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Simple Summary: Nanoparticle radiosensitizers can be used to increase the efficacy of radiotherapy. In this work a multiscale computational model has been developed to assess the distribution of nanoparticles during and after intratumoural injection into a realistic tumour. The aim of the study is to assess how particle surface charge and injection location can affect the distribution of nanoparticles within the tumour, with the optimal result being a uniform concentration across the tumour. This work aims to aid the development of radiosensitizers and guide clinical trials. Radiosensitizers have proven to be an effective method of improving radiotherapy outcomes, with the distribution of particles being a crucial element to delivering optimal treatment outcomes due to the short range of effect of these particles. Here we present a computational model for the transport of nanoparticles within the tumour, whereby the fluid velocity and particle deposition are obtained and used as input into the convection-diffusion equation to calculate the spatio-temporal concentration of the nanoparticles. The effect of particle surface charge and injection locations on the distribution of nanoparticle concentration within the interstitial fluid and deposited onto cell surfaces is assessed. The computational results demonstrate that negatively charged particles can achieve a more uniform distribution throughout the tumour as compared to uncharged or positively charged particles, with particle volume within the fluid being 100% of tumour volume and deposited particle volume 44.5%. In addition, varying the injection location from the end to the middle of the tumour caused a reduction in particle volume of almost 20% for negatively charged particles. In conclusion, radiosensitizing particles should be negatively charged to maximise their spread and penetration within the tumour. Choosing an appropriate injection location can further improve the distribution of these particles. [ABSTRACT FROM AUTHOR]

Radio-sensitizing nanoparticles are a potential method to increase the damage caused to cancerous cells during the course of radiotherapy. The distribution of these particles in a given targeted tumour is a relevant factor in determining the efficacy of nanoparticle-enhanced treatment. In this study, a three-part mathematical model is shown to predict the distribution of nanoparticles after direct injection into a tumour. In contrast with previous studies, here, a higher value of diffusivity for charged particles was used and the concentration profile of deposited particles was studied. Simulation results for particle concentrations both in the interstitial fluid and deposited onto cells are compared for different values of particle surface charges during and after injection. Our results show that particles with a negative surface charge can spread farther from the injection location as compared to uncharged particles with charged particles occupying 100% of the tumour volume compared to 8.8% for uncharged particles. This has implications for the future development of radiosensitizers and any associated trials. [ABSTRACT FROM AUTHOR]

Background. Targeted treatments have been incorporated into oncology protocols, often with more traditional therapies, and are not totally free of adverse reactions, some of which affect the orofacial region. Methods. The authors searched PubMed, the Cochrane Library, and the US Food and Drug Administration Approved Drug Products database to identify reported adverse effects of targeted agents in the orofacial region as well as other implications in oral health care. Their principal focus was the relatively newer category of molecularly targeted drugs which are called small molecules (SMs). Results. The authors identified several categories of SMs and biological agents (for example, monoclonal antibodies) with adverse effects in the orofacial region. The oral and perioral regions are also fields for which there are therapeutic applications for targeted therapies, particularly to treat malignant neoplasms such as head and neck cancers. Conclusions. SMs are the most rapidly growing group of targeted cancer treatments. Patients receiving SMs and other targeted antineoplastic agents may require oral medicine advice and special-care dentistry. Practical Implications. In this narrative review, the authors focus mainly on the orofacial adverse effects of targeted cancer therapies and outline many of the agents that are in use so the dentally focused reader can familiarize themselves with these adverse effects and agents. [ABSTRACT FROM AUTHOR]

The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) may function as suppressors or promoters of tumor metastasis according to their messenger RNA targets. Previous studies have suggested that miR-9 and miR-151-5p are associated with metastasis in breast cancer and hepatocellular carcinoma, respectively. We aimed to further establish the potential roles of miR-9 and miR-151-5p in tumor invasion and metastasis and investigate their use as biomarkers. Methods: We used quantitative real-time PCR (qRT-PCR) to measure differences in miR-9 and miR-151-5p expression between primary breast tumors and their lymph-node metastases in 194 paired tumor samples from 97 patients. We also correlated expression levels with histologic data to investigate their utility as biomarkers. Results: There were no significant differences in miR-9 expression between the primary tumors and lymph nodes; however, miR-151-5p expression was significantly lower in the lymph-node metastases than in their corresponding tumors (p < 0.05). miR-9 levels were elevated in primary breast tumors from patients diagnosed with higher-grade tumors (p < 0.05); however, no differences were observed in miR-151-5p levels between different grades of tumor. Interestingly, miR-9 levels were elevated in invasive lobular carcinomas (ILC) compared with invasive ductal carcinomas (IDC; p < 0.01). Conclusions: In aggregate, these data suggest that miR-151-5p upregulation may suppress metastasis in primary breast tumors. Both miRNAs may serve as useful biomarkers in future clinical trials in breast cancer. [ABSTRACT FROM AUTHOR]

Background: MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and highmalignant potential with PDAC, in order to identifymiRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. Methods: Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. Results: Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 39UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. Conclusions: Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers. [ABSTRACT FROM AUTHOR]

The article focuses on a case study that was conducted to determine whether CDKN1C methylation is a frequent event in myeloid leukemia and plasma cell neoplasms. Thirty-six multiple myeloma (MM) patients were included in the study. The Durie-Salmon staging system and the International Prognostic Index (IPI) were used for clinical and prognostic discrimination of patients. The study showed that CDKN1C methylation is not a frequent event in myeloid and plasma cell neoplasms.

Abstract Background The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. Methods In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV aggressive , those with < 5 CTCs as Stage IV indolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. Results For all patients, Stage IV indolent patients had longer median overall survival than those with Stage IV aggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV indolent vs. 18.7 months Stage IV aggressive , p < 0.0001). Moreover, patients with Stage IV indolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. Conclusions We confirm the identification of two subgroups of MBC, Stage IV indolent and Stage IV aggressive , independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Personalised strategies in cancer care are required to overcome the therapeutic challenges posed by variability between patients and disease subsets. To this end, enhanced precision tools must be developed to describe the molecular drivers of malignant proliferation. Such tools must also identify druggable targets and biomarkers in order to provide essential information regarding drug development and therapeutic outcome. Here we discuss how proteomics-based approaches provide a set of viable methodologies capable of delivering quantitative information throughout the main stages of personalised oncology and a ratiometric platform that delivers systems-wide methods for drug evaluation. [ABSTRACT FROM AUTHOR]

Biomarkers in breast cancer to monitor minimal residual disease have remained elusive. We hypothesized that genomic analysis of circulating free DNA (cfDNA) isolated from plasma may form the basis for a means of detecting and monitoring breast cancer. We profiled 251 genomes using Affymetrix SNP 6.0 arrays to determine copy number variations (CNVs) and loss of heterozygosity (LOH), comparing 138 cfDNA samples with matched primary tumor and normal leukocyte DNA in 65 breast cancer patients and eight healthy female controls. Concordance of SNP genotype calls in paired cfDNA and leukocyte DNA samples distinguished between breast cancer patients and healthy female controls (P < 0.0001) and between preoperative patients and patients on follow-up who had surgery and treatment (P = 0.0016). Principal component analyses of cfDNA SNP/copy number results also separated presurgical breast cancer patients from the healthy controls, suggesting specific CNVs in cfDNA have clinical significance. We identified focal high-level DNA amplification in paired tumor and cfDNA clustered in a number of chromosome arms, some of which harbor genes with oncogenic potential, including USP17L2 (DUB3), BRF1, MTA1, and JAG2. Remarkably, in 50 patients on follow-up, specific CNVs were detected in cfDNA, mirroring the primary tumor, up to 12 yr after diagnosis despite no other evidence of disease. These data demonstrate the potential of SNP/CNV analysis of cfDNA to distinguish between patients with breast cancer and healthy controls during routine follow-up. The genomic profiles of cfDNA infer dormancy/minimal residual disease in the majority of patients on followup. [ABSTRACT FROM AUTHOR]