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1.
Nutrients ; 13(10)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34684550

RESUMO

Aim: Recently, more attention has been paid to the role of nutritional intervention in preventing the side effects of chemotherapy in oncology patients. Therefore, the aim of the present study was to analyze the effects of oral nutritional supplements on the body composition and biochemical parameters in women with breast cancer receiving postoperative adjuvant chemotherapy. Patients and Methods: The study involved women diagnosed with breast cancer who underwent surgical treatment and were qualified for chemotherapy (doxorubicin and cyclophosphamide). Women were divided into two groups, depending on whether oral nutritional supplements were used during chemotherapy. Anthropometric and biochemical parameters were analyzed twice in all patients: before and after six weeks of chemotherapy. Propensity score (PS) matching was performed to select patients balanced in terms of age, BMI, and clinicopathological features of the tumor. Statistical comparisons were conducted in a propensity-matched cohort of patients. Results: The value of BMI was maintained constant in the supplemented women older than 56 years after six weeks of chemotherapy. Regardless of age in the supplemented women, a significant increase in muscle mass, fat free mass (FFM), and fat free mass index (FFMI) was demonstrated. An increase in fat mass (FM) including visceral fat was observed only in the non-supplemented control. Regardless of age or initial FM, supplemented women exhibited a constant level of albumin. Moreover, in the supplemented women with normal initial FM, the stable values of triglycerides and HDL cholesterol were maintained after six weeks of chemotherapy. Conclusion: The present study demonstrated that oral nutritional supplements could improve body composition and prevent hypoalbuminemia and lipid abnormalities in women with breast cancer undergoing chemotherapy.


Assuntos
Composição Corporal , Neoplasias da Mama/fisiopatologia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Suplementos Nutricionais , Antropometria , Antineoplásicos Alquilantes/uso terapêutico , Índice de Massa Corporal , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Lipídeos/sangue , Mastectomia , Pessoa de Meia-Idade , Período Pós-Operatório , Pontuação de Propensão , Albumina Sérica/metabolismo , Resultado do Tratamento
2.
BMC Cancer ; 21(1): 1005, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496789

RESUMO

BACKGROUND: Weight changes are common among breast cancer patients. The majority of studies to date have focused on weight gain after a breast cancer diagnosis and its implications on health in survivors. Fewer studies have examined weight loss and its related characteristics. Weight changes have been reported to be influenced by several factors such as age, treatment, stage and pre-diagnostic weight. We evaluated weight changes during key treatment time points in early stage breast cancer patients. METHODS: We characterized 389 female patients diagnosed in Hawaii with early stage breast cancer from 2003 to 2017 in the Multiethnic Cohort (MEC) linked with Kaiser Permanente Hawaii electronic medical record data. We evaluated weight changes from surgery to 4 years post-diagnosis with six time points along a patient's treatment trajectory (chemotherapy, radiation, endocrine, or surgery alone) and annually thereafter, adjusting for age, race/ethnicity and initial body mass index (BMI). RESULTS: We found key time points of significant weight change for breast cancer patients according to their adjuvant treatment. In patients who had surgery alone (S), surgery-radiation (SR), or surgery-endocrine therapy (SE), the majority of patients had stable weight, although this consistently decreased over time. However, the percentages of patients with weight loss and weight gain during this time steadily increased up to 4 years after initial surgery. Weight loss was more common than weight gain by about 2 fold in these treatment groups. For patients with surgery-chemotherapy (SC), there was significant weight loss seen within the first 3 months after surgery, during the time when patients receive chemotherapy. And this weight loss persisted until year 4. Weight gain was less commonly seen in this treatment group. CONCLUSIONS: We identified key time points during breast cancer treatment that may provide a therapeutic window to positively influence outcomes. Tailored weight management interventions should be utilized to promote overall health and long term survivorship.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/fisiopatologia , Quimioterapia Adjuvante/métodos , Mastectomia/métodos , Radioterapia/métodos , Ganho de Peso , Perda de Peso , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/terapia , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico
3.
BMC Cancer ; 21(1): 1052, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34563150

RESUMO

BACKGROUND: Breast cancer is the second leading cause of cancer in the world. It is the commonest type of cancer in Ethiopia. Cognitive problems are common among breast cancer patients. The study aimed to assess cognitive functioning and its associated factors among breast cancer patients at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia 2020. METHODS: Institution-based comparative cross-sectional study was conducted. Study subjects were 117 breast cancer patients on chemotherapy and 117 women without breast cancer who volunteered for the study. Data was collected from May-June 2020. The Mini-mental status exam (MMSE) was used to assess cognitive functioning. Data were entered into Epi Data version 4.6.0.2 and analyzed using STATA version 14 software. Univariable and multivariable linear regression model was fitted to identify factors associated with cognitive functioning. A two-tailed p-value less than 0.05 was used to declare statistical significance. RESULTS: Among the total breast cancer patients 41.9% were diagnosed with earlier sage of the diseases (stage I and II), while the rest 58.1% were diagnosed with stage III and stage IV breast cancer. A significant difference in the MMSE score was observed among breast cancer patients and controls (19.76 ± 5.29, 25.18 ± 4.68 p <  0.0001) respectively. In multivariable linear regression analysis being non-breast cancer (Adjusted beta coefficient (Adj.ß.coff). = 3.34, 95% CI (1.92-4.76) p <  0.001), hemoglobin gm/dl (Adj.ß.coff =0.34, 95% CI (0.04-0.63) p = 0.02), and primary education (Adj.ß.coff =2.98 95%CI (1.16-4.96) p = 0.001) secondary level and more education (Adj.ß.coff = 5.47, 95%CI (3.51-7.28) p < 0.001) were significantly associated with MMSE cognitive score. CONCLUSION: Breast cancer patients had lower mean MMSE scores when compared to non-breast cancer women. Higher hemoglobin level and higher level of education increase the MMSE cognitive score. Clinicians should incorporate routine screening of cognitive functioning for breast cancer patients and further study is required to evaluate cognitive impairment among breast cancer patients in Ethiopia.


Assuntos
Neoplasias da Mama/fisiopatologia , Transtornos Cognitivos/diagnóstico , Cognição/fisiologia , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Institutos de Câncer , Intervalos de Confiança , Estudos Transversais , Escolaridade , Etiópia , Feminino , Hemoglobina A/análise , Humanos , Modelos Lineares , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Estadiamento de Neoplasias
4.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502189

RESUMO

Since its discovery, mitophagy has been viewed as a protective mechanism used by cancer cells to prevent the induction of mitochondrial apoptosis. Most cancer treatments directly or indirectly cause mitochondrial dysfunction in order to trigger signals for cell death. Elimination of these dysfunctional mitochondria by mitophagy could thus prevent the initiation of the apoptotic cascade. In breast cancer patients, resistance to doxorubicin (DOX), one of the most widely used cancer drugs, is an important cause of poor clinical outcomes. However, the role played by mitophagy in the context of DOX resistance in breast cancer cells is not well understood. We therefore tried to determine whether an increase in mitophagic flux was associated with the resistance of breast cancer cells to DOX. Our first objective was to explore whether DOX-resistant breast cancer cells were characterized by conditions that favor mitophagy induction. We next tried to determine whether mitophagic flux was increased in DOX-resistant cells in response to DOX treatment. For this purpose, the parental (MCF-7) and DOX-resistant (MCF-7dox) breast cancer cell lines were used. Our results show that mitochondrial reactive oxygen species (ROS) production and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression are higher in MCF-7dox in a basal condition compared to MCF-7, suggesting DOX-resistant breast cancer cells are prone to stimuli to induce a mitophagy-related event. Our results also showed that, in response to DOX, autophagolysosome formation is induced in DOX-resistant breast cancer cells. This mitophagic step following DOX treatment seems to be partly due to mitochondrial ROS production as autophagolysosome formation is moderately decreased by the mitochondrial antioxidant mitoTEMPO.


Assuntos
Neoplasias da Mama/fisiopatologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Lisossomos , Mitofagia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Doxorrubicina/uso terapêutico , Feminino , Humanos , Células MCF-7 , Mitocôndrias/metabolismo
5.
Life Sci ; 284: 119924, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480935

RESUMO

AIMS: The present study aimed to verify the effects of resistance training (RT) and successive detraining on body composition, muscle strength and lipid profile as primary outcome, and the oxidative stress and inflammatory markers as second outcome of postmenopausal Breast Cancer (BC) survivors undergoing tamoxifen (TA). MAIN METHODS: Fourteen postmenopausal BC survivors underwent 12 weeks of resistance exercise training and subsequently 12 weeks of detraining. Anthropometric parameters, lipid profile, muscle strength, inflammatory cytokines and the oxidative stress markers, were assessed before, after the training period and after detraining period. KEY FINDINGS: One-way ANOVA showed that fat mass decrease (39.4 ± 6.9 to 37.7 ± 6.8%) and free-fat mass increase (39.3 ± 4.9 to 40.3 ± 5.6%) after RT. Muscle strength increased in response to training but decreased after the detraining period. Triglycerides (156 ± 45 to 123 ± 43 mg/dL) and total cholesterol (202 ± 13 to 186 ± 16 mg/dL) decreased after the RT and HDL-cholesterol (47 ± 9 to 56 ± 9 mg/dL) increased after RT and remained higher (53 ± 10 mg/dL) than after detraining. IL-6 increases (24.65 ± 10.85 to 41.42 ± 22.88 pg/mL) and IL-17 (2.42 ± 0.32 to 1.69 ± 0.19 pg/mL), TBARS (1.91 ± 0.19 to 1.03 ± 0.1 µmol/L), SOD (24.65 ± 10.85 to 41.42 ± 22.88 U/gHb) and Catalase activity (445.9 ± 113.0 to 345.8 ± 81.7 k/gHb·s) reduced after RT and remained lower after detraining. SIGNIFICANCE: Resistance exercise training improves health markers of BC survivors undergoing TA and detraining are not sufficient to reverse the positive effects in oxidative stress markers.


Assuntos
Biomarcadores Tumorais/sangue , Composição Corporal , Neoplasias da Mama/fisiopatologia , Sobreviventes de Câncer , Exercício Físico , Lipídeos/sangue , Força Muscular , Tamoxifeno/uso terapêutico , Adulto , Idoso , Composição Corporal/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Inflamação/patologia , Pessoa de Meia-Idade , Força Muscular/efeitos dos fármacos , Tamoxifeno/farmacologia
6.
Theranostics ; 11(16): 7658-7670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335956

RESUMO

SNAI1 is widely regarded as a master driver of epithelial-mesenchymal transition (EMT) and associated with breast cancer progression and metastasis. This pro-malignant role is strongly linked to posttranslational modification, especially phosphorylation, which controls its protein levels and subcellular localization. While multiple kinases are implicated in regulation of SNAI1 stability, the precise mechanism by which SNAI1 is stabilized in tumors remains to be fully elucidated. Methods: A series of in vitro and in vivo experiments were conducted to reveal the regulation of SNAI1 by Serine/Threonine Kinase 39 (STK39) and the role of STK39 in breast cancer metastasis. Results: We identified STK39, a member of Stem 20-like serine/threonine kinase family, as a novel posttranslational regulator that enhances the stability of SNAI1. Inhibition of STK39 via knockdown or use of a specific inhibitor resulted in SNAI1 destabilization. Mechanistically, STK39 interacted with and phosphorylated SNAI1 at T203, which is critical for its nuclear retention. Functionally, STK39 inhibition markedly impaired the EMT phenotype and decreased tumor cell migration, invasion, and metastasis both in vitro and in vivo. These effects were rescued by ectopic SNAI1 expression. In addition, depletion of STK39 dramatically enhanced sensitivity to chemotherapeutic agents. Conclusions: Our study demonstrated that STK39 is a key mediator of SNAI1 stability and is associated with the pro-metastatic cellular process, highlighting the STK39-SNAI1 signaling axis as promising therapeutic targets for treatments of metastatic breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos SCID , Invasividade Neoplásica/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo
7.
Clin Ter ; 172(4): 305-314, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34247213

RESUMO

Introduction: Background The aim of the paper is related to our experience defining the diagnostic accuracy of breast elastosonog-raphy. Objective: The aim of our study is therefore to define the diagnostic accuracy of breast elastosonography in the differential diagnosis of nodular breast neoformations to improve the characterization of the solid lesion and reduce the number of needle aspiration unnecessary for benign formations. Material and methods: A total of 88 patients were enrolled, who came to the Department with an ultrasound diagnosis of a breast lesion. Each lesion was subjected to mammography and B-mode ultrasonogra-phy with an evaluation of size, echogenicity, and vascularization pres-ence or absence. The use of the ultrasound machine and the respective probe has made it possible to make the measurements. All nodules were subjected to ultrasound-guided FNAC. These data were compared with the results of elastosonographic examination. Results: FNAC results were as follows: CIN 1 in 18 nodules, CIN 2 in 22 nodules, CIN 3 in 36 nodules, CIN 4 in 6 nodules, and CIN 5 in 6 nodules. The sensitivity and specificity of elastosonography found in our case series reported values in line with data reported in the literature, confirming the method's high reliability. Conclusions: The elastosonography could become a complemen-tary technique to mammography and ultrasonography in the future, reducing the costs and risks of additional examinations. Therefore, we believe it is essential to contribute with this additional finding to increasingly accredit this pathway and reduce the discomfort to patients of more invasive methods.


Assuntos
Biópsia por Agulha Fina/métodos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/fisiopatologia , Neoplasias/diagnóstico , Neoplasias/fisiopatologia , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
8.
Front Immunol ; 12: 599207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267742

RESUMO

Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, numerous cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, serves as an alternative inhibitory receptor to be targeted in the clinic. The impacts of LAG3 on immune cell populations and coregulation of immune responses in breast cancer remain largely unknown. To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from 2,994 breast cancer patients. We estimated the landscape of the relationship between LAG3 and 10 types of cell populations of breast cancer. We investigated the correlation pattern between LAG3 and immune modulators in pancancer, particularly the synergistic role of LAG3 with other immune checkpoint members in breast cancer. LAG3 expression was closely related to the malignancy of breast cancer and may serve as a potential biomarker. LAG3 may play an important role in regulating the tumor immune microenvironment of T cells and other immune cells. More important, LAG3 may synergize with CTLA4, PD1/PDL1, and other immune checkpoints, thereby contributing more evidence to improve combination cancer immunotherapy by simultaneously targeting LAG3, PD1/PDL1, and CTLA4.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Expressão Gênica , Antígenos CD/imunologia , Neoplasias da Mama/classificação , Neoplasias da Mama/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Transcriptoma , Microambiente Tumoral/imunologia
9.
Anticancer Res ; 41(7): 3233-3246, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230117

RESUMO

BACKGROUND/AIM: Upper limb breast cancer-related lymphedema (BCRL) is a chronic and severe condition affecting a significant percentage of breast cancer survivors. Even though its physiopathology is well-known, there is no worldwide consensus on BCRL evaluation and a gold-standard treatment. This narrative review aims at providing a brief descriptive overview with regard to BCRL treatment modalities. MATERIALS AND METHODS: We conducted a literature search within the PubMed database, and 33 articles out of 56 were selected, including reviews, systematic reviews, and meta-analyses aiming find the most updated evidence regarding BCRL treatment modalities. RESULTS: Physical exercise (aerobic exercise, resistance exercise, aquatic therapy), bandages, and intermittent pneumatic compression were shown to be most effective in BCRL patients, in terms of swelling reduction in the acute-intensive phase. Furthermore, physical exercise was beneficial also as a maintenance tool. Manual lymphatic drainage demonstrated efficacy in preventing secondary lymphedema if applied immediately after breast cancer surgery or in early phases of BCRL or as a maintenance tool. Complementary procedures such as acupuncture, reflexology, yoga and photo-biomodulation therapy did not show conclusive results in BCRL treatment. Surgery was shown effective in managing symptoms (liposuction), preventing (lymphaticovenular anastomosis) and treating BCRL (vascularized lymph node transfer). CONCLUSION: BCRL is still a challenging condition either for breast cancer survivors and clinicians, deeply impacting patient functioning and quality of life. Due to the lack of globally accepted criteria in evaluating BCRL, to date a gold standard treatment for this widespread issue is still needed.


Assuntos
Linfedema Relacionado a Câncer de Mama/terapia , Neoplasias da Mama/cirurgia , Linfedema Relacionado a Câncer de Mama/fisiopatologia , Neoplasias da Mama/fisiopatologia , Terapias Complementares/métodos , Exercício Físico/fisiologia , Feminino , Humanos , Sobreviventes
10.
Sci Rep ; 11(1): 15414, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326419

RESUMO

The purpose of this study was to investigate the relationship between heart rate variability (HRV), a non-invasive tool for evaluating autonomic function, and routine coagulation indices (RCIs) in patients with breast cancer (BC). Forty-six BC patients were enrolled in this study. Blood biochemistry tests were performed to extract RCIs, including prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). Five-minute electrocardiograms were collected for analysis of HRV parameters (SDNN, RMSSD, LF, HF, LF n.u., HF n.u., LF/HF). Multiple linear regression models examined the relationship of HRV parameters with RCIs. RMSSD, LF n.u., HF n.u., LF/HF were significantly associated with PT. Specifically, the value of PT increased by 0.192 ± 0.091 or 0.231 ± 0.088 s, respectively for each 1 standard deviation (SD) increase in RMSSD or HF n.u.; it increased by 0.230 ± 0.088 or 0.215 ± 0.088 s, respectively for each 1 - SD decrease in LF n.u. or ln (LF/HF) (all P < 0.05). RMSSD was significantly associated with APTT, i.e., the value of APTT increased by 1.032 ± 0.470 s for each 1 - SD increase in RMSSD (P < 0.05). HRV parameters were associated with RCIs in patients with BC. These observations suggest that the autonomic nervous system and coagulation indices in BC patients are linked, potentially explaining the reason that they are both associated with the prognosis.


Assuntos
Coagulação Sanguínea , Neoplasias da Mama/sangue , Neoplasias da Mama/fisiopatologia , Frequência Cardíaca , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Testes de Coagulação Sanguínea , Índice de Massa Corporal , Neoplasias da Mama/patologia , Eletrocardiografia/métodos , Feminino , Humanos , Modelos Lineares , Pessoa de Meia-Idade
11.
J Toxicol Sci ; 46(7): 329-339, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193770

RESUMO

Lidocaine has been shown to inhibit the invasion and metastasis of breast cancer, but the mechanism still remains unclear. This study explored the relationship between lidocaine and circulating seeding of breast cancer cells from the perspective of nerve fiber formation. The cell lines MDA-MB-231 and 4T1 were subcutaneously inoculated in mice to simulate the tumor self-seeding by circulating cancer cells. Lidocaine was used to treat these mice and tumor growth was observed. Silver staining was performed to observe the distribution of nerve fibers in tumor-bearing tissues, and immunohistochemical analysis was performed to observe the expression levels of nerve-related proteins. The results showed that lidocaine treatment effectively inhibited tumor growth and nerve fiber formation, and down-regulated the expression levels of protein gene product 9.5, neurofilament, nerve growth factor (NGF), and neuronatin (Nnat). Overexpression NGF and Nnat both could reverse the therapeutic effects of lidocaine. These results suggest that the effect of lidocaine on inhibiting breast cancer invasion and metastasis may be achieved by targeting Nnat, regulating the production of NGFs in cancer cells, and subsequently inhibiting the formation of nerve fibers.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Lidocaína/farmacocinética , Lidocaína/uso terapêutico , Metástase Neoplásica/prevenção & controle , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Metástase Neoplásica/tratamento farmacológico , Proteínas do Tecido Nervoso/efeitos dos fármacos
12.
Carbohydr Polym ; 268: 118192, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34127212

RESUMO

Breast cancer (BC) is considered as one the most prevalent cancers worldwide. Due to its high resistance to chemotherapy and high probability of metastasis, BC is one of the leading causes of cancer-related deaths. The controlled release of chemotherapy drugs to the precise site of the tumor tissue will increase the therapeutic efficacy and decrease side effects of systemic administration. Among various drug delivery systems, natural polymers-based drug carriers have gained significant attention for cancer therapy. Chitosan, a natural polymer obtained by de-acetylation of chitin, holds huge potential for drug delivery applications because chitosan is non-toxic, non-immunogenic, biocompatible, chemically modifiable, and can be processed to form various formulations. In the current review, we will discuss the prospects and challenges of chitosan-based drug delivery systems in treating BC.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quitosana/química , Portadores de Fármacos/química , Animais , Neoplasias da Mama/classificação , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Humanos , Nanopartículas/química , Transdução de Sinais/fisiologia
13.
PLoS Comput Biol ; 17(6): e1009066, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34129639

RESUMO

Collective dynamics in multicellular systems such as biological organs and tissues plays a key role in biological development, regeneration, and pathological conditions. Collective tissue dynamics-understood as population behaviour arising from the interplay of the constituting discrete cells-can be studied with on- and off-lattice agent-based models. However, classical on-lattice agent-based models, also known as cellular automata, fail to replicate key aspects of collective migration, which is a central instance of collective behaviour in multicellular systems. To overcome drawbacks of classical on-lattice models, we introduce an on-lattice, agent-based modelling class for collective cell migration, which we call biological lattice-gas cellular automaton (BIO-LGCA). The BIO-LGCA is characterised by synchronous time updates, and the explicit consideration of individual cell velocities. While rules in classical cellular automata are typically chosen ad hoc, rules for cell-cell and cell-environment interactions in the BIO-LGCA can also be derived from experimental cell migration data or biophysical laws for individual cell migration. We introduce elementary BIO-LGCA models of fundamental cell interactions, which may be combined in a modular fashion to model complex multicellular phenomena. We exemplify the mathematical mean-field analysis of specific BIO-LGCA models, which allows to explain collective behaviour. The first example predicts the formation of clusters in adhesively interacting cells. The second example is based on a novel BIO-LGCA combining adhesive interactions and alignment. For this model, our analysis clarifies the nature of the recently discovered invasion plasticity of breast cancer cells in heterogeneous environments.


Assuntos
Movimento Celular/fisiologia , Modelos Biológicos , Análise de Sistemas , Fenômenos Biofísicos , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Biologia Computacional , Simulação por Computador , Feminino , Humanos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Biologia de Sistemas
14.
Sci Rep ; 11(1): 12105, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103606

RESUMO

Cognitive complaints after chemotherapy are common in breast cancer patients, but the neural bases for these complaints remain unclear. This pilot study explored resting-state functional connectivity (FC) as a marker of subtle cognitive changes in breast cancer patients who experience cognitive complaints. Chemotherapy-treated (n = 20, at least 6 months off therapy) and untreated (n = 17, disease-control) female breast cancer patients with cognitive complaints and healthy controls (n = 20) were recruited. The FC of the right dorsolateral prefrontal cortex was calculated, and any correlations between this FC and neuropsychological assessments were determined. Chemotherapy-treated patients with cognitive complaints displayed increased FC between the right dorsolateral prefrontal cortex and both the contralateral cerebellar lobule VII and the cerebellar vermis XI, compared to the disease-control and healthy-control groups, despite unimpaired neuropsychological performance. The increased FC was negatively correlated with executive function and attention in breast cancer survivors with cognitive complaints. Our pilot study findings provide evidence that cerebellar-cortical FC changes may be a pathophysiological basis for chemotherapy-related cognitive complaints. In addition, the FC changes have the potential to reflect minor or compensated cognitive function impairment in breast cancer patients.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/complicações , Neoplasias da Mama/fisiopatologia , Cerebelo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Transtornos Cognitivos/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Encefálico , Sobreviventes de Câncer , Cerebelo/fisiopatologia , Córtex Cerebral/fisiopatologia , Cognição , Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Projetos Piloto , Córtex Pré-Frontal
15.
J Vis Exp ; (170)2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33970144

RESUMO

Breast cancer (BC) remains a leading cause of death for women. Despite more than $700 million invested in BC research annually, 97% of candidate BC drugs fail clinical trials. Therefore, new models are needed to improve our understanding of the disease. The NIH Microphysiological Systems (MPS) program was developed to improve the clinical translation of basic science discoveries and promising new therapeutic strategies. Here we present a method for generating MPS for breast cancers (BC-MPS). This model adapts a previously described approach of culturing primary human white adipose tissue (WAT) by sandwiching WAT between adipose-derived stem cell sheets (ASC)s. Novel aspects of our BC-MPS include seeding BC cells into non-diseased human breast tissue (HBT) containing native extracellular matrix, mature adipocytes, resident fibroblasts, and immune cells; and sandwiching the BC-HBT admixture between HBT-derived ASC sheets. The resulting BC-MPS is stable in culture ex vivo for at least 14 days. This model system contains multiple elements of the microenvironment that influence BC including adipocytes, stromal cells, immune cells, and the extracellular matrix. Thus BC-MPS can be used to study the interactions between BC and its microenvironment. We demonstrate the advantages of our BC-MPS by studying two BC behaviors known to influence cancer progression and metastasis: 1) BC motility and 2) BC-HBT metabolic crosstalk. While BC motility has previously been demonstrated using intravital imaging, BC-MPS allows for high-resolution time-lapse imaging using fluorescence microscopy over several days. Furthermore, while metabolic crosstalk was previously demonstrated using BC cells and murine pre-adipocytes differentiated into immature adipocytes, our BC-MPS model is the first system to demonstrate this crosstalk between primary human mammary adipocytes and BC cells in vitro.


Assuntos
Neoplasias da Mama/fisiopatologia , Mama/patologia , Diferenciação Celular , Feminino , Humanos , Microambiente Tumoral
16.
Medicine (Baltimore) ; 100(18): e25844, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950998

RESUMO

ABSTRACT: The aim of this study was to develop a new breast density classification system for dedicated breast computed tomography (BCT) based on lesion detectability analogous to the ACR BI-RADS breast density scale for mammography, and to evaluate its interrater reliability.In this retrospective study, 1454 BCT examinations without contrast media were screened for suitability. Excluding datasets without additional ultrasound and exams without any detected lesions resulted in 114 BCT examinations. Based on lesion detectability, an atlas-based BCT density (BCTD) classification system of breast parenchyma was defined using 4 categories. Interrater reliability was examined in 40 BCT datasets between 3 experienced radiologists.Among the included lesions were 63 cysts (55%), 18 fibroadenomas (16%), 7 lesions of fatty necrosis (6%), and 6 breast cancers (5%) with a median diameter of 11 mm. X-ray absorption was identical between lesions and breast tissue; therefore, the lack of fatty septae was identified as the most important criteria for the presence of lesions in glandular tissue. Applying a lesion diameter of 10 mm as desired cut-off for the recommendation of an additional ultrasound, an atlas of 4 BCTD categories was defined resulting in a distribution of 17.5% for density A, 39.5% (B), 31.6% (C), and 11.4% (D) with an intraclass correlation coefficient (ICC) among 3 readers of 0.85 to 0.87.We propose a dedicated atlas-based BCTD classification system, which is calibrated to lesion detectability. The new classification system exhibits a high interrater reliability and may be used for the decision whether additional ultrasound is recommended.


Assuntos
Neoplasias da Mama/diagnóstico , Mama/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/fisiopatologia , Cisto Mamário/diagnóstico , Densidade da Mama/fisiologia , Neoplasias da Mama/fisiopatologia , Tomada de Decisão Clínica/métodos , Conjuntos de Dados como Assunto , Diagnóstico Diferencial , Necrose Gordurosa/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Estudos Retrospectivos , Terminologia como Assunto , Ultrassonografia Mamária
17.
Mol Biol Rep ; 48(4): 3439-3449, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33999319

RESUMO

Heat shock protein 90 (Hsp90) is a key chaperone that is abnormally expressed in cancer cells, and therefore, designing novel compounds to inhibit chaperone activities of the Hsp90 is a promising therapeutic approach for cancer drug discovery. Debio-0932 is a second-generation Hsp90 inhibitor that exhibited promising anticancer activity against a wide variety of cancer types with a strong binding affinity for Hsp90 and high oral bioavailability. Anticancer activities of the Debio-0932 were tested in MCF-7 and MDA-MB-231 cell lines. Molecular docking results indicated that Debio-0932 was selectively bound to the ATP binding pocket of the Hsp90 with an estimated free energy of binding - 7.24 kcal/mol. Antiproliferative activity of Debio-0932 was determined by XTT assay and Debio-0932 exhibited a cytotoxic effect on MCF-7 and MDA-MB-231 cells in a time and dose-depended manner. Apoptosis inducer role of Debio-0932 was evaluated in MCF-7 and MDA-MB-231 cells with fluorometric apoptosis/necrosis detection kit. Treatment with Debio-0932 stimulated apoptosis in both breast cancer cell lines. mRNA and protein expression levels of Bax, Bcl-2 and Casp-9 were determined in MCF-7 and MDA-MB-231 cells by RT-PCR and Western blotting respectively. Debio-0932 stimulated the down-regulation of anti-apoptotic protein Bcl-2 and the up-regulation of apoptotic protein Bax and cleavage of Casp-9 in cancer cells. Moreover, the anti-invasive potential of Debio-0932 was evaluated in endothelial cells (HUVEC) by wound-healing assay. Debio-0932 decreased the migration of HUVEC cells as compared to the control group. These results indicate that Debio-0932 is a promising compound to treat triple-negative breast cancer and hormone receptor-positive breast cancer, and their metastases.


Assuntos
Apoptose , Benzodioxóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Imidazóis/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzodioxóis/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Caspase 9/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/uso terapêutico , Células MCF-7 , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética
18.
Biochemistry (Mosc) ; 86(2): 217-229, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33832420

RESUMO

Retinoic acid (RA) binding proteins, CRABP1 and CRABP2, are molecular chaperones that mediate intracellular activity of RA, the key promoter of cell differentiation with tumor suppressor activity. One of the main functions of CRABP2 is delivery and transfer of RA to the nuclear receptors RAR/RXR, which leads to activation of the transcription of a wide range of retinoid-responsive genes. The functions of CRABP1 are less studied but are apparently associated with sequestration of RA in cytoplasm and limitation of its transcriptional activity, suggesting involvement of this protein in the development of RA resistance. The mechanisms regulating activity of CRABP1 are also poorly understood. Comparison of the CRABP1 level in tumor cell lines of various origins, performed for the first time here, showed absence of the CRABP1 protein in the cell lines of tumors considered to be RA-resistant, and pronounced production of this protein in the RA-sensitive cells. However, analysis carried out with a panel of breast cancer cell lines with different levels of RA-sensitivity showed that there was no correlation between the production of CRABP1 protein and the sensitivity of the cells to RA. At the same time, we found strong correlation between the expression of CRABP1 and CRABP2 proteins in all studied cell types, regardless of their origin and RA-sensitivity/resistance. Moreover, suppression of the CRABP1 level in both RA-sensitive and RA-resistant cells was shown in the cells with cells with knockdown of CRABP2 gene. The revealed CRABP2-dependent regulation of CRABP1 production is a new mechanism of the intracellular retinoic signaling system.


Assuntos
Neoplasias da Mama/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Tretinoína/farmacologia , Células A549 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Transdução de Sinais , Tretinoína/uso terapêutico
19.
Commun Biol ; 4(1): 477, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859337

RESUMO

The tumor microenvironment (TME) is multi-cellular, spatially heterogenous, and contains cell-generated gradients of soluble molecules. Current cell-based model systems lack this complexity or are difficult to interrogate microscopically. We present a 2D live-cell chamber that approximates the TME and demonstrate that breast cancer cells and macrophages generate hypoxic and nutrient gradients, self-organize, and have spatially varying phenotypes along the gradients, leading to new insights into tumorigenesis.


Assuntos
Neoplasias da Mama/fisiopatologia , Carcinogênese , Macrófagos/fisiologia , Células Tumorais Cultivadas/fisiologia , Microambiente Tumoral , Animais , Técnicas de Cultura de Células , Camundongos
20.
PLoS One ; 16(4): e0250102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33901219

RESUMO

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Estudos de Coortes , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neoplasias Ovarianas , Prognóstico , Fatores de Risco , Singapura/epidemiologia , Inquéritos e Questionários
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