue , Neoplasias/patologia , Neoplasias/terapia , Mutação Puntual , RNA-Seq , Valores de Referência , Sensibilidade e Especificidade , Análise Espacial , Fatores de Tempo , Sequenciamento Completo do Exoma
16.
Clin Nutr ; 40(5): 2923-2935, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33964502

RESUMO

BACKGROUND: Research reporting plasma micronutrient status and its impact on clinical outcomes in paediatric cancer is scarce. Therefore, we investigated the prevalence of plasma micronutrient abnormalities and their impact on clinical outcomes and treatment complications. METHODS: A multicentre prospective-cohort study of children aged <18 years diagnosed with cancer was performed between Aug 2010-Jan 2014. Clinical and nutritional data were collected at diagnosis, 3, 6, 9, 12 and 18 months. Micronutrient status was established using in-house laboratory references (vitamin B12, vitamin A and Vitamin E/Ch) and aged adjusted Z-scores (Mg, Se, Zn and Cu) generated from a cohort of healthy Scottish children. Clinical outcomes were classified as "event free survival (EFS)" or "event" (relapse, death, new metastasis or becoming palliative) and treatment complications. Descriptive statistics, logistic regression and multilevel analysis were performed. RESULTS: Eighty-two patients [median (IQR) 3.9 (1.9-8.8) years, 56% males] were recruited. Of these, 72 (88%) samples were available, 74% (53/72) patients had micronutrient abnormalities at baseline; deficiencies (25%, 18/72), excesses (19%, 14/72) and a combination of both (29%, 21/72), which continued for 18 months. Vitamin A deficiency (15%, 3/20) and excess (50%, 10/20) were most prevalent at 18 months, whilst vitamin E/Cholesterol and vitamin B12 were mostly within the normal range. Prevalence of Zn deficiency at diagnosis was 36% (16/44 adjusted for CRP), which remained at these levels throughout the study. Reduction in each selenium concentration unit increased the odds of an event by 2% (OR 0.02) and lower Se predicted higher complications at diagnosis [ß (-1.2); t (-2.1); 95% CI (-2.9 - (-0.04)); p = 0.04], 3 months [ß (-3.9); t (-4.2); 95% CI (-5.57 - (-2.02)); p < 0.001] and 12 months [ß (-2.3); t (-2.4); 95% CI (-4.10 - (-0.34)); p = 0.02]. CONCLUSIONS: Given the prevalence of micronutrient abnormalities and the negative impact of low selenium on clinical outcome, micronutrient status should be assessed and monitored in paediatric cancer patients. Larger multicentre population based studies and clinical trials are now warranted.


Assuntos
Desnutrição/sangue , Desnutrição/complicações , Micronutrientes/sangue , Neoplasias/sangue , Neoplasias/complicações , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Neoplasias/terapia , Estudos Prospectivos , Escócia , Resultado do Tratamento
17.
JAMA Oncol ; 7(8): 1141-1148, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34047762

RESUMO

Importance: Patients with cancer and health care workers (HCWs) are at high risk of SARS-CoV-2 infection. Assessing the antibody status of patients with cancer and HCWs can help understand the spread of COVID-19 in cancer care. Objective: To evaluate serum SARS-CoV-2 antibody status in patients with cancer and HCWs during the COVID-19 pandemic in Japan. Design, Setting, and Participants: Participants were enrolled for this prospective cross-sectional study between August 3 and October 30, 2020, from 2 comprehensive cancer centers in the epidemic area around Tokyo, Japan. Patients with cancer aged 16 years or older and employees were enrolled. Participants with suspected COVID-19 infection at the time of enrollment were excluded. Exposures: Cancer of any type and cancer treatment, including chemotherapy, surgery, immune checkpoint inhibitors, radiotherapy, and targeted molecular therapy. Main Outcomes and Measures: Seroprevalence and antibody levels in patients with cancer and HCWs. Seropositivity was defined as positivity to nucleocapsid IgG (N-IgG) and/or spike IgG (S-IgG). Serum levels of SARS-CoV-2 IgM and IgG antibodies against the nucleocapsid and spike proteins were measured by chemiluminescent enzyme immunoassay. Results: A total of 500 patients with cancer (median age, 62.5 years [range, 21-88 years]; 265 men [55.4%]) and 1190 HCWs (median age, 40 years [range, 20-70 years]; 382 men [25.4%]) were enrolled. In patients with cancer, 489 (97.8%) had solid tumors, and 355 (71.0%) had received anticancer treatment within 1 month. Among HCWs, 385 (32.3%) were nurses or assistant nurses, 266 (22.4%) were administrative officers, 197 (16.6%) were researchers, 179 (15.0%) were physicians, 113 (9.5%) were technicians, and 50 (4.2%) were pharmacists. The seroprevalence was 1.0% (95% CI, 0.33%-2.32%) in patients and 0.67% (95% CI, 0.29%-1.32%) in HCWs (P = .48). However, the N-IgG and S-IgG antibody levels were significantly lower in patients than in HCWs (N-IgG: ß, -0.38; 95% CI, -0.55 to -0.21; P < .001; and S-IgG: ß, -0.39; 95% CI, -0.54 to -0.23; P < .001). Additionally, among patients, N-IgG levels were significantly lower in those who received chemotherapy than in those who did not (median N-IgG levels, 0.1 [interquartile range (IQR), 0-0.3] vs 0.1 [IQR, 0-0.4], P = .04). In contrast, N-IgG and S-IgG levels were significantly higher in patients who received immune checkpoint inhibitors than in those who did not (median N-IgG levels: 0.2 [IQR, 0.1-0.5] vs 0.1 [IQR, 0-0.3], P = .02; S-IgG levels: 0.15 [IQR, 0-0.3] vs 0.1[IQR, 0-0.2], P = .02). Conclusions and Relevance: In this cross-sectional study of Japanese patients with cancer and HCWs, the seroprevalence of SARS-CoV-2 antibodies did not differ between the 2 groups; however, findings suggest that comorbid cancer and treatment with systemic therapy, including chemotherapy and immune checkpoint inhibitors, may influence the immune response to SARS-CoV-2.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , COVID-19/sangue , Estudos Transversais , Feminino , Pessoal de Saúde , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Pandemias/prevenção & controle , Estudos Prospectivos , Adulto Jovem
18.
Ann Neurol ; 90(1): 159-169, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029423

RESUMO

OBJECTIVE: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer. METHODS: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests. RESULTS: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005). INTERPRETATION: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.


Assuntos
Encéfalo/diagnóstico por imagem , AVC Isquêmico/complicações , Neoplasias/complicações , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio , Humanos , Molécula 1 de Adesão Intercelular/sangue , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico por imagem , Estudos Prospectivos , Trombomodulina/sangue , Ultrassonografia Doppler Transcraniana , Molécula 1 de Adesão de Célula Vascular/sangue
19.
Eur J Epidemiol ; 36(8): 841-848, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34036468

RESUMO

Systemic inflammation markers have been linked to increased cancer risk and mortality in a number of studies. However, few studies have estimated pre-diagnostic associations of systemic inflammation markers and cancer risk. Such markers could serve as biomarkers of cancer risk and aid in earlier identification of the disease. This study estimated associations between pre-diagnostic systemic inflammation markers and cancer risk in the prospective UK Biobank cohort of approximately 440,000 participants recruited between 2006 and 2010. We assessed associations between four immune-related markers based on blood cell counts: systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and risk for 17 cancer sites by estimating hazard ratios (HR) using flexible parametric survival models. We observed positive associations with risk for seven out of 17 cancers with SII, NLR, PLR, and negative associations with LMR. The strongest associations were observed for SII for colorectal and lung cancer risk, with associations increasing in magnitude for cases diagnosed within one year of recruitment. For instance, the HR for colorectal cancer per standard deviation increment in SII was estimated at 1.09 (95% CI 1.02-1.16) in blood drawn five years prior to diagnosis and 1.50 (95% CI 1.24-1.80) in blood drawn one month prior to diagnosis. We observed associations between systemic inflammation markers and risk for several cancers. The increase in risk the last year prior to diagnosis may reflect a systemic immune response to an already present, yet clinically undetected cancer. Blood cell ratios could serve as biomarkers of cancer incidence risk with potential for early identification of disease in the last year prior to clinical diagnosis.


Assuntos
Biomarcadores/sangue , Inflamação/sangue , Inflamação/imunologia , Neoplasias/epidemiologia , Adulto , Idoso , Bancos de Espécimes Biológicos , Biomarcadores Tumorais/análise , Contagem de Células Sanguíneas , Estudos de Coortes , Feminino , Humanos , Incidência , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neutrófilos/patologia , Estudos Prospectivos , Reino Unido/epidemiologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-33991954

RESUMO

Lipid analysis is a powerful tool that can elucidate the pathogenic roles of lipids in metabolic diseases, and facilitate the development of potential biomarkers. Lipid analysis by large-scale lipidomics requires a high-speed and high-throughput analytical platform. In the present study, a high-speed analytical method for lipid analysis using nanoflow ultrahigh-performance liquid chromatography-electrospray ionisation-tandem mass spectrometry (nUHPLC-ESI-MS/MS) was optimised by investigating the effects of column flow rate, pump flow rate, dwell time, initial binary mobile phase composition, and gradient duration on the separation efficiency of standard lipid mixtures. The minimum gradient time for high-speed lipid separation was determined by examining the time-based separation efficiency and spectral overlap of isobaric lipid species during selected reaction monitoring-based quantification of sphingomyelin and a second isotope of phosphatidylcholine, which differ in molecular weight by only 1 Da. Finally, the optimised nUHPLC-ESI-MS/MS method was applied to analyse 200 plasma samples from patients with liver, gastric, lung, and colorectal cancer to evaluate its performance by measuring previously identified candidate lipid biomarkers. About 73% of the reported marker candidates (6 out of 7 in liver, 5/9 in gastric, 4/6 in lung, and 6/7 in colorectal cancer) could be assigned using the optimised method, supporting its use for high-throughput lipid analysis.


Assuntos
Lipídeos/sangue , Neoplasias/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lipidômica , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...