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1.
Ann Med ; 53(1): 770-776, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34080499

RESUMO

Objectives: Hypertension is thought to be a contributor to mortality in coronavirus disease 2019 patients; however, limited clinical data on the outcomes of COVID-19 in patients with hypertension are available.Methods: This study was designed to confirm whether hypertension affects the outcomes of COVID-19. Results: A total of 983 patients with COVID-19 (female, 48%; male, 52%) were enrolled. Significantly higher odds of 60-day mortality (p = .017) were observed in the hypertensive group. In the hypertensive group, even after adjustment in multivariate analysis, the subgroup of patients 70 years old and older had higher 28-day mortality and total 60-day mortality rates than the other age subgroups (bothp < .05). A total of 297 (89%) COVID-19 patients with hypertension survived, and 35 (11%) died. In addition, compared with hypertensive patients who survived COVID-19, non-survivors had more pre-existing conditions, including cardiovascular diseases and stroke, higher blood pressure on admission, more severe inflammation, and more liver and kidney damage.Conclusion: Hypertension does not affect the outcome of COVID-19, which is different than the conclusions drawn in other studies. However, the 28-day mortality and total 60-day mortality rates of hypertensive patients (age ≥ 70) with COVID-19 were significantly elevated, and compared with the group of survivors, non-surviving COVID-19 patients with hypertension were older, had more basic diseases and had a more severe clinical condition.


Assuntos
COVID-19/complicações , COVID-19/mortalidade , Hipertensão/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de Sobrevida
2.
Nat Commun ; 12(1): 3424, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103524

RESUMO

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.


Assuntos
Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Antígenos CD40/metabolismo , Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia , Interleucina-6/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Deleção de Genes , Glioblastoma/tratamento farmacológico , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Testes de Neutralização , Fator de Transcrição STAT3/metabolismo , Análise de Sobrevida
3.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065991

RESUMO

Although there are many patients with brain tumors worldwide, there are numerous difficulties in overcoming brain tumors. Among brain tumors, glioblastoma, with a 5-year survival rate of 5.1%, is the most malignant. In addition to surgical operations, chemotherapy and radiotherapy are generally performed, but the patients have very limited options. Temozolomide is the most commonly prescribed drug for patients with glioblastoma. However, it is difficult to completely remove the tumor with this drug alone. Therefore, it is necessary to discuss the potential of anticancer drugs, other than temozolomide, against glioblastomas. Since the discovery of cisplatin, platinum-based drugs have become one of the leading chemotherapeutic drugs. Although many studies have reported the efficacy of platinum-based anticancer drugs against various carcinomas, studies on their effectiveness against brain tumors are insufficient. In this review, we elucidated the anticancer effects and advantages of platinum-based drugs used in brain tumors. In addition, the cases and limitations of the clinical application of platinum-based drugs are summarized. As a solution to overcome these obstacles, we emphasized the potential of a novel approach to increase the effectiveness of platinum-based drugs.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Compostos de Platina/uso terapêutico , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Compostos de Platina/farmacologia , Análise de Sobrevida , Resultado do Tratamento
4.
An Acad Bras Cienc ; 93(3): e20190961, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34105700

RESUMO

We study a five-parameter model called the Weibull Burr XII (WBXII) distribution, which extends several models, including new ones. This model is quite flexible in terms of the hazard function, which exhibits increasing, decreasing, upside-down bathtub, and bathtub shapes. Its density function allows different forms such as left-skewed, right-skewed, reversed-J, and bimodal. We aim to provide some general mathematical quantities for the proposed distribution, which can be useful to real data analysis. We develop a shiny application to provide interactive illustrations of the WBXII density and hazard functions. We estimate the model parameters using maximum likelihood and derive a profile log-likelihood for all members of the Weibull-G family. The survival analysis application reveals that the WBXII model is suitable to accommodate left-skewed tails, which are very common when the variable of interest is the time to failure of a product. The income application is related to player salaries within a professional sports league and it is peculiar because the mean of the player's salaries is much higher than for most professions. Both applications illustrate that the new distribution provides much better fits than other models with the same and less number of parameters.


Assuntos
Distribuições Estatísticas , Funções Verossimilhança , Análise de Sobrevida
5.
Nat Commun ; 12(1): 2705, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976187

RESUMO

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Próstata/genética , Processamento de Proteína Pós-Traducional , Receptores Androgênicos/genética , ADP-Ribosilação/efeitos dos fármacos , Adenocarcinoma , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Masculino , Metribolona/farmacologia , Proteínas de Neoplasias/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise de Sobrevida
6.
Nat Commun ; 12(1): 2699, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976188

RESUMO

Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2- and IRS1-targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB, disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance.


Assuntos
Neoplasias da Mama/genética , Proteína Forkhead Box O3/genética , Proteínas Substratos do Receptor de Insulina/genética , Fator de Crescimento Insulin-Like II/genética , MicroRNAs/genética , Receptor ErbB-2/genética , Receptor IGF Tipo 1/genética , Animais , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Calcineurina/genética , Calcineurina/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação Fisiológica , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Fosforilação , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Análise de Sobrevida , Trastuzumab/farmacologia , Carga Tumoral/efeitos dos fármacos
7.
Nat Commun ; 12(1): 2700, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976213

RESUMO

Resistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients.


Assuntos
Genoma Humano , Aprendizado de Máquina , Proteínas de Neoplasias/genética , Neoplasias/radioterapia , Tolerância a Radiação/genética , Atlas como Assunto , Linhagem Celular Tumoral , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/mortalidade , Radiação Ionizante , Análise de Sobrevida , Transcriptoma , Resultado do Tratamento
8.
Nat Commun ; 12(1): 3045, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031378

RESUMO

Conservation breeding programs such as zoos play a major role in preventing extinction, but their sustainability may be impeded by neutral and adaptive population genetic change. These changes are difficult to detect for a single species or context, and impact global conservation efforts. We analyse pedigree data from 15 vertebrate species - over 30,000 individuals - to examine offspring survival over generations of captive breeding. Even accounting for inbreeding, we find that the impacts of increasing generations in captivity are highly variable across species, with some showing substantial increases or decreases in offspring survival over generations. We find further differences between dam and sire effects in first- versus multi-generational analysis. Crucially, our multispecies analysis reveals that responses to captivity could not be predicted from species' evolutionary (phylogenetic) relationships. Even under best-practice captive management, generational fitness changes that cannot be explained by known processes (such as inbreeding depression), are occurring.


Assuntos
Cruzamento , Genética Populacional , Feminino , Humanos , Endogamia , Masculino , Linhagem , Filogenia , Estudos Retrospectivos , Análise de Sobrevida
9.
Biomed Res Int ; 2021: 9678363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997045

RESUMO

Background: The preoperative platelet-to-lymphocyte ratio (PLR) evaluates the prognosis of gastric cancer patients. However, whether preoperative PLR may be used to evaluate the prognosis of mucinous gastric carcinoma (MGC) patients is poorly investigated. The present study evaluated the effect of preoperative PLR on overall survival in gastric cancer patients with a mucinous component. Methods: A total of 336 MGC were enrolled in this study, and the characteristics of the tumor, including pathological features and clinical data, were retrospectively analyzed. Results: A high PLR was associated with larger tumor size, advanced tumor invasion, lymph node metastasis, advanced TNM stage, tumor location, total gastrectomy, low hemoglobin level, low albumin level, high fibrinogen level, high platelet level, and high neutrophil-to-lymphocyte ratio (NLR, all P's < 0.05). Multivariate analysis identified age (HR = 1.876; 95% CI 1.361-2.585, P < 0.001), TNM stage (HR = 2.350; 95% CI 1.216-4.542, P = 0.011), globulin (HR = 1.520; 95% CI 1.067-2.165, P = 0.020), total gastrectomy (HR = 0.537; 95% CI 0.373-0.772, P = 0.001), and PLR (HR = 1.582; 95% CI 1.066-2.348, P = 0.023) as independent prognostic factors for OS. Conclusion: Preoperative PLR is related to pathological features and may independently evaluate the survival of MGC. Therefore, preoperative PLR may help physicians develop treatment plans and evaluate survival in these patients.


Assuntos
Plaquetas/citologia , Linfócitos/citologia , Neoplasias Gástricas/sangue , Neoplasias Gástricas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Análise de Sobrevida
10.
Anticancer Res ; 41(5): 2321-2331, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952457

RESUMO

BACKGROUND/AIM: The mechanisms of galectin-1 in radioresistance may not only involve intracellular but also extracellular effects because galectin-1 can be secreted into the extracellular matrix. We, therefore, aimed to investigate the role of the galectin-1 tumor microenvironment on radiosensitivity in a murine tumor model. MATERIALS AND METHODS: Wild-type or stable galectin-1-down-regulated cancer cells (melanoma (B16F10) and lung cancer (LLC1)) were injected (subcutaneous injection) into wild-type or knockout (galectin-1, B cells, and T cells) mice that were subject to 0 or 8 Gy irradiation. RESULTS: Galectin-1-down-regulated B16F10 cells showed increased radiosensitivity when injected into galectin-1 knockout mice. Interestingly, radioresistance of wild-type LCC1 tumors was noted when injected into galectin-1 and B cell knockout mice. However, radiosensitization was observed in T cell knockout mice with wild-type LCC1 cells. CONCLUSION: The role of endogenous galectin-1 in radioresistance exists in cases without extracellular galectin-1. Extracellular galectin-1 requires endogenous galectin-1 to radiosensitize tumors in mice.


Assuntos
Galectina 1/genética , Neoplasias Experimentais/radioterapia , Tolerância a Radiação/genética , Microambiente Tumoral/efeitos da radiação , Animais , Linhagem Celular Tumoral , Galectina 1/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Análise de Sobrevida , Carga Tumoral/genética , Carga Tumoral/efeitos da radiação , Microambiente Tumoral/genética
11.
Lancet ; 397(10286): 1711-1724, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33939953

RESUMO

BACKGROUND: COVID-19 has disproportionately affected minority ethnic populations in the UK. Our aim was to quantify ethnic differences in SARS-CoV-2 infection and COVID-19 outcomes during the first and second waves of the COVID-19 pandemic in England. METHODS: We conducted an observational cohort study of adults (aged ≥18 years) registered with primary care practices in England for whom electronic health records were available through the OpenSAFELY platform, and who had at least 1 year of continuous registration at the start of each study period (Feb 1 to Aug 3, 2020 [wave 1], and Sept 1 to Dec 31, 2020 [wave 2]). Individual-level primary care data were linked to data from other sources on the outcomes of interest: SARS-CoV-2 testing and positive test results and COVID-19-related hospital admissions, intensive care unit (ICU) admissions, and death. The exposure was self-reported ethnicity as captured on the primary care record, grouped into five high-level census categories (White, South Asian, Black, other, and mixed) and 16 subcategories across these five categories, as well as an unknown ethnicity category. We used multivariable Cox regression to examine ethnic differences in the outcomes of interest. Models were adjusted for age, sex, deprivation, clinical factors and comorbidities, and household size, with stratification by geographical region. FINDINGS: Of 17 288 532 adults included in the study (excluding care home residents), 10 877 978 (62·9%) were White, 1 025 319 (5·9%) were South Asian, 340 912 (2·0%) were Black, 170 484 (1·0%) were of mixed ethnicity, 320 788 (1·9%) were of other ethnicity, and 4 553 051 (26·3%) were of unknown ethnicity. In wave 1, the likelihood of being tested for SARS-CoV-2 infection was slightly higher in the South Asian group (adjusted hazard ratio 1·08 [95% CI 1·07-1·09]), Black group (1·08 [1·06-1·09]), and mixed ethnicity group (1·04 [1·02-1·05]) and was decreased in the other ethnicity group (0·77 [0·76-0·78]) relative to the White group. The risk of testing positive for SARS-CoV-2 infection was higher in the South Asian group (1·99 [1·94-2·04]), Black group (1·69 [1·62-1·77]), mixed ethnicity group (1·49 [1·39-1·59]), and other ethnicity group (1·20 [1·14-1·28]). Compared with the White group, the four remaining high-level ethnic groups had an increased risk of COVID-19-related hospitalisation (South Asian group 1·48 [1·41-1·55], Black group 1·78 [1·67-1·90], mixed ethnicity group 1·63 [1·45-1·83], other ethnicity group 1·54 [1·41-1·69]), COVID-19-related ICU admission (2·18 [1·92-2·48], 3·12 [2·65-3·67], 2·96 [2·26-3·87], 3·18 [2·58-3·93]), and death (1·26 [1·15-1·37], 1·51 [1·31-1·71], 1·41 [1·11-1·81], 1·22 [1·00-1·48]). In wave 2, the risks of hospitalisation, ICU admission, and death relative to the White group were increased in the South Asian group but attenuated for the Black group compared with these risks in wave 1. Disaggregation into 16 ethnicity groups showed important heterogeneity within the five broader categories. INTERPRETATION: Some minority ethnic populations in England have excess risks of testing positive for SARS-CoV-2 and of adverse COVID-19 outcomes compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Causes are likely to be multifactorial, and delineating the exact mechanisms is crucial. Tackling ethnic inequalities will require action across many fronts, including reducing structural inequalities, addressing barriers to equitable care, and improving uptake of testing and vaccination. FUNDING: Medical Research Council.


Assuntos
COVID-19/etnologia , Grupos Étnicos/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Admissão do Paciente/estatística & dados numéricos , Adulto , COVID-19/epidemiologia , COVID-19/mortalidade , Estudos de Coortes , Inglaterra , Humanos , Estudos Observacionais como Assunto , Análise de Sobrevida
12.
Crit Rev Oncol Hematol ; 162: 103352, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33991662

RESUMO

In numerous types of cancer, the primary tumor site can show a correlation with disease behavior and survival outcomes. In salivary gland tumors (SGTs) this association remains controversial. This study assessed the association between primary sites of SGTs and prognosis. Studies from five databases were assessed and a meta-analysis was performed using studies that presented 95 % confidence interval (95 % CI), hazard ratio (HR) and survival analysis. Gathered information from 46,361 patients showed that site had a prognostic impact on SGTs. Tumors involving minor salivary glands showed worse overall survival (HR = 1.60; 95 % CI = 1.17-2.19; p = 0.003), disease-specific survival (HR=1.63; 95 % CI = 1.12-2.37; p = 0.01), and cause-specific survival (HR=2.10; 95 % CI = 1.72-2.55; p = 0.00001). Tumors from major salivary glands showed better recurrence-free survival (HR=2.31; 95 % CI = 1.77-3.02; p = 0.00001), and locoregional control of disease (HR=2.66; 95 % CI = 1.20-5.91; p = 0.02). Our results showed that the primary site of SGTs has an impact on patient prognosis.


Assuntos
Neoplasias das Glândulas Salivares , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/epidemiologia , Neoplasias das Glândulas Salivares/terapia , Análise de Sobrevida
13.
Comput Methods Programs Biomed ; 206: 106115, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33992900

RESUMO

BACKGROUND AND OBJECTIVE: With the recent surge in availability of large biomedical databases mostly derived from electronic health records, the need for the development of scalable marginal survival models with faster implementation cannot be more timely. The presence of clustering renders computational complexity, especially when the number of clusters is high. Marginalizing conditional survival models can violate the proportional hazards assumption for some frailty distributions, disrupting the connection to a conditional model. While theoretical connections between proportional hazard and accelerated failure time models exist, a computational framework to produce both for either marginal or conditional perspectives is lacking. Our objective is to provide fast, scalable bridged-survival models contained in a unified framework from which the effects and standard errors for the conditional hazard ratio, the marginal hazard ratio, the conditional acceleration factor, and the marginal acceleration factor can be estimated, and related to one another in a transparent fashion. Methods We formulate a Weibull parametric frailty likelihood for clustered survival times that can directly estimate the four estimands. Under a nonlinear mixed model specification with positive stable frailties powered by Gaussian quadrature, we put forth a novel closed form of the integrated likelihood that lowered the computational threshold for fitting these models. The method is illustrated on a real dataset generated from electronic health records examining tooth-loss. RESULTS: Our novel closed form of the integrated likelihood significantly lowered the computational threshold for fitting these models by a factor of 12 (36 compared to 3 min) for the R package parfm, and a factor of 2400 for Gaussian Quadrature (4.6 days compared to 3 min) in SAS. Moreover, each of these estimands are connected by simple relationships of the parameters and the proportional hazards assumption is preserved for the marginal model. Our framework provides a flow of analysis enabling the fit of any/all of the 4 perspective-parameterization combinations. Conclusions We see the potential usefulness of our framework of bridged parametric survival models fitted with the Static-Stirling closed form likelihood. Bridged-survival models provide insights on subject-specific and population-level survival effects when their relation is transparent. SAS and R codes, along with implementation details on a pseudo data are provided.


Assuntos
Modelos Estatísticos , Análise por Conglomerados , Funções Verossimilhança , Distribuição Normal , Probabilidade , Modelos de Riscos Proporcionais , Análise de Sobrevida
14.
Medicine (Baltimore) ; 100(21): e26192, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032780

RESUMO

ABSTRACT: To assess effectiveness and safety associated with radioactive stenting for hilar cholangiocarcinoma (HCCA) patients.This single-center retrospective study compared baseline and treatment data of recruited consecutive patients with HCCA underwent either normal or radioactive stenting between January 2016 and December 2019. Clinical success was defined by total bilirubin (TBIL) levels falling below 70% of the preoperative baseline within 2 weeks post stent insertion.Sixty-five patients with inoperable HCCA underwent normal (n = 35) or radioactive (n = 30) stenting at our center. Technical success of both types of the normal and radioactive stent insertion was 100%. Each patient received 1 stent. In the radioactive stent group, each patient received 1 radioactive seed strand (RSS), containing 10 to 12 radioactive seeds. Clinical success rates were 86.8% and 100% in normal and radioactive groups, respectively (P = .495). We observed stent dysfunction in 9 patients (normal group) and 7 patients (radioactive group) (P = .824). Median duration of stent patency was 165 days (normal group) and 226 days (radioactive group) (P < .001). During follow-up, all patients died from tumor progression, with respective median survival of 198 days (normal group) and 256 days (radioactive group) (P < .001). Seven and 5 patients in the normal and radioactive groups suffered from stent-related complications (P = .730).Radioactive stenting is effective and safe for inoperable HCCA patient and may prolong stent patency and survival.


Assuntos
Neoplasias dos Ductos Biliares/complicações , Colangiocarcinoma/complicações , Colestase/prevenção & controle , Radioisótopos do Iodo/administração & dosagem , Cuidados Paliativos/métodos , Stents , Idoso , Neoplasias dos Ductos Biliares/radioterapia , Colangiocarcinoma/radioterapia , Desenho de Equipamento , Feminino , Humanos , Radioisótopos do Iodo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Stents/efeitos adversos , Análise de Sobrevida
15.
Nat Commun ; 12(1): 2474, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931648

RESUMO

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Fusão Gênica , Humanos , Mutação INDEL , Integrinas/genética , Integrinas/metabolismo , Leucemia Mieloide Aguda/genética , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , RNA-Seq , Fatores de Risco , Transdução de Sinais/genética , Análise de Sobrevida , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
16.
Tumour Biol ; 43(1): 57-70, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935125

RESUMO

OBJECTIVES: The tumor stage represents the single most important prognostic factor for colorectal cancer (CRC), although more accurate prognostics remain much needed. Previously, we identified CA125 as an independent significant prognostic factor, which we have further validated along with CEA, CA19-9, and CA242 in a large cohort of CRC patients. METHODS: Using enzyme-linked immunosorbent assays, we analyzed preoperative serum samples in 322 CRC patients operated on between 1998 and 2003. RESULTS: Using the Spearman's rho model, we calculated the correlation between our previous findings on MUC16 and CA125, for which the correlation coefficient was 0.808 (p < 0.001). The Cox regression analysis of the linear and logarithmic values of CEA, CA125, CA242, and CA19-9 identified only CA125 (hazard ratio [HR] 1.03; 95% confidence interval [95% CI] 1.02-1.04; p < 0.001) as significant when using the linear values. Survival among CRC patients with a high CA125 level was poor compared with CRC patients with a low CA125 level (HR 2.48; 95% CI 1.68-3.65; p < 0.001). In subgroup analyses, patients with high CA125 levels and aged ≤67 or >67, with stage I-II or III-IV, and both colon and rectal cancer exhibited poor prognoses. In the multivariate analysis, we used clinical pathological variables in the model, where age, gender, and stage served as the background characteristics. We dichotomized CA125 using the Youden maximal cutoff point, and the median values for CEA, CA19-9, and CA242. CA125 emerged as the only marker remaining significant and independent together with stage, location, and age (HR 1.91; 95% CI 1.24-2.95; p 0.003). CONCLUSIONS: CA125 represents a significant and independent prognostic factor in CRC patients, superior to CEA. Furthermore, CA242 served as a better prognostic marker than both CEA and CA19-9. We recommend including both CA125 and CA242 in prognostic clinical trials among CRC patients.


Assuntos
Antígenos Glicosídicos Associados a Tumores/sangue , Antígeno Ca-125/sangue , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Proteínas de Membrana/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Estudos de Coortes , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida
17.
BMJ Health Care Inform ; 28(1)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33980502

RESUMO

OBJECTIVES: Prior research has reported an increased risk of fatality for patients with cancer, but most studies investigated the risk by comparing cancer to non-cancer patients among COVID-19 infections, where cancer might have contributed to the increased risk. This study is to understand COVID-19's imposed HR of fatality while controlling for covariates, such as age, sex, metastasis status and cancer type. METHODS: We conducted survival analyses of 4606 cancer patients with COVID-19 test results from 16 March to 11 October 2020 in UK Biobank and estimated the overall HR of fatality with and without COVID-19 infection. We also examined the HRs of 13 specific cancer types with at least 100 patients using a stratified analysis. RESULTS: COVID-19 resulted in an overall HR of 7.76 (95% CI 5.78 to 10.40, p<10-10) by following 4606 patients with cancer for 21 days after the tests. The HR varied among cancer type, with over a 10-fold increase in fatality rate (false discovery rate ≤0.02) for melanoma, haematological malignancies, uterine cancer and kidney cancer. Although COVID-19 imposed a higher risk for localised versus distant metastasis cancers, those of distant metastases yielded higher overall fatality rates due to their multiplicative effects. DISCUSSION: The results confirmed prior reports for the increased risk of fatality for patients with COVID-19 plus hematological malignancies and demonstrated similar findings of COVID-19 on melanoma, uterine, and kidney cancers. CONCLUSION: The results highlight the heightened risk that COVID-19 imposes on localised and haematological cancer patients and the necessity to vaccinate uninfected patients with cancer promptly, particularly for the cancer types most influenced by COVID-19. Results also suggest the importance of timely care for patients with localised cancer, whether they are infected by COVID-19 or not.


Assuntos
/mortalidade , Nível de Saúde , Neoplasias/mortalidade , Vigilância em Saúde Pública , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Neoplasias/patologia , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
18.
Anticancer Res ; 41(5): 2501-2509, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952478

RESUMO

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive tumor that is resistant to treatment. The expression and prognostic value of programmed cell death-ligand 1 (PD-L1) and its association with epithelial-mesenchymal transition (EMT) in PPC remains unclear. PATIENTS AND METHODS: The expression of PD-L1 and EMT markers, such as E-cadherin, vimentin, zinc finger E-box-binding homeobox 1 (ZEB-1), and cellular mesenchymal-epithelial transition (c-Met) was evaluated by immuno - histochemistry in 16 patients with PPC who underwent surgical resection. RESULTS: The expression of PD-L1 varied between carcinomatous and sarcomatous areas. Positive correlations between PD-L1 and vimentin expression in carcinomatous areas (r=0.668, p=0.005) and PD-L1 and ZEB-1 expression in sarcomatous areas (r=0.562, p=0.023) were found. High PD-L1 and ZEB-1 expression in sarcomatous areas predicted poor survival (p=0.045 and p=0.012, respectively). CONCLUSION: PD-L1 expression associated with ZEB1 expression in the sarcomatoid component of patients with PPC may be useful for predicting patient prognosis.


Assuntos
Antígeno B7-H1/genética , Carcinoma/genética , Neoplasias Pulmonares/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Carcinoma/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/patologia , Análise de Sobrevida
20.
Artigo em Inglês | MEDLINE | ID: mdl-33975677

RESUMO

Early detection of gastric cancer is remaining a challenge. This review summarizes current knowledge on non-invasive methods that could be used for the purpose. The role of traditional cancer markers such as CEA, CA 72-4, CA 19-9, CA 15-3, and CA 12-5 lies mainly in therapy monitoring than early detection. Most extensive studied biomarkers (pepsinogens, ABC method) are aiming at the detection of precancerous lesions with modest sensitivity for cancer. Tests based on the detection of cancer-specific methylation patterns (PanSeer), circulating proteins and mutations in circulating tumour DNA (CancerSEEK), as well as miRNA panels have demonstrated promising results bringing those closer to practice. More extensive research is required before tests based on the detection of circulating tumour cells, extracellular vesicles and cell-free RNA could reach the practice. Detection of volatile organic compounds in the human breath is a promising development; sensor technologies for this purpose could be very attractive in screening settings.


Assuntos
Detecção Precoce de Câncer/métodos , Endoscopia/métodos , Neoplasias Gástricas/diagnóstico por imagem , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Análise de Sobrevida
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