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1.
Anticancer Res ; 41(9): 4471-4478, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475071

RESUMO

AIM: This study aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in elderly patients with Stage I-III colon cancer for long-term oncologic outcomes. PATIENTS AND METHODS: We retrospectively reviewed 175 patients aged >75 years who underwent radical surgery for Stage I-III colon cancer between 2000 and 2015 at our institute. Overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) were evaluated according to NLR values using propensity score analysis. Patients were allocated to the higher NLR (H-NLR) or the lower NLR (L-NLR) group with a cut-off value of 2.3, based on receiver operating characteristic curve. RESULTS: Before case matching, there were significant differences between the two groups for CSS (p=0.023) and RFS (p<0.001), but not for OS (p=0.069). Similar results were obtained after case matching, with significant differences observed for CSS (p=0.003) and RFS (p=0.027), but not for OS (p=0.145). CONCLUSION: NLR may be a prognostic factor in elderly patients with colon cancer.


Assuntos
Neoplasias do Colo/sangue , Neoplasias do Colo/cirurgia , Neutrófilos/metabolismo , Pontuação de Propensão , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Procedimentos Cirúrgicos do Sistema Digestório , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
2.
Anticancer Res ; 41(9): 4629-4636, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475091

RESUMO

BACKGROUND/AIM: We aimed to develop a novel recurrence prediction model for stage II-III colon cancer using simple auto-artificial intelligence (AI) with improved accuracy compared to conventional statistical models. PATIENTS AND METHODS: A total of 787 patients who had undergone curative surgery for stage II-III colon cancer between 2000 and 2018 were included. Binomial logistic regression analysis was used to calculate the effect of variables on recurrence. The auto-AI software 'Prediction One' (Sony Network Communications Inc.) was used to predict recurrence with the same dataset used for the conventional statical model. Predictive accuracy was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: The AUC of the multivariate model was 0.719 (95%CI=0.655-0.784), whereas that of the AI model was 0.815, showing a significant improvement. CONCLUSION: This auto-AI prediction model demonstrates improved accuracy compared to the conventional model. It could be constructed by clinical surgeons who are not familiar with AI.


Assuntos
Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Inteligência Artificial , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Curva ROC , Medição de Risco , Resultado do Tratamento , Adulto Jovem
3.
Molecules ; 26(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34361570

RESUMO

A novel series of 4-anilinoquinazoline analogues, DW (1-10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Células HT29 , Humanos
4.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360883

RESUMO

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Suplementos Nutricionais , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Valeratos/farmacologia , Adenocarcinoma/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo
5.
Nat Commun ; 12(1): 5006, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408135

RESUMO

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.


Assuntos
Tecido Adiposo/citologia , Reprogramação Celular , Neoplasias do Colo/fisiopatologia , Células-Tronco Neoplásicas/citologia , Nicho de Células-Tronco , Tecido Adiposo/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
6.
World J Surg Oncol ; 19(1): 238, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380513

RESUMO

BACKGROUND: Only 50-70% of elderly colon cancer patients could complete the recommended 6 months of postoperative chemotherapy. It is unknown whether a shorter duration of postoperative capecitabine-alone chemotherapy would compromise survival. We thus conducted this study to analyze the association between postoperative chemotherapy duration of a capecitabine-alone regimen and cancer-specific survival (CSS) and disease-free survival (DFS) of surgery-treated elderly colon cancer patients. METHODS: We performed a retrospective cohort study of surgically treated stage III and high-risk stage II colon cancer patients aged ≥ 70 treated at two medical centers. Cox proportional hazard regression models were utilized to calculate crude and adjusted hazard ratios (HRs). The nonlinear relationship between postoperative chemotherapy duration and survival was analyzed through restricted cubic spline regression analysis, and the threshold effect was calculated by the two-piecewise Cox proportional hazard model. RESULTS: A total of 1217 surgery-treated colon cancer patients between August 1, 2013, and September 1, 2019, were reviewed, and 257 stage III and high-risk stage II patients aged ≥ 70 were enrolled. Postoperative chemotherapy with capecitabine was administered to 114 patients, and 143 patients only received surgery. As the duration of chemotherapy increased by 1 week, the risk of cancer-specific death was reduced by 11% (HR = 0.89, 95% confidence interval (CI) 0.82-0.96), and the risk of recurrence was reduced by 10% (HR = 0.90, 0.82-0.96). Nonlinearity exploration suggested a threshold effect of capecitabine duration on CSS in stage III disease. The HR for death was 0.79 (95% CI, 0.68-0.92) with duration ≤ 16 weeks and 1.34 (95% CI, 0.91-1.97) with duration > 16 weeks. CONCLUSIONS: The postoperative capecitabine duration was significantly associated with a decrease in death risk and recurrence risk in elderly colon cancer patients. However, the threshold effect of capecitabine duration on survival suggests that short-term chemotherapy may improve survival in elderly stage III colon cancer patients.


Assuntos
Neoplasias do Colo , Fluoruracila , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
7.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360565

RESUMO

A series of novel mono and bishydrazones each bearing a 2-oxindole moiety along with substituted phenylaminopropanamide, pyrrolidin-2-one, benzimidazole, diphenylmethane, or diphenylamine fragments were synthesized, and their anticancer activities were tested by MTT assay against human melanoma A375 and colon adenocarcinoma HT-29 cell lines. In general, the synthesized compounds were more cytotoxic against HT-29 than A375. 3-((4-Methoxyphenyl)(3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazinyl)propyl)amino)-N'-(2-oxoindolin-3-ylidene)propanehydrazide and (N',N‴)-1,1'-(methylenebis(4,1-phenylene))bis(5-oxo-N'-(2-oxoindolin-3-ylidene)pyrrolidine-3-carbohydrazide) were identified as the most active compounds against HT-29 in 2D and 3D cell cultures. The same compounds showed the highest antioxidant activity among the synthesized compounds screened by ferric reducing antioxidant power assay (FRAP). Their antioxidant activity is on par with that of a well-known antioxidant ascorbic acid.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias do Colo/tratamento farmacológico , Hidrazonas/química , Isatina/química , Melanoma/tratamento farmacológico , Antineoplásicos/síntese química , Antioxidantes/síntese química , Apoptose , Proliferação de Células , Neoplasias do Colo/patologia , Humanos , Melanoma/patologia , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
9.
FASEB J ; 35(9): e21834, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403553

RESUMO

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Dispositivos Lab-On-A-Chip , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Instabilidade de Microssatélites , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/uso terapêutico , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/secundário , Modelos Biológicos , Metástase Neoplásica/patologia , Especificidade de Órgãos , Oxaliplatina/uso terapêutico
10.
Nat Immunol ; 22(9): 1152-1162, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34385712

RESUMO

The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.


Assuntos
Neoplasias do Colo/patologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/imunologia , Animais , Proliferação de Células/fisiologia , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Fator 1-alfa Nuclear de Hepatócito/genética , Memória Imunológica/imunologia , Inflamação/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Transcrição Genética/genética , Proteínas Supressoras de Tumor/metabolismo
11.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443472

RESUMO

Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart has been previously; and in this study, its anticancer efficacy is investigated. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and the upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rose to 36.9 and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anticancer effect, and FER showed a greater proapoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estirenos/farmacologia , Antineoplásicos/química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/química , Curcumina/metabolismo , Ciclina B1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/agonistas , Fase G2/efeitos dos fármacos , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenol/química , Fenol/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Estirenos/química , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/agonistas
12.
Acta Oncol ; 60(10): 1241-1249, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34279175

RESUMO

BACKGROUND: Prediction models are useful tools in the clinical management of colon cancer patients, particularly when estimating the recurrence rate and, thus, the need for adjuvant treatment. However, the most used models (MSKCC, ACCENT) are based on several decades-old patient series from clinical trials, likely overestimating the current risk of recurrence, especially in low-risk groups, as outcomes have improved over time. The aim was to develop and validate an updated model for the prediction of recurrence within 5 years after surgery using routinely collected clinicopathologic variables. MATERIAL AND METHODS: A population-based cohort from the Swedish Colorectal Cancer Registry of 16,134 stage I-III colon cancer cases was used. A multivariable model was constructed using Cox proportional hazards regression. Three-quarters of the cases were used for model development and one quarter for internal validation. External validation was performed using 12,769 stage II-III patients from the Norwegian Colorectal Cancer Registry. The model was compared to previous nomograms. RESULTS: The nomogram consisted of eight variables: sex, sidedness, pT-substages, number of positive and found lymph nodes, emergency surgery, lymphovascular and perineural invasion. The area under the curve (AUC) was 0.78 in the model, 0.76 in internal validation, and 0.70 in external validation. The model calibrated well, especially in low-risk patients, and performed better than existing nomograms in the Swedish registry data. The new nomogram's AUC was equal to that of the MSKCC but the calibration was better. CONCLUSION: The nomogram based on recently operated patients from a population registry predicts recurrence risk more accurately than previous nomograms. It performs best in the low-risk groups where the risk-benefit ratio of adjuvant treatment is debatable and the need for an accurate prediction model is the largest.


Assuntos
Neoplasias do Colo , Recidiva Local de Neoplasia , Área Sob a Curva , Estudos de Coortes , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Humanos , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Nomogramas , Estudos Retrospectivos
13.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299098

RESUMO

BACKGROUND: This study was designed to investigate the effect of cluster differentiation (CD)39 and CD73 inhibitors on the expresion of tumour-associated macrophages (TAMs), M1- versus M2-tumour phenotypes in mice with colon cancer. METHODS: An in vivo study of co-culture with colon cancer cells and immune cells from the bone marrow (BM) of mice was performed. After the confirmation of the effect of polyoxotungstate (POM-1) as an inhibitor of CD39 on TAMs, the mice were randomly divided into a control group without POM-1 and a study group with POM-1, respectively, after subcutaneous injection of CT26 cells. On day 14 after the injection, the mice were sacrificed, and TAMs were evaluated using fluorescence-activated cell sorting. RESULTS: In the in vivo study, the co-culture with POM-1 significantly increased the apoptosis of CT26 cells. The cell population from the co-culture with POM-1 showed significant increases in the expression of CD11b+ for myeloid cells, lymphocyte antigen 6 complex, locus C (Ly6C+) for monocytes, M1-tumour phenotypes from TAMs, and F4/80+ for macrophages. In the in vivo study, tumour growth in the study group with POM-1 was significantly limited, compared with the control group without POM-1. The expressions of Ly6C+ and major histocompatibility complex class II+ for M1-tumour phenotypes from TAMs on F4/80+ from the tumour tissue in the study group had significantly higher values compared with the control group. CONCLUSION: The inhibition of CD39 with POM-1 prevented the growth of colon cancer in mice, and it was associated with the increased expression of M1-tumour phenotypes from TAMs in the cancer tissue.


Assuntos
Apirase/antagonistas & inibidores , Neoplasias do Colo/prevenção & controle , Polímeros/farmacologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Compostos de Tungstênio/farmacologia , Animais , Antígenos CD , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Prognóstico , Células Tumorais Cultivadas , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299028

RESUMO

Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antipsicóticos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Sinergismo Farmacológico , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasias do Colo/patologia , Quimioterapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas
16.
Anticancer Res ; 41(7): 3511-3517, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230146

RESUMO

BACKGROUND/AIM: We previously found crypts in symmetric fission (CSF) and in asymmetric fission (CAF) in colectomy-specimens with ulcerative colitis. We now analyzed CSF and CAF (CSAF) in biopsies from 80 patients with inflammatory bowel disease (IBD) without dysplasia or carcinoma. PATIENTS AND METHODS: One unselected double-biopsy from affected endoscopic areas was investigated in the 80 cases. RESULTS: A total of 353 crypts in fission were found. The median number of CAF/biopsy was 3.7 and for CSF/biopsy, 0.7 (p<0.00001). CONCLUSION: CSAF often occur in unselected biopsies from patients with IBD. Whereas the increased frequency of CSF might mirror a compensatory mechanism of crypt production in areas occupied by inflammation, CAF reflects a pathological aberration of cryptogenesis, probably generated by somatic mutations. The biological significance of CAF in IBD without dysplasia or carcinoma, deserves to be further investigated.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Biópsia/métodos , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias do Colo/patologia , Feminino , Humanos , Inflamação/patologia , Mucosa Intestinal/patologia , Masculino , Suécia
17.
Anticancer Res ; 41(7): 3567-3572, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230152

RESUMO

BACKGROUND/AIM: Medullary carcinoma (MC) of the colon is a rare subtype of colorectal adenocarcinoma (CRC) with unique histomorphology and frequent mismatch repair (MMR) deficiency. MC with exclusive squamous differentiation has not been reported. We report an unusual case of MC with squamous differentiation and tested this differentiation potential in other MMR-deficient CRC cases. CASE REPORT: A 68-year-old woman presented with a large ascending colon mass and biopsy showed squamoid tumor morphology with immunoprofile concerning for squamous cell carcinoma (SCC). She underwent right hemicolectomy. Immunohistochemistry and next-generation sequencing (NGS) were performed for tumor classification. Macroscopically, the tumor was large and locally advanced. It metastasized to the lung without lymph node metastasis. Microscopically, the tumor cells were monotonous with cytological features of both MC and SCC. Immunostains were diffusely positive for p40 and CK5/6, but negative for other lineage markers including CDX2, CK20, and SATB2. The tumor was MMR deficient with loss of MLH1 and PMS2. NGS confirmed BRAF V600E mutation. In comparison, a tissue microarray comprising 64 previously diagnosed MMR deficient CRC was tested for squamous differentiation, and only 1 case showed focal CK5/6 expression, but none was positive for p40. CONCLUSION: MC with exclusive squamous differentiation not only posed significant diagnostic challenges, but also unveiled unrecognized differentiation plasticity in this tumor type.


Assuntos
Carcinoma Medular/patologia , Carcinoma de Células Escamosas/patologia , Diferenciação Celular/fisiologia , Neoplasias do Colo/patologia , Idoso , Carcinoma Medular/genética , Carcinoma de Células Escamosas/genética , Diferenciação Celular/genética , Colo/patologia , Neoplasias do Colo/genética , Feminino , Humanos , Mutação/genética
18.
Anticancer Res ; 41(7): 3683-3688, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230167

RESUMO

BACKGROUND/AIM: There are no clinically significant cutoff values of serum vitamin D levels and time points to predict the prognosis of colon cancer, particularly in patients who underwent curative surgical resection. PATIENTS AND METHODS: We retrospectively analyzed serum vitamin D levels in 795 patients with stages I to III colon cancer who underwent curative surgical resection. RESULTS: Patients with vitamin D levels below 12 ng/ml at one year after surgical resection demonstrated a significantly reduced disease-free survival (DFS) than those who did not have vitamin D deficiency (p=0.01). In the multivariate analysis, an age of 70 years or older [hazard ratio (HR)=1.992; p=0.001], pathologic stage (HR=3.739; p<0.001), and vitamin D deficiency (less than 12 ng/ml) at one year after surgery (HR=0.563; p=0.020) were factors unfavorably influencing DFS. CONCLUSION: In patients with stages I to III of colon cancer, vitamin D deficiency at one year after surgical resection was associated with increased disease relapse.


Assuntos
Neoplasias do Colo/patologia , Recidiva Local de Neoplasia/patologia , Deficiência de Vitamina D/patologia , Vitamina D/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias/métodos , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Deficiência de Vitamina D/metabolismo , Adulto Jovem
19.
JSLS ; 25(2)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248343

RESUMO

Introduction: Simultaneous robot assisted colon and liver resections are being performed more frequently at present due to the expanded adoption of the robotic platform for surgical management of metastatic colon cancer. However, this approach has not been studied in detail with only case series available in the literature. The aim of this systematic review was to evaluate the current body of evidence on the feasibility of performing simultaneous robotic colon and liver resections. Methods: A systematic review was performed through PubMed to identify relevant articles describing simultaneous colon and liver resections for metastatic colon cancer. Results: A total of 28 patients underwent simultaneous resections robotically with an average operative time of 420.3 minutes and average blood loss of 275.6 ml. Postoperative stay was 8.6 days on average with all cases achieving negative surgical margins. Conclusions: Robotic simultaneous resection of colorectal cancer with liver metastases is technically feasible and seems oncologically equivalent to open or laparoscopic surgery. Further studies are urgently needed to assess benefits of robotic surgery in the patient population.


Assuntos
Colectomia/métodos , Neoplasias do Colo/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Neoplasias do Colo/patologia , Terapia Combinada , Humanos , Laparoscopia/métodos , Neoplasias Hepáticas/secundário , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Duração da Cirurgia
20.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201061

RESUMO

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mutação , Proteínas Nucleares/metabolismo , Proteoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Vemurafenib/farmacologia , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Proteoma/análise , Células Tumorais Cultivadas
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