Folate-Functionalization Enhances Cytotoxicity of Multivalent DNA Nanocages on Triple-Negative Breast Cancer Cells

DNA is an excellent programmable polymer for the generation of self-assembled multivalent nanostructures useful for biomedical applications. Herein, we developed (i) folate-functionalized nanocages (Fol-NC), very efficiently internalized by tumor cells overexpressing the alpha isoform of the folate receptor; (ii) AS1411-linked nanocages (Apt-NC), internalized through nucleolin, a protein overexpressed in the cell surface of many types of cancers; and (iii) nanostructures that harbor both folate and AS1411 aptamer functionalization (Fol-Apt-NC). We analyzed the specific miRNA silencing activity of all types of nanostructures harboring miRNA sequestering sequences complementary to miR-21 and the cytotoxic effect when loaded with doxorubicin in a drug-resistant triple-negative breast cancer cell line. We demonstrate that the presence of folate as a targeting ligand increases the efficiency in miR-21 silencing compared to nanocages functionalized with AS1411. Double-functionalized nanocages (Fol-Apt-NC), loaded with doxorubicin, resulted in an increase of over 51% of the cytotoxic effect on MDA-MB-231 cells compared to free doxorubicin, demonstrating, besides selectivity, the ability of nanocages to overcome Dox chemoresistance. The higher efficiency of the folate-functionalized nanocages is due to the way of entrance, which induces more than four times higher intracellular stability and indicates that the folate-mediated route of cell entry is more efficient than the nucleolin-mediated one when both folate and AS1411 modifications are present

Is panoramic radiography really a key examination before chemo-radiotherapy treatment for oropharyngeal cancer?

Aim: To evaluate the diagnostic accuracy of panoramic radiography (PAN) for the identification of infectious foci of the tooth and periradicular bone before definitive chemo-radiotherapy treatment for oropharyngeal cancer, using multislice spiral computed tomography (MSCT) imaging as the reference standard. Materials and methods: 50 patients with oropharyngeal cancer who had performed both pre-treatment MSCT and PAN were retrospectively evaluated. Pre-radiotherapy MSCT showed 65 deep caries, 37 root remnants, 143 stage III periodontal diseases, and 77 apical periodontitis, for a total of 322 infectious foci. The same number of healthy teeth (control group) was selected via MSCT to be analysed by PAN. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy for PAN images with respect to MSCT imaging were examined. Results: PAN showed sensitivity, negative predictive value, and diagnostic accuracy of 100% for deep caries, root remnants, and stage III periodontal disease, whereas there were 46.8%, 64.7%, and 72.1% apical periodontitis respectively. Conclusions: PAN did not show great diagnostic accuracy in the assessment of apical periodontitis, and therefore maxillofacial MSCT carried out before chemo-radiotherapy treatment should always be examined to identify dental and jaw diseases. Deep caries, root remnants, and stage III periodontal disease were perfectly detected on PAN

Intestinal Taxa Abundance and Diversity in Inflammatory Bowel Disease Patients: An Analysis including Covariates and Confounders

Intestinal dysbiosis has been widely documented in inflammatory bowel diseases (IBDs) and is thought to influence the onset and perpetuation of gut inflammation. However, it remains unclear whether such bacterial changes rely in part on the modification of an IBD-associated lifestyle (e.g., smoking and physical activity) and diet (e.g., rich in dairy products, cereals, meat and vegetables). In this study, we investigated the impact of these habits, which we defined as confounders and covariates, on the modulation of intestinal taxa abundance and diversity in IBD patients. 16S rRNA gene sequence analysis was performed using genomic DNA extracted from the faecal samples of 52 patients with Crohn's disease (CD) and 58 with ulcerative colitis (UC), which are the two main types of IBD, as well as 42 healthy controls (HC). A reduced microbial diversity was documented in the IBD patients compared with the HC. Moreover, we identified specific confounders and covariates that influenced the association between some bacterial taxa and disease extent (in UC patients) or behaviour (in CD patients) compared with the HC. In particular, a PERMANOVA stepwise regression identified the variables "age", "eat yogurt at least four days per week" and "eat dairy products at least 4 days per week" as covariates when comparing the HC and patients affected by ulcerative proctitis (E1), left-sided UC (distal UC) (E2) and extensive UC (pancolitis) (E3). Instead, the variables "age", "gender", "eat meat at least four days per week" and "eat bread at least 4 days per week" were considered as covariates when comparing the HC with the CD patients affected by non-stricturing, non-penetrating (B1), stricturing (B2) and penetrating (B3) diseases. Considering such variables, our analysis indicated that the UC extent differentially modulated the abundance of the Bifidobacteriaceae, Rikenellaceae, Christensenellaceae, Marinifilaceae, Desulfovibrionaceae, Lactobacillaceae, Streptococcaceae and Peptostreptococcaceae families, while the CD behaviour influenced the abundance of Christensenellaceae, Marinifilaceae, Rikenellaceae, Ruminococcaceae, Barnesiellaceae and Coriobacteriaceae families. In conclusion, our study indicated that some covariates and confounders related to an IBD-associated lifestyle and dietary habits influenced the intestinal taxa diversity and relative abundance in the CD and UC patients compared with the HC. Indeed, such variables should be identified and excluded from the analysis to characterize the bacterial families whose abundance is directly modulated by IBD status, as well as disease extent or behaviour

A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism

The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase–DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme–CPT (camptothecin)– DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5 DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism

treatment patterns in elderly patients with locally advanced head and neck squamous cell carcinoma la hnscc results from an eortc led survey

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Fostering Functional Occupation and Mobility in People with Intellectual Disability and Visual Impairment Through Technology-Aided Support

Objectives: The study assessed a smartphone-based technology system, which was designed to support functional occupation and mobility in people with severe to profound intellectual disability and visual impairment. Methods: The technology system provided (a) verbal orientation cues to guide the participants to a desk with two containers (and two groups of 10 objects that were to be transported to two different destinations), (b) verbal instructions to take the objects (one at a time), (c) verbal orientation cues to reach the destinations where the objects taken had to be transported, (d) instructions to put away the objects at the destinations, and (e) praise and brief periods of preferred stimulation. Seven participants were involved in the study, which was carried out according to a nonconcurrent multiple baseline across participants design. Results: During the baseline (when the technology system was not available), the participants produced few or no correct responses (i.e., failed to collect, transport, and deposit objects at the right destinations). During the intervention phase (i.e., with the support of the technology system), their mean frequency of correct responses per session was between close to 19 and close to 20 (out of a maximum possible of 20) and their mean session duration varied between about 16 and 29 min. Conclusions: The data suggest that the technology system used in this study may be a viable resource to support activity and mobility in people with intellectual and visual disabilities

Role of perfusion CT in the evaluation of metastatic nodal tumor response after radiochemotherapy in head and neck cancer: preliminary findings

OBJECTIVE: To assess changes of CT perfusion parameters (ΔPCTp) of cervical lymph node metastases from head and neck cancer (HNC) before and after radiochemotherapy (RT-CT) and their association with nodal tumor persistence. PATIENTS AND METHODS: Eligibility criteria included HNC (Stage III-IV) candidates for RT-CT. Patients underwent perfusion CT (PCT) at baseline 3 weeks and 3 months after RT-CT. Blood volume (BV), blood flow (BF), mean transit time (MTT) and permeability surface (PS) were calculated. PET/CT examination was also performed at baseline and 3 months after treatment for metabolic assessment. RESULTS: Between July 2012 and May 2016, 27 patients were evaluated. Overall, only 3 patients (11%) experienced tumor persistence in the largest metastatic lymph node. A significant reduction of all PCTp values (p<0.0001), except MTT (from 6.3 to 5.7 s; p=0.089), was observed at 3 weeks post-RT-CT compared to baseline. All PCTp values including MTT were significantly lower at 3-month follow-up compared to baseline (p<0.05). Moreover, a statistical significant association was observed between nodal tumor persistence and high BF values (p=0.045) at 3 months after treatment that did not occur for the other parameters. CONCLUSIONS: Our preliminary findings show that all PCTp except MTT are significantly reduced after RT-CT. High BF values at 3 months post-RTCT are predictive of nodal tumor persistence