The fibrinolytic system plays an important role in breast cancer, favoring progression through extracellular-matrix degradation, angiogenesis, apoptosis and cellular proliferation. The expression of ...urokinase-type plasminogen activator (uPA) in breast cancer tissue is widely recognized as an unfavorable prognostic factor. However, fibrinolytic activity associated with uPA cannot be reliably measured in the blood because of the rapid inhibition of uPA by plasminogen activator inhibitor-1 (PAI-1). By contrast, circulating microvesicles (Mvs) in peripheral blood protect bound enzymes from inhibition. Mvs are extracellular vesicles, released from various types of cells, and their size fluctuates between 100 and 1,000 nm. Mvs carry DNA, RNA, miRNA, and proteins, thereby serving as a source of horizontal communication between cells. We investigated whether fibrinolytic activity on circulating Mvs reflects breast cancer progression. The study population consisted of 13 patients with breast cancer and 13 healthy women. The cancer patients included 4 patients in remission, 3 patients with locally advanced cancer, and 6 with metastatic disease. Mvs were isolated from peripheral blood, quantified by a protein concentration method, and their fibrinolytic potential was measured by their capacity to generate plasmin. Although the quantity of Mvs found in patients with cancer and healthy individuals was similar, plasmin generated on Mvs was twice the amount in patients with metastasis than in healthy women (P < 0.05), underlying the value of this distinctive parameter. The data suggest that in breast cancer patients, higher fibrinolytic activity of circulating Mvs could be related to progression and metastasis of breast cancer.
Purpose:
The aim of this study was to evaluate the demographic characteristics, clinical and pathological factors, and the outcome of cancer and COVID-19 patients in Mexico.
Patients and methods:
A ...prospective, multicentric study was performed through a digital platform to have a national registry of patients with cancer and positive SARS-CoV-2 test results through reverse transcription quantitative polymerase chain reaction (RT-qPCR). We performed the analysis through a multivariate logistic regression model and Cox proportional hazard model.
Results:
From May to December 2020, 599 patients were registered with an average age of 56 years with 59.3% female; 27.2% had hypertension. The most frequent diagnoses were breast cancer (30.4%), lymphoma (14.7%), and colorectal cancer (14.0%); 72.1% of patients had active cancer and 23.5% of patients (141/599) were deceased, the majority of which were men (51.7%). This study found that the prognostic factors that reduced the odds of death were gender (OR = 0.42, p = 0.031) and oxygen saturation (OR = 0.90, p = 0.0001); meanwhile, poor ECOG (OR = 5.4, p = 0.0001), active disease (OR = 3.9, p = 0.041), dyspnea (OR = 2.5, p = 0.027), and nausea (OR = 4.0, p = 0.028) increased the odds of death. In the meantime, the factors that reduce survival time were age (HR = 1.36, p = 0.035), COPD (HR = 8.30, p = 0.004), having palliative treatment (HR = 10.70, p = 0.002), and active cancer without treatment (HR = 8.68, p = 0.008).
Conclusion:
Mortality in cancer patients with COVID-19 is determined by prognostic factors whose identification is necessary. In our cancer population, we have observed that being female, younger, non-COPD, with non-active cancer, good performance status, and high oxygen levels reduce the probability of death.
Obesity has been associated with an increased risk of biologically aggressive variants in breast cancer. Women with obesity often have tumors diagnosed at later stages of the disease, associated with ...a poorer prognosis and a different response to treatment. Human cell lines have been derived from specific subtypes of breast cancer and have served to define the cell physiology of corresponding breast cancer subtypes. However, there are no current cell lines for breast cancer specifically derived from patients with different BMIs. The availability of those breast cancer cell lines should allow to describe and unravel functional alterations linked to these comorbidities.
Cell cultures were established from tumor explants. Once generated, the triple negative subtype in a patient with obesity and a patient with a normal BMI were chosen for comparison. For cellular characterization, the following assays were conducted: proliferation assays, chemo - sensitivity assays for doxorubicin and paclitaxel, wound healing motility assays, matrix invasion assays, breast cancer cell growth to estradiol by chronic exposure to leptin, induction of endothelial permeability and tumorigenic potential in athymic mice with normo - versus hypercaloric diets with an evaluation of the epithelium - mesenchymal transformation proteins.
Two different cell lines, were established from patients with breast cancer: DSG-BC1, with a BMI of 21.9 kg/m2 and DSG-BC2, with a BMI of 31.5 kg/m2. In vitro, these two cell lines show differential growth rates, motility, chemosensitivity, vascular permeability, response to leptin with an activation of the JAK2/STAT3/AKT signaling pathway. In vivo, they displayed distinct tumorigenic potential. In particular, DSG-BC2, presented higher tumorigenicity when implanted in mice fed with a hypercaloric diet.
To our knowledge, these primary cultures are the first in vitro representation of both breast cancer and obesity. DSG - BC2 presented a more aggressive in vivo and in vitro phenotype. These results support the hypothesis that breast cancer generated in an obese metabolic state may represent a contrasting variant within the same disease. This new model will allow both further comprehension, functional studies and the analysis of altered molecular mechanisms under the comorbidity of obesity and breast cancer.
Acral melanoma (AM) is the most common melanoma in non-Caucasian populations, yet it remains largely understudied. As AM lacks the UV-radiation mutational signatures that characterize other cutaneous ...melanomas, it is considered devoid of immunogenicity and is rarely included in clinical trials assessing novel immunotherapeutic regimes aiming to recover the antitumor function of immune cells. We studied a Mexican cohort of melanoma patients from the Mexican Institute of Social Security (IMSS) (n = 38) and found an overrepresentation of AM (73.9%). We developed a multiparametric immunofluorescence technique coupled with a machine learning image analysis to evaluate the presence of conventional type 1 dendritic cells (cDC1) and CD8 T cells in the stroma of melanoma, two of the most relevant immune cell types for antitumor responses. We observed that both cell types infiltrate AM at similar and even higher levels than other cutaneous melanomas. Both melanoma types harbored programmed cell death protein 1 (PD-1
) CD8 T cells and PD-1 ligand (PD-L1
) cDC1s. Despite this, CD8 T cells appeared to preserve their effector function and expanding capacity as they expressed interferon-γ (IFN-γ) and KI-67. The density of cDC1s and CD8 T cells significantly decreased in advanced stage III and IV melanomas, supporting these cells' capacity to control tumor progression. These data also argue that AM could respond to anti-PD-1-PD-L1 immunotherapy.
Patients with triple-negative breast cancer (TNBC) have a poor prognosis, partly because of the absence of targeted therapies. Recognition of the key role of immune responses against cancer has ...allowed the advent of immunotherapy, focused on the inhibition of negative immune checkpoints, such as CTLA-4. CTLA-4 is also expressed in some cancer cells, but its activity in tumor cells is not completely understood. Thus, the aim of the present work was to determine the biological landscape and functions of CTLA-4 expressed in TNBC cells through preclinical and
in silico
analysis. Exploration of CTLA-4 by immunohistochemistry in 50 TNBC tumors revealed membrane and cytoplasmic expression at different intensities. Preclinical experiments, using TNBC cell lines, showed that stimulation of CTLA-4 with CD80 enhances activation of the ERK1/2 signaling pathway, while CTLA-4 blockade by Ipilimumab induces the activation of AKT and reduces cell proliferation
in vitro
. We then developed an analytic pipeline to define the effects of CTLA-4 in available public data that allowed us to identify four distinct tumor clusters associated with CTLA-4 activation, which are characterized by enrichment of distinctive pathways associated with cell adhesion, MAPK signaling, TGF-ß, VEGF, TNF-α, drug metabolism, ion and amino acid transport, and KRAS signaling, among others. In addition, blockade of CTLA-4 induced increased secretion of IL-2 by tumor cells, suggesting that the receptor regulates cellular functions that may impact the immune microenvironment. This is relevant because a deep characterization of immune infiltrate, conducted using public data to estimate the abundancies of immune-cell types, showed that CTLA-4-activated-like tumors present a conditional immune state similar to an escape phenotype exploited by cancer cells. Finally, by interrogating transcriptional predictors of immunotherapy response, we defined that CTLA-4 activation correlates with high immune scores related to good clinical predicted responses to anti-CTLA-4 therapy. This work sheds new light on the roles of activated CLTA-4 in the tumor compartment and suggests an important interplay between tumor CLTA-4-activated portraits and immune-infiltrating cell populations.
Oncologic patients with covid 19: A mexican endeavor Daniela Shveid-Gerson; Alejandro Noguez-Ramos; Diana A. Villegas-Osorno ...
Revista medica del hospital general de mexico s.s.a,
10/2021, Letnik:
84, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Introduction: The coronavirus disease 2019 (COVID-19) pandemic is a worldwide challenge. There are few reports regarding its behavior in cancer patients. Materials and methods: Retrospective study ...including cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ABC Medical Center in Mexico City. We include general and oncological variables. We analyzed clinical features and treatment of COVID-19 and its outcomes such as hospitalization and death. Results: We report 86 patients with cancer and SARS-CoV-2 infection. The vast majority of patients 80 (93.1%) had a solid tumor while the most frequent primary tumor was breast 40 (46.5%) and lung 8 (9.3%). The clinical stage of patients was I in 22.1%, II in 16.3%, III in 31.4%, and IV in 24.4%. Antibiotics were used in 37 patients (43%) and corticosteroids in 32 (37.2%). Discussion: During disease evolution, 11 (12.8%) patients were hospitalized and 6 (7.0%) died. Variables of significant association with hospitalization include gender (men, odds ratio OR 5.6), previous cardiac disease (OR 25.1), and hematologic malignancy (OR 8.1). Associations with higher mortality rates were gender (men, OR 15), clinical Stage III/IV cancer (OR 11.3), type 2 diabetes mellitus (OR 14.7), previous cardiac disease (OR 19.2), and targeted therapy (OR 9.0). Conclusions: We found lower hospitalization and mortality rates compared to what had been previously reported both in Mexico around the globe. Men and patients with previous cardiac disease had a significant higher risk of hospitalization and death. Hematologic malignancies (lymphoma) were associated with higher hospitalization. Clinical Stage III/IV, targeted therapy, and type 2 diabetes mellitus showed a statistically significant association with mortality risk.
Introduction: The Coronavirus disease (COVID-19) pandemic is a worldwide challenge. There are few useful tools to predict patient outcomes. Identification of biomarkers able to predict progression of ...the disease could improve the treatment of these patients. Objective: The objective of the study was to identify biomarkers of disease progression among patients with severe COVID-19 pneumonia. Materials and methods: A retrospective cohort study was conducted among severe COVID-19 pneumonia patients hospitalized in the American British Cowdray Medical Center in Mexico City. Disease progression was defined as use of vasoactive amines, need of non-invasive or invasive mechanical ventilation or death. Studied biomarkers included neutrophil/lymphocyte index, lymphocyte/platelet Ratio, C reactive protein, procalcitonin, D Dimer, lactic dehydrogenase (LDH), ferritin, 25–OH–Vitamin D, and interleukin 6. Results: We report 46 patients with severe COVID-19 pneumonia. Mean age was 51 years, the majority of whom 30 (65%) male. Median hospitalization was 9 days. 23 (50%) of patients presented disease progression. Ferritin and LDH were strongly associated with disease progression among our cohort. In addition, age was associated with worst prognosis with a relative risk 4.5 (1.2-16.9, p = 0.003). Conclusions: Age, ferritin, and LDH were associated with disease progression among patients with severe COVID-19 pneumonia.
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