Obesity is nowadays considered a pandemic which prevalence’s has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules (adipokines, cytokines, hormones), responsible for altering the metabolic, inflammatory, and immune landscape. The crosstalk between adipocytes and tumor cells fuels the tumor microenvironment with pro-inflammatory factors, promoting tissue injury, mutagenesis, invasion, and metastasis. Although classically established as a risk factor for cancer and treatment toxicity, recent evidence suggests mild obesity is related to better outcomes, with obese cancer patients showing better responses to treatment when compared to lean cancer patients. This phenomenon is termed obesity paradox and has been reported in different types and stages of cancer. The mechanisms underlying this paradoxical relationship between obesity and cancer are still not fully described but point to systemic alterations in metabolic fitness and modulation of the tumor microenvironment by obesity-associated molecules. Obesity impacts the response to cancer treatments, such as chemotherapy and immunotherapy, and has been reported as having a positive association with immune checkpoint therapy. In this review, we discuss obesity’s association to inflammation and cancer, also highlighting potential physiological and biological mechanisms underlying this association, hoping to clarify the existence and impact of obesity paradox in cancer development and treatment.
The enzyme cyclooxygenase 2 (COX-2) is known to be involved in tumorigenesis and metastasis in certain types of cancer. Nevertheless, the prognostic value of COX-2 overexpression and its polymorphisms in patients with non-small cell lung cancer (NSCLC) have yet to be fully elucidated. The aim of the present study was to investigate the association between the three most commonly studied COX-2 gene polymorphisms (−1195 G/A, −765 G/C and 8473 T/C) with COX-2 expression and lung cancer risk in a Brazilian cohort. In the present hospital based, case-control retrospective study, 104 patients with NSCLC and 202 cancer free control subjects were genotyped for −1195 G/A, −765 G/C and 8473 T/C polymorphisms using allelic discrimination with a reverse transcription quantitative polymerase chain reaction method. COX-2 mRNA expression was analyzed in surgically resected tumors from 34 patients with NSCLC. The results revealed that COX-2 expression levels were higher in tumor tissue compared with normal lung tissue. However, this overexpression of COX-2 was not associated with the patient outcome, and furthermore, none of the analyzed polymorphisms were associated with the risk of developing lung cancer, COX-2 overexpression, or the overall survival of the patients with NSCLC. Taken together, the findings described in the present study do not support a major role for COX-2 polymorphisms and COX-2 overexpression in lung carcinogenesis within the Brazilian population.
This work aims to evaluate the biosimilar and biobetters of rituximab developed in Bio-Manguinhos regarding their ability to bind to the CD20 antigen and the in vitro biological activity. Methodology: Through flow cytometry assays it was possible to analyze the binding properties of the constructs to the CD20 antigen on the surface of leukemia cells (K562 CD20+) and the presence of NKG2DL in the constructs. Potential ADCC and CDC were evaluated using the CytoTox96 kit, a non-radioactive cytotoxicity colorimetric assay capable of measuring the lactate dehydrogenase in the medium, and NK cells expanded in vitro as effector cells. Results: Flow cytometry assays have demonstrated that the constructs produced in Bio-Manguinhos are capable of binding to CD20+ cells and that NKG2DLs are present in the biobetters constructs. ADCC and CDC assays demonstrated that the presence of NKG2DLs in the constructs improved the in vitro biological activity of the mAb, evidencing a higher percentage of cell lysis of the biobetter when compared to the biosimilar and rituximab (MabThera) antibodies. Conclusion: The conclusion is that the antibodies developed are capable of binding to CD20 expressing cells and the biobetters presented improved biological activity in vitro when compared to the biosimilar and reference rituximab, suggesting that the addition of the NK-cell ligand to the anti-CD20 mAb may enhance the therapeutic efficacy of rituximab and other therapeutic antibodies. To reinforce this hypothesis, we have established an in vivo model consisting in xenografts of CD20+ the human lymphoma cell line (RAJI) in immunodeficient mice. The immunodeficient animals will be treated with primary human NK cells and/or the mAbs of interest to evaluate the in vivo enhancing function of the new conformations of the anti CD20 mAbs.
The global cancer data released by the GLOBOCAN database showed 18.3 million new cases in 2018. About 440,000 of these cases correspond to leukemia, a cancer that urges for treatment modalities. Recently, CAR T-cell immunotherapy was approved for the treatment of acute B cell leukemias (B-ALL) and some lymphomas with promising results. However, the major drawbacks of CART treatments are the high costs, being prohibitive for many of the patients. We developed an alternative low-cost approach to gene modify T cells to express CAR using the Sleeping Beauty (SB) system and electroporation. In addition, we show that it is not necessary to activate or expand T cells ex vivo when using this system, an aspect that renders this approach to a point-of-care (POC) strategy. Objective: The objective of this present study is to demonstrate that the POC strategy is efficient in NSG animals xenografted with human leukemia when treated with the POC CART cells. Methodology: Peripheral blood mononuclear cells were isolated using Ficoll and electroporated using the Nucleofector II combined with plasmids enconding 19BBz CAR (in the pT3 SB transposon backbone) and the SB100x transposase. The phenotype was assessed by flow cytometry. The in vitro cytotoxicity assay was performed using Calcein-AM dye on target cells incubated with different ratios of effector cells. 8-12-week-old-female-NSG were injected iv. 5x10 6 RS4;11 GFP and after 3 days were treated with different doses of recently electroporated CART cells. All animal procedures were approved by the Animal Ethics Committee. Results: The expression of CAR on the first day (d+1) was about 5%-15%. In addition, cell lysis assays against RS4;11 and Nalm-6 on d+1 showed no potential to eliminate the target cells in vitro, as expected. The in vivo experiments were performed with NSG mice engrafted with RS4;11 BALL cells followed by T cell injection 3 days later. Animals treated with 10 7 CART cells (expression of approximately 10% of 19BBz) provided 100% survival when comparing the control and mock (electroporated without plasmids) group. The mock treated group has the ability to eliminate leukemia cells from the peripheral blood and showed better survival as compared to untreated control group. We were able to show a survival improvement even using reduced doses of lymphocytes, such as 10 6 or 10 5. Furthermore, we compared the same donor using the POC approach and expansion of CART cells with anti-CD3/28 for 12 days (clinical methodology nowadays), and the results showed similar, indicating that the POC approach is interchangeable with the labor and cost-intensive expansion protocol. Conclusion: This methodology proved effective in the animal model and is much cheaper when compared to the approved clinical approach for the use of CAR T cells. This aspect could grant greater access of patients to this very promising treatment strategy.
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