Liquidhope: methylome and genomic profiling from very limited quantities of plasma-derived DNA.

Analysis of the methylome of tumor cell-free deoxyribonucleic acid (DNA; cfDNA) has emerged as a powerful non-invasive technique for cancer subtyping and prognosis. However, its application is frequently hampered by the quality and total cfDNA yield. Here, we demonstrate the feasibility of very low-input cfDNA for whole-methylome and copy-number profiling studies using enzymatic conversion of unmethylated cysteines [enzymatic methyl-seq (EM-seq)] to better preserve DNA integrity. We created a model for predicting genomic subtyping and prognosis with high accuracy. We validated our tool by comparing whole-genome CpG sequencing with in situ cohorts generated with bisulfite conversion and array hybridization, demonstrating that, despite the different techniques and sample origins, information on cfDNA methylation is comparable with in situ cohorts. Our findings support use of liquid biopsy followed by EM-seq to assess methylome of cancer patients, enabling validation in external cohorts. This advance is particularly relevant for rare cancers like neuroblastomas where liquid-biopsy volume is restricted by ethical regulations in pediatric patients.

Use of Functional Foods and Oral Supplements as Adjuvants in Cancer Treatment.

In cancer patients treated with radiotherapy to the abdominopelvic region, dietary modifications and the use of functional foods (fortified food with added ingredients to provide specific health improving benefits, such as antioxidants, omega-3 fatty acids, and glutamine), may contribute to the improvement of the toxic effects of treatment, including nausea, diarrhea, and constipation, among others. With the aim of analyzing which coadjuvant foods benefit these patients, scientific evidence was gathered by a group of experts. For these patients, the authors recommend a diet that includes sufficient foods rich in antioxidants and polyphenols instead of supplements. Docosahexaenoic and eicosapentaenoic acids have proven useful for the management of anorexia/cachexia in pancreatic cancer patients. Probiotics composed of Lactobacillus spp. and Bifidobacterium spp. are regarded as safe even in patients with neutropenia and have been proven to decrease gastrointestinal symptoms. Several factors should be considered before probiotic supplementation, these include the stage of the disease, radiation dose, and symptomatology of each patient. There is no demonstrated clear benefit to the use of glutamine, so it is not recommended due to its high cost.

Rankl Impairs Lactogenic Differentiation Through Inhibition of the Prolactin/Stat5 Pathway at Midgestation.

Prolactin and progesterone both orchestrate the proliferation and differentiation of the mammary gland during gestation. Differentiation of milk secreting alveoli depends on the presence of prolactin receptor, the downstream Jak2-Stat5 pathway and the transcription factor Elf5. A strict regulation of Rank signaling is essential for the differentiation of the mammary gland and in particular for alveolar commitment. Impaired alveologenesis and lactation failure are observed in both, knockout and Rank overexpressing mice; however, the underlying molecular mechanism responsible for these phenotypes remains largely unknown. Using genome-wide expression analyses and functional studies, we show here that Rankl (RL) exposure leads to impaired secretory differentiation of alveolar cells not only in MMTV-RANK but also in wild-type (WT) mammary acini. Conversely, pharmacological blockage of Rank signaling at midgestation in WT mice leads to precocious and exacerbated lactogenesis. Mechanistically, RL negatively regulates Stat5 phosphorylation and Elf5 expression at the onset of lactogenesis. Continuous RL exposure leads to the expansion of basal and bipotent cells in WT and MMTV-RANK acini. Overall, we demonstrate that enhanced Rank signaling impairs secretory differentiation during pregnancy by inhibition of the prolactin/p-Stat5 pathway.

Evaluation of circulating tumor DNA by electropherogram analysis and methylome profiling in high-risk neuroblastomas.

Background: Liquid biopsy has emerged as a promising, non-invasive diagnostic approach in oncology because the analysis of circulating tumor DNA (ctDNA) reflects the precise status of the disease at diagnosis, progression, and response to treatment. DNA methylation profiling is also a potential solution for sensitive and specific detection of many cancers. The combination of both approaches, DNA methylation analysis from ctDNA, provides an extremely useful and minimally invasive tool with high relevance in patients with childhood cancer. Neuroblastoma is an extracranial solid tumor most common in children and responsible for up to 15% of cancer-related deaths. This high death rate has prompted the scientific community to search for new therapeutic targets. DNA methylation also offers a new source for identifying these molecules. However, the limited blood sample size which can be obtained from children with cancer and the fact that ctDNA content may occasionally be diluted by non-tumor cell-free DNA (cfDNA) complicate optimal quantities of material for high-throughput sequencing studies. Methods: In this article, we present an improved method for ctDNA methylome studies of blood-derived plasma from high-risk neuroblastoma patients. We assessed the electropherogram profiles of ctDNA-containing samples suitable for methylome studies, using 10 ng of plasma-derived ctDNA from 126 samples of 86 high-risk neuroblastoma patients, and evaluated several bioinformatic approaches to analyze DNA methylation sequencing data. Results: We demonstrated that enzymatic methyl-sequencing (EM-seq) outperformed bisulfite conversion-based method, based on the lower proportion of PCR duplicates and the higher percentage of unique mapping reads, mean coverage, and genome coverage. The analysis of the electropherogram profiles revealed the presence of nucleosomal multimers, and occasionally high molecular weight DNA. We established that 10% content of the mono-nucleosomal peak is sufficient ctDNA for successful detection of copy number variations and methylation profiles. Quantification of mono-nucleosomal peak also showed that samples at diagnosis contained a higher amount of ctDNA than relapse samples. Conclusions: Our results refine the use of electropherogram profiles to optimize sample selection for subsequent high-throughput analysis and support the use of liquid biopsy followed by enzymatic conversion of unmethylated cysteines to assess the methylomes of neuroblastoma patients.

Antitumor Effect of Epigallocatechin Gallate and Vincristine in Mice with L5178Y Lymphoma.

The main objective of research into new therapies is the search for more efficacy and fewer toxic effects in cancer treatments. On one hand, vincristine (VCR) is a chemotherapeutic used in different kinds of tumors. On the other hand, epigallocatechin gallate (EGCG) is a green tea metabolite that has shown an antineoplastic effect in diverse investigations, so the objective of this work is to evaluate the antitumor effects of the EGCG/VCR combination on tumor volume and survival. To achieve this objective, the solid model of lymphoma L5178Y was used in BALB/c mice with different doses of VCR, EGCG, and their combination allowed tumor growth and survival time recording. After tumor collection, measurements, and immunohistochemistry for p53, Bcl2, and Cyclin D1 were performed. The results showed that the EGCG/vincristine combination had a greater antitumor effect than those effects of vincristine and EGCG. It can be attributed to the fact that the greatest inhibition of Bcl2 was present in gathering of EGCG harvest with vincristine. Therefore, the combination of EGCG with vincristine has a better antineoplastic effect by inhibiting tumor development and increasing survival on both substances independently.

Novel Nanotechnological Strategies for Skin Anti-aging.

BACKGROUND: Nanoparticle formulations development for anti-aging treatment is increasing due to their multifunctional properties. These nanotechnological strategies can target cellular/ molecular pathways of the skin affected by the aging process. However, a review of these strategies is required to discuss their efficacy/safety and establish the needs for further research. OBJECTIVE: Innovative nanotechnological advances for skin anti-aging/rejuvenation are summarized and discussed in this work. METHODS: The information in this review was extracted from recent and relevant studies using nanotechnology for anti-aging treatment from scientific databases. RESULTS AND DISCUSSION: Results show an enhanced skin anti-aging effect of actives-loaded nanoparticles of next generation (nanostructured lipid carriers, fullerenes, transfersomes, protransfersomes, niosomes, ethosomes, transethosomes, glycerosomes, phytosomes) compared with nanocarriers of first generation or conventional formulations. Anti-aging active ingredients such as, flavonoids (rutin, hesperidin, quercetagetine, quercetin, epigallocatechin-3-gallate, myricetin, silibinin, curcuminoids, isoflavones); vitamins (E, D₃, CoQ10); acids (hyaluronic, ascorbic, rosmarinic, gallic); extracts (Citrus sinensis, Tagetes erecta L., Achillea millefolium L., Citrus aurantium L., Glycyrrhiza glabra L., Aloe vera, propolis earned by Apis mellifera); and other compounds (adenosine, beta-glucan, heptapetide DEETGEF, resveratrol, cycloastragenol, melatonin, botulinum toxin, grapeseed oil), have been successfully entrapped into nanoparticles for skin rejuvenation. This encapsulation has improved their solubility, bioavailability, stability, permeability, and effectivity for skin anti-aging, providing a controlled drug release with minimized side effects. CONCLUSION: Recent studies show a trend of anti-aging herbal active ingredients-loaded nanoparticles, enhancing the moisturizing, antioxidant, regenerating and photoprotective activity of the skin. Suitable safety/shelf-life stability of these novel formulations is key to a successful translation to the clinic/industry.

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause.

An impaired transendothelial migration potential of chronic lymphocytic leukemia (CLL) cells can be linked to ephrin-A4 expression.

Chronic lymphocytic leukemia (CLL) cell migration into lymphoid tissues is an important aspect of the pathobiology of this disease. Here, we investigated the role of ephrin-A4 (EFNA4) in the transendothelial migration (TEM) capacity of CLL and normal B cells through interacting with endothelial EphA2 (erythropoietin-producing hepatocellular carcinoma). CLL cells showed a remarkable impairment in the adhesion to and transmigration through human umbilical vein endothelial cell (HUVEC) monolayers, correlating with their higher EFNA4 expression. In vitro, TEM was mediated by EFNA4 binding to endothelial EphA2 receptor, which is highly expressed in tumor necrosis factor-alpha-activated HUVECs as well as in the CD31(+) endothelial cells of human lymph nodes. The pretreatment of CLL cells with EphA2 homodimers further impaired their adhesion to and transmigration through HUVEC monolayers, whereas pretreatment of HUVECs with EFNA4 homodimers improved those phenomena in both CLL and normal B cells, suggesting that EFNA4 signaling negatively contributed to TEM. In fact, EFNA4 signaling into CLL cells significantly reduced their adhesion to intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and several extracellular matrix molecules and impaired CCL-19-mediated TEM and chemotaxis. Our results suggest that EFNA4-EphA2 interactions are involved in CLL cell trafficking between blood and the tissues and therefore may become a therapeutic target in the future.

Development of Poly (Methyl vinyl ether-alt-maleic acid) Microneedles for Transdermal Delivery of Atorvastatin Calcium.

AIMS: Biodegradable polymeric microneedles containing atorvastatin calcium were developed in order to improve the percutaneous absorption of the drug, useful for the treatment of hypercholesterolemia. BACKGROUND: The use of physical enhancers like microneedles have shown good results to increase the delivery of drugs through the skin, the use of microneedles has very important advantages for transdermal drug delivery, for example, they are painless, easy to use and safe, they increase time interval of drug activity, dose, and reductions in adverse reactions, they also offer, the facility to remove the system instantly of the skin. OBJECTIVE: Develop polymer microneedles loaded with a calcium atorvastatin and evaluate them by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, postwetting- bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies to demonstrate the use of microneedles atorvastatin is able to cross the skin. METHODS: The microneedles were made with poly (methyl vinyl ether-alt-maleic acid) as biodegradable polymer using the technique of casting in solution in a mold. After solidification these microneedles were characterized by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, post-wetting-bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies. RESULTS: In general, the performances were satisfactory for optimal formulation in terms of DSC with no interactions between drug and excipients, SEM shows microneedles with a conical shape, bioadhesion of 1570 g.f, post wetting-bioadhesion of 1503.4 g.f, breaking strength of 1566.7g.f that is sufficient to disrupt Stratum corneum, good drug release and a flux of 33.4 µg/cm2*h with a tLag of 15.14 h for the in vitro percutaneous absorption. CONCLUSION: The results indicate that it is possible to generate microneedles to increase the percutaneous absorption of calcium atorvastatin transdermally, with the potential to be used as an alternative to the oral route for the treatment of dyslipidemias.

Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.

Alteration of medial-edge epithelium cell adhesion in two Tgf-beta3 null mouse strains.

Although palatal shelf adhesion is a crucial event during palate development, little work has been carried out to determine which molecules are responsible for this process. Furthermore, whether altered palatal shelf adhesion causes the cleft palate presented by Tgf-beta3 null mutant mice has not yet been clarified. Here, we study the presence/distribution of some extracellular matrix and cell adhesion molecules at the time of the contact of palatal shelves in both wild-type and Tgf-beta3 null mutant palates of two strains of mice (C57/BL/6J (C57), and MF1) that develop cleft palates of different severity. We have performed immunohistochemistry with antibodies against collagens IV and IX, laminin, fibronectin, the alpha5- and beta1-integrins, and ICAM-1; in situ hybridization with a Nectin-1 riboprobe; and palatal shelf cultures treated or untreated with TGF-beta3 or neutralizing antibodies against fibronectin or the alpha5-integrin. Our results show the location of these molecules in the wild-type mouse medial edge epithelium (MEE) of both strains at the time of the contact of palatal shelves; the heavier (C57) and milder (MF1) alteration of their presence in the Tgf-beta3 null mutants; the importance of TGF-beta3 to restore their normal pattern of expression; and the crucial role of fibronectin and the alpha5-integrin in palatal shelf adhesion. We thus provide insight into the molecular bases of this important process and the cleft palate presented by Tgf-beta3 null mutant mice.

Chromosome 12p Amplification in Triple-Negative/BRCA1-Mutated Breast Cancer Associates with Emergence of Docetaxel Resistance and Carboplatin Sensitivity.

Taxanes are the mainstay of treatment in triple-negative breast cancer (TNBC), with de novo and acquired resistance limiting patient's survival. To investigate the genetic basis of docetaxel resistance in TNBC, exome sequencing was performed on matched TNBC patient-derived xenografts (PDX) sensitive to docetaxel and their counterparts that developed resistance in vivo upon continuous drug exposure. Most mutations, small insertions/deletions, and copy number alterations detected in the initial TNBC human metastatic samples were maintained after serial passages in mice and emergence of resistance. We identified a chromosomal amplification of chr12p in a human BRCA1-mutated metastatic sample and the derived chemoresistant PDX, but not in the matched docetaxel-sensitive PDX tumor. Chr12p amplification was validated in a second pair of docetaxel-sensitive/resistant BRCA1-mutated PDXs and after short-term docetaxel treatment in several TNBC/BRCA1-mutated PDXs and cell lines, as well as during metastatic recurrence in a patient with BRCA1-mutated breast cancer who had progressed on docetaxel treatment. Analysis of clinical data indicates an association between chr12p amplification and patients with TNBC/basal-like breast cancer, a BRCA1 mutational signature, and poor survival after chemotherapy. Detection of chr12p amplification in a cohort of TNBC PDX models was associated with an improved response to carboplatin. Our findings reveal tumor clonal dynamics during chemotherapy treatments and suggest that a preexisting population harboring chr12p amplification is associated with the emergence of docetaxel resistance and carboplatin responsiveness in TNBC/BRCA1-mutated tumors. SIGNIFICANCE: Chr12p copy number gains indicate rapid emergence of resistance to docetaxel and increased sensitivity to carboplatin, therefore sequential docetaxel/carboplatin treatment could improve survival in TNBC/BRCA1 patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4258/F1.large.jpg.

Bizarreness and Emotion Identification in Grete Stern Photomontages: Gender and Age Disparities.

Although the International Affective Picture System (IAPS) is used to evaluate emotions (valence, arousal, and dominance evoked by a large set of photographs), bizarre images in works of art have not been assessed with the IAPS procedures. Understood here as strange, non-sense, and absurd mental contents or expressions accompanied by surprise and confusion emotions, bizarreness was assessed after healthy adult volunteers assigned this specified variable to 140 Grete Stern's photomontages overtly intended to illustrate strange, absurd, and non-sensical contents in dream reports. The images were presented to 21 Young Males (YM) and 30 Young Females (YF) who were instructed to use the IAPS Self-Assessment Manikin, along with an additional bizarre-to-normal scale, to evaluate their response to them. The valence and the bizarre-to-normal ratings showed a dissimilar pattern of distribution between genders. Ratings of scales were different, and a greater variation in scales occurred according to gender. When bizarreness was appraised, gender differences became more evident especially for YF, who rated half of the images as bizarre, and with a diminished feeling of control, while the neutral and normal images were deemed more pleased and controlled. Valence, bizarreness, and dominance formed a different component than arousal in both groups. Negative correlations between valence and dominance, and between valence and bizarreness were also found in both groups, plus a positive one for dominance and bizarreness in YF, along with curvilinear relationships among all scales. On a second experiment, 10 photomontages evaluated by YF as bizarre or as normal were administered to 18 Old Males (OM) and 28 Old Females (OF). OF's arousal showed less neutral evaluations than OM's. In OF the bizarre images evoked either more excitation or calmness than in OM. The distribution of the bizarre-to-normal scale was significantly different across the evaluations in YM, YF, OM, and OF. The use of this extended IAPS instrument to explore bizarreness and emotional variables in response to art images seems suitable and potentially valuable to characterize bizarre, absurd, or non-sensical mental states and their brain correlates.

Radiopharmacokinetic and dosimetric parameters of 188Re-lanreotide in athymic mice with induced human cancer tumors.

Radiolabeled peptides, like the somatostatin analogs, have been used for peptide receptor-mediated radionuclide therapy (PRMRT) in metastatic neuroendocrine tumors. The eight amino acid peptide 3-(2-naphthalenyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide,cyclic(2-->7)-disulfide (9Cl) (lanreotide) was found to bind to the five somatostatin tumor receptors. Lanreotide has been labeled via the bifunctional chelating agent, DOTA, to (111)In, and (90)Y. A direct labeling method was used to label lanreotide with (188)Re. Athymic mice with implanted human cancer tumors (uterine-cervix, renal, and neuroblastoma) were injected with radiochemically pure (188)Re-lanreotide (1.11 MBq). The percent injected activity (%IA/g) from serial blood samples was the input data for the WinNonlin computer program to obtain radiopharmacokinetic parameters. The organs' percent injected activity per gram of tissue (%IA/g) was extrapolated to the weights of a 70 kg male model organs and the number of nuclear transitions (N) were the input for the OLINDA/EXM program to obtain dosimetry estimates. Induced uterine-cervix tumors (HeLa cells) show a mean 2.4 %IA/g uptake up to 24 h and the tumor/blood ratio was over 1.85 (1.5-24 h post-injection) confirming (188)Re-lanreotide remains bound to the tumor. The estimated tumor absorbed dose was 460 mGy/MBq. Human effective dose was 0.0182 mSv/MBq. Therefore, (188)Re-lanreotide is a good candidate for PRMRT and a clinical trial is being planned in order to acquire individual dosimetric data.

EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation.

A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival.

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation.

RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormone-dependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. ©2016 AACR.

Information and Communication Technologies in the Care of the Elderly: Systematic Review of Applications Aimed at Patients With Dementia and Caregivers.

BACKGROUND: The interest in applying information and communications technology (ICT) in older adult health care is frequently promoted by the increasing and unsustainable costs of health care services. In turn, the unprecedented growth of the elderly population around the globe has urged institutions, companies, industries, and governments to respond to older adults' medical needs. OBJECTIVE: The aim of this review is to systematically identify the opportunities that ICT offers to health services, specifically for patients with dementia and their families. METHODS: A systematic review of the literature about ICT applications that have been developed to assist patients with Alzheimer's disease (AD) and their primary caregivers was conducted. The bibliographic search included works published between January 2005 and July 2015 in the databases Springer Link, Scopus, and Google Scholar. Of the published papers, 902 were obtained in the initial search, of which 214 were potentially relevant. Included studies fulfilled the following inclusion criteria: (1) studies carried out between the years of 2005 and 2015, (2) studies were published in English or Spanish, (3) studies with titles containing the keywords, (4) studies with abstracts containing information on ICT applications and AD, and (5) studies published in indexed journals, proceedings, and book chapters. RESULTS: A total of 26 studies satisfied the inclusion criteria for the current review. Among them, 16 were aimed at the patient with AD and 10 at the primary caregivers and/or family members. The studies targeted applications that included assistive technology (44%, 7/16), telecare (37%, 6/16), and telemedicine (31%, 5/16). The information systems (56%, 9/16) and Internet (44%, 7/16) were the most commonly used enabling technologies for the studies. Finally, areas of attention more covered by the studies were care (56%, 9/16), treatment (56%, 9/16), and management (50%, 8/16). Furthermore, it was found that 20 studies (77%, 8/26) evaluated their ICT applications through carrying out tests with patients with dementia and caregivers. CONCLUSIONS: The key finding of this systematic review revealed that the use of ICT tools can be strongly recommended to be used as a lifestyle in the elderly in order to improve the quality of life for the elderly and their primary caregivers. Since patients with AD are completely dependent in most activities, it is necessary to give attention to their primary caregivers to avoid stress and depression. In addition, the use of ICT in the daily life of caregivers can help them understand the disease process and manage situations in a way that is beneficial for both parties. It is expected that future developments concerning technological projects can support this group of people.

Microneedles: a valuable physical enhancer to increase transdermal drug delivery.

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery. Microneedles have been fabricated with a range of sizes, shapes, and materials. Most in vitro drug delivery studies have shown these needles to increase skin permeability to a broad range of drugs that differ in molecular size and weight. In vivo studies have demonstrated satisfactory release of oligonucleotides and insulin and the induction of immune responses from protein and DNA vaccines. Microneedles inserted into the skin of human subjects were reported to be painless. For all these reasons, microneedles are a promising technology to deliver drugs into the skin. This review presents the main findings concerning the use of microneedles in transdermal drug delivery. It also covers types of microneedles, their advantages and disadvantages, enhancement mechanisms, and trends in transdermal drug delivery.

Eph-ephrin bidirectional signaling comes into the context of lymphocyte transendothelial migration.

A better knowledge of the molecular mechanisms that govern leukocyte trafficking is of major relevance for the clinics. Both normal and pathologic extravasation of lymphocytes are a fine-tuned spatio-temporal event of migratory path-finding likely regulated by molecular guidance cues underlying cell movements in other systems. We have recently reported that members of the Eph family of receptor tyrosine kinases, namely EphA2 and one of its ligands, ephrin-A4 (EFNA4) can mediate in the traffic of chronic lymphocytic leukemia (CLL) cells and presumably of normal B cells between the blood and the tissues. The importance of EphA2-EFNA4 interactions at the endothelium-lymphocyte interface during TEM could rely on their attractive/repulsive properties. In the present work, we expand on those results by including additional insights and new suggestions for future studies that discuss the relevance of these molecules in overall cell adhesion dynamic events.