Standard cancer therapies sometimes fail to deliver chemotherapeutic drugs to tumor cells in a safe and effective manner.
Nanotechnology takes the lead in providing new therapeutic options for cancer ...due to major potential for selective targeting and controlled drug release. Antibodies and antibody fragments are attracting much attention as a source of targeting ligands to bind specific receptors that are overexpressed on cancer cells.
Therefore, researchers are devoting time and effort to develop targeting strategies based on nanoparticles functionalized with antibodies, which hold great promise to enhance therapeutic efficacy and circumvent severe side effects.
Several methods have been described to immobilize antibodies on the surface of nanoparticles. However, selecting the most appropriate for each application is challenging but also imperative to preserve antigen binding ability and yield stable antibody-conjugated nanoparticles.
From this perspective, we aim to provide considerable knowledge on the most widely used methods of functionalization that can be helpful for decision-making and design of conjugation protocols as well. This review summarizes adsorption, covalent conjugation (carbodiimide, maleimide and “click” chemistries) and biotin-avidin interaction, while discussing the advantages, limitations and relevant therapeutic approaches currently under investigation.
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•Tumor targeting is promising to address some drawbacks of conventional chemotherapy.•Antibody-conjugated nanoparticles favor a safe and effective drug delivery to tumor.•Immobilization of antibodies should be well-oriented and keep biological activity.•Functionalization of nanoparticles includes covalent and non-covalent methods.•The ideal conjugation method allows a site-specific reaction and a stable coupling.
Objective: To estimate the prevalence of metabolically healthy obesity (MHO) according to different definitions. Methods: Population-based sample of 2803 women and 2557 men participated in the study. ...Metabolic abnormalities were defined using six sets of criteria, which included different combinations of the following: waist; blood pressure; total, high-density lipoprotein or low-density lipoprotein-cholesterol; triglycerides; fasting glucose; homeostasis model assessment; high-sensitivity C-reactive protein; personal history of cardiovascular, respiratory or metabolic diseases. For each set, prevalence of MHO was assessed for body mass index (BMI); waist or percent body fat. Results: Among obese (BMI >or=30 kg/m2) participants, prevalence of MHO ranged between 3.3 and 32.1% in men and between 11.4 and 43.3% in women according to the criteria used. Using abdominal obesity, prevalence of MHO ranged between 5.7 and 36.7% (men) and 12.2 and 57.5% (women). Using percent body fat led to a prevalence of MHO ranging between 6.4 and 43.1% (men) and 12.0 and 55.5% (women). MHO participants had a lower odd of presenting a family history of type 2 diabetes. After multivariate adjustment, the odds of presenting with MHO decreased with increasing age, whereas no relationship was found with gender, alcohol consumption or tobacco smoking using most sets of criteria. Physical activity was positively related, whereas increased waist was negatively related with BMI-defined MHO. Conclusion: MHO prevalence varies considerably according to the criteria used, underscoring the need for a standard definition of this metabolic entity. Physical activity increases the likelihood of presenting with MHO, and MHO is associated with a lower prevalence of family history of type 2 diabetes.
In sporadic colorectal cancer (CRC), KRAS are alternative to BRAF mutations and occur, respectively, in 30 and 10% of cases. Few reports addressed the association between KRAS-BRAF mutations and ...tumour progression specifically in sporadic microsatellite-stable (MSS) CRC. We screened KRAS and BRAF in 250 MSS primary CRC and 45 lymph node (LN) metastases and analysed the pathological features of the cases to understand the involvement of KRAS-BRAF activation in progression and metastasis. Forty-five per cent of primary MSS CRCs carried mutations in at least one of these genes and mutations were associated with wall invasion (P=0.02), presence and number of LN metastases (P=0.02 and P=0.03, respectively), distant metastases (P=0.004) and advanced stage (P=0.01). We demonstrated that KRAS and BRAF are alternative events in Tis and T1 MSS CRC and, KRAS rather than BRAF mutations, contributed to the progression of MSS CRC. The frequency of KRAS and/or BRAF mutations was higher in LN metastases than in primary carcinomas (P=0.0002). Mutated LN metastases displayed KRAS associated or not with BRAF mutations. BRAF mutations were never present as a single event. Concomitant KRAS and BRAF mutations increased along progression of MSS CRCs, suggesting that activation of both genes is likely to harbour a synergistic effect.
Cancers are complex tissues composed by genetically altered cancer cells and stromal elements such as inflammatory/immune cells, fibroblasts, endothelial cells and pericytes, neuronal cells, and a ...non-cellular component, the extracellular matrix. The complex network of interactions and crosstalk established between cancer cells and the supportig cellular and non-cellular components of the microenvironment are of extreme importance for tumor initiation and progression, strongly impacting the course and the outcome of the disease. Therefore, a better understanding of the tumorigenic processes implies the combined study of the cancer cell and the biologic, chemical and mechanic constituents of the tumor microenvironment, as their concerted action plays a major role in the carcinogenic pathway and is a key determinant of the efficacy of anti-cancer treatments. The use of animal models (e.g. Mouse, Zebrafish and Drosophila) to study cancer has greatly impacted our understanding of the processes governing initiation, progression and metastasis and allowed the discovery and pre-clinical validation of novel cancer treatments as it allows to recreate tumor development in a more pathophysiologic environment.
Objective The aim of this study was to cross-culturally adapt and validate the Brazilian Portuguese version of SCI-R to adults with type 2 diabetes. Materials and methods The SCI-R is a 15-question ...survey that reflects how well patients with diabetes have adhered to treatment recommendations. A pretest (n = 40) was first performed to improve comprehension of the survey items. A final version was then self-administered in another 75 adults with type 2 diabetes to determine the survey's reliability and validity according to its association with HbA1c. Finally, we conducted a test-retest reliability analysis over three weeks to stabilize the sample and determine intra-observer variability. Results After the pretest phase, the final sample's (N = 75) mean age was 59.9 ± 7.5 years and mean HbA1c level was 8.6 ± 1.5% (70 ± 16.4 mmol/mol). The initial Cronbach's alpha was 0.61; however, further analysis showed that four items had low item correlation and were excluded from the final version, which increased the Cronbach's alpha to 0.63. In predictive validity analysis, HbA1c levels correlated significantly with total survey scores (r = -0.38, P = 0.001). The intra-class correlation coefficient between baseline and three-week scores was 0.93, which indicates high reproducibility. Conclusions The Brazilian Portuguese version of the SCI-R is a valid tool for measuring treatment adherence in adults with type 2 diabetes.
IntroductionKRAS is the most frequently mutated oncogene in colorectal cancer (CRC), being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of ...non-response to anti-EGFR therapies. As such, extensive research has been done to exploit KRAS and its downstream signalling effectors as therapeutic targets. However, KRAS proved difficult to target, and inhibition of its signalling effectors has never resulted in significant clinical responses, highlighting the need for a better understanding of KRAS-associated signals. Since the tumour microenvironment plays a key role in tumour aggressiveness, research on this area became an attractive alternative as new targets for therapy may arise from the study of cancer cell-microenvironment crosstalk. The aim of this study was to characterise, at the molecular and functional levels, the role of mutant KRAS in mediating CRC cells-fibroblasts crosstalk.Material and methodsUsing fibroblasts-conditioned media (CM) as a chemoattractant, we performed matrigel invasion assays with KRAS mutant CRC cell lines in which we silenced KRAS using siRNA. Additionally, we performed ELISA assays to quantify the levels of fibroblasts-secreted factors and resorting to western blot we evaluated the expression of some cell surface proteins.Results and discussionsBy performing in vitro invasion assays we observed that the CM promoted CRC cell invasion in a KRAS-dependent manner. Analysis of the CM for the detection of pro-invasive factors, revealed the presence of high levels of HGF. Accordingly, neutralisation of HGF in the fibroblasts CM abrogated CRC invasion, and supplementation of control CM with HGF induced invasion in a KRAS-dependent manner. Additionally, we have also observed that KRAS regulates the expression of HGF receptor, C-MET, along with other C-MET co-receptors.ConclusionIn conclusion, our results show that KRAS may be an important modulator of response to fibroblasts-secreted factors that induce CRC cells invasion. Therefore, this work suggests that targeting of C-MET can be a useful tool to abrogate invasion of KRAS mutant tumours and sets a rational to test C-MET inhibitors in the treatment of KRAS mutant CRC patients, who currently lack effective therapeutic options.
To assess the distribution of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein (CRP) according to the different definitions of metabolically healthy obesity (MHO).
A ...total of 881 obese (body mass index (BMI) > or =30 kg/m2) subjects derived from the population-based CoLaus Study participated in this study. MHO was defined using six sets of criteria including different combinations of waist, blood pressure, total high-density lipoprotein cholesterol or low-density lipoprotein -cholesterol, triglycerides, fasting glucose, homeostasis model, high-sensitivity CRP, and personal history of cardiovascular, respiratory or metabolic diseases. IL-1β, IL-6 and TNF-α were assessed by multiplexed flow cytometric assay. CRP was assessed by immunoassay.
On bivariate analysis some, but not all, definitions of MHO led to significantly lower levels of IL-6, TNF-α and CRP compared with non-MH obese subjects. Most of these differences became nonsignificant after multivariate analysis. An posteriori analysis showed a statistical power between 9 and 79%, depending on the inflammatory biomarker and MHO definition considered. Further increasing sample size to overweight+obese individuals (BMI > or =25 kg/m2, n=2917) showed metabolically healthy status to be significantly associated with lower levels of CRP, while no association was found for IL-1β. Significantly lower IL-6 and TNF-α levels were also found with some but not all MHO definitions, the differences in IL-6 becoming nonsignificant after adjusting for abdominal obesity or percent body fat.
MHO individuals present with decreased levels of CRP and, depending on MHO definition, also with decreased levels in IL-6 and TNF-α. Conversely, no association with IL-1β levels was found.
BACKGROUND AND AIMPreoperative biliary drainage (PBD) in patients with pancreatic cancer remains debatable. The aim of this study was to analyse the indications for PBD in patients performing ...pancreaticoduodenectomy (PD) and to evaluate the impact of this procedure on postoperative outcome. METHODSObservational retrospective cohort study of patients undergoing PD for pancreatic cancer. Clinical data and postoperative outcome, namely complications and 90-day mortality, were prospectively collected and compared between patients performing PBD or direct surgery (DS). RESULTSEighty-two patients were included: 40 underwent PBD and 42 performed DS. Major complications (27.5% vs 33.3%, P=0.156) and 90-day mortality (10% vs 16.7%, P=0.376) were similar between the two groups. There was a trend for higher mean total bilirubin in patients with PBD (P=0.073). The indication for PBD was suspicion of cholangitis/choledocholithiasis or need to perform neoadjuvant chemotherapy in 24 (60%) patients. In the remaining, elevated bilirubin was probably the only reason to perform PBD. Length of hospital stay was longer in PBD group (P=0.003). On multiple logistic regression, 90-day mortality was not related with preoperative bilirubin levels, biliary drainage or its indication, but solely with age (OR 1.15, 95%CI 1.05-1.31, P=0.008). CONCLUSIONSPBD is often performed in patients undergoing PD without a formal indication, mainly due to high bilirubin levels. No increased morbidity/mortality was observed but length of hospital stay was prolonged in patients performing PBD.
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