Glycosylation of cancer extracellular vesicles: Capture strategies, functional roles and potential clinical applications

Glycans are major constituents of extracellular vesicles (EVs). Alterations in the glycosylation pathway are a common feature of cancer cells, which gives rise to de novo or increased synthesis of particular glycans. Therefore, glycans and glycoproteins have been widely used in the clinic as both stratification and prognosis cancer biomarkers. Interestingly, several of the known tumor-associated glycans have already been identified in cancer EVs, highlighting EV glycosylation as a potential source of circulating cancer biomarkers. These particles are crucial vehicles of cell–cell communication, being able to transfer molecular information and to modulate the recipient cell behavior. The presence of particular glycoconjugates has been described to be important for EV protein sorting, uptake and organ-tropism. Furthermore, specific EV glycans or glycoproteins have been described to be able to distinguish tumor EVs from benign EVs. In this review, the application of EV glycosylation in the development of novel EV detection and capture methodologies is discussed. In addition, we highlight the potential of EV glycosylation in the clinical setting for both cancer biomarker discovery and EV therapeutic delivery strategies.This work was funded by FEDER funds through the Operational Programme for Competitiveness Factors COMPETE 2020 (POCI-01-0145-FEDER-016585; POCI-01-0145-FEDER-007274) and national funds through the Foundation for Science and Technology (FCT), under the projects:PTDC/BBB-EBI/0567/2014 to C.A.R and UID/BIM/04293/2013; and the project NORTE-01-0145-FEDER-000029, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Bone mechanical stimulation with piezoelectric materials

This chapter summarized explores in vivo use of a piezoelectric polymer for bone mechanical stimulatio

Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Pancreatic ductal adenocarcinoma (PDAC) is known by its aggressiveness and lack of effective therapeutic options. Thus, improvement in current knowledge of molecular changes associated with pancreatic cancer is urgently needed to explore novel venues of diagnostics and treatment of this dismal disease. While there is mounting evidence that long noncoding RNAs (lncRNAs) transcribed from intronic and intergenic regions of the human genome may play different roles in the regulation of gene expression in normal and cancer cells, their expression pattern and biological relevance in pancreatic cancer is currently unknown. In the present work we investigated the relative abundance of a collection of lncRNAs in patients' pancreatic tissue samples aiming at identifying gene expression profiles correlated to pancreatic cancer and metastasis.</p> <p>Methods</p> <p>Custom 3,355-element spotted cDNA microarray interrogating protein-coding genes and putative lncRNA were used to obtain expression profiles from 38 clinical samples of tumor and non-tumor pancreatic tissues. Bioinformatics analyses were performed to characterize structure and conservation of lncRNAs expressed in pancreatic tissues, as well as to identify expression signatures correlated to tissue histology. Strand-specific reverse transcription followed by PCR and qRT-PCR were employed to determine strandedness of lncRNAs and to validate microarray results, respectively.</p> <p>Results</p> <p>We show that subsets of intronic/intergenic lncRNAs are expressed across tumor and non-tumor pancreatic tissue samples. Enrichment of promoter-associated chromatin marks and over-representation of conserved DNA elements and stable secondary structure predictions suggest that these transcripts are generated from independent transcriptional units and that at least a fraction is under evolutionary selection, and thus potentially functional.</p> <p>Statistically significant expression signatures comprising protein-coding mRNAs and lncRNAs that correlate to PDAC or to pancreatic cancer metastasis were identified. Interestingly, <it>loci </it>harboring intronic lncRNAs differentially expressed in PDAC metastases were enriched in genes associated to the MAPK pathway. Orientation-specific RT-PCR documented that intronic transcripts are expressed in sense, antisense or both orientations relative to protein-coding mRNAs. Differential expression of a subset of intronic lncRNAs (<it>PPP3CB</it>, <it>MAP3K14 </it>and <it>DAPK1 loci</it>) in metastatic samples was confirmed by Real-Time PCR.</p> <p>Conclusion</p> <p>Our findings reveal sets of intronic lncRNAs expressed in pancreatic tissues whose abundance is correlated to PDAC or metastasis, thus pointing to the potential relevance of this class of transcripts in biological processes related to malignant transformation and metastasis in pancreatic cancer.</p

Myocardial infarction risk and tamoxifen therapy for breast cancer

Tamoxifen prevents recurrence after breast cancer and breast cancer among high-risk women, and may prevent myocardial infarction (MI). To assess the impact of tamoxifen on MI risk, we conducted a case–control study of first MI after breast cancer nested among women diagnosed with breast cancer, while enrolled in a health maintenance organisation from 1980 to 2000. We obtained information on breast cancer treatment and MI risk factors through medical record reviews and interviews. Data were analysed using conditional logistic regression. Of 11 045 women with breast cancer, 134 met MI criteria and were matched to two MI-free control subjects on year of birth and breast cancer diagnosis. After adjusting for smoking, hypertension and diabetes, tamoxifen was unassociated with MI (odds ratio (OR)=1.2, 95% confidence interval (CI)=0.7–1.9). Duration, cumulative dose and recency of use were not associated with MI. Radiation therapy was associated with MI (OR=2.0, 95% CI=1.1–3.5), an association that varied slightly but not statistically significantly by tamoxifen use (radiation with tamoxifen, OR=2.0, 95% CI=0.9–4.4; radiation without tamoxifen, OR=2.9, 95% CI=1.2–7.5). Tamoxifen treatment for breast cancer does not appear to increase or decrease MI risk, although radiation therapy appears to increase MI risk

Can "presumed consent" justify the duty to treat infectious diseases? An analysis

<p>Abstract</p> <p>Background</p> <p>AIDS, SARS, and the recent epidemics of the avian-flu have all served to remind us the debate over the limits of the moral duty to care. It is important to first consider the question of whether or not the "duty to treat" might be subject to contextual constraints. The purpose of this study was to investigate the opinions and beliefs held by both physicians and dentists regarding the occupational risks of infectious diseases, and to analyze the argument that the notion of "presumed consent" on the part of professionals may be grounds for supporting the duty to treat.</p> <p>Methods</p> <p>For this cross-sectional survey, the study population was selected from among physicians and dentists in Ankara. All of the 373 participants were given a self-administered questionnaire.</p> <p>Results</p> <p>In total, 79.6% of the participants said that they either had some degree of knowledge about the risks when they chose their profession or that they learned of the risks later during their education and training. Of the participants, 5.2% said that they would not have chosen this profession if they had been informed of the risks. It was found that 57% of the participants believed that there is a standard level of risk, and 52% of the participants stated that certain diseases would exceed the level of acceptable risk unless specific protective measures were implemented.</p> <p>Conclusion</p> <p>If we use the presumed consent argument to establish the duty of the HCW to provide care, we are confronted with problems ranging over the difficulty of choosing a profession autonomously, the constant level of uncertainty present in the medical profession, the near-impossibility of being able to evaluate retrospectively whether every individual was informed, and the seemingly inescapable problem that this practice would legitimize, and perhaps even foster, discrimination against patients with certain diseases. Our findings suggest that another problem can be added to the list: one-fifth of the participants in this study either lacked adequate knowledge of the occupational risks when they chose the medical profession or were not sufficiently informed of these risks during their faculty education and training. Furthermore, in terms of the moral duty to provide care, it seems that most HCWs are more concerned about the availability of protective measures than about whether they had been informed of a particular risk beforehand. For all these reasons, the presumed consent argument is not persuasive enough, and cannot be used to justify the duty to provide care. It is therefore more useful to emphasize justifications other than presumed consent when defining the duty of HCWs to provide care, such as the social contract between society and the medical profession and the fact that HCWs have a greater ability to provide medical aid.</p

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

The metabolic microenvironment of melanomas: prognostic value of MCT1 and MCT4

BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.This work was supported by FAPESP grant to VLV (2012/04194-1) and CP (2015/25351-6). VMG received a doctoral fellowship (SFRH/BD/51997/2012) from Fundacao para a Ciencia e a Tecnologia (FCT) and ON. 2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000017) co-funded by Programa Operacional Regional do Norte (ON.2- O Novo Norte), Quadro de Referencia Estrategico Nacional (QREN), through Fundo Europeu de Desenvolvimento Regional (FEDER).info:eu-repo/semantics/publishedVersio