Multicore iron oxide nanoparticles for magnetic hyperthermia and combination therapy against cancer cells.

HYPOTHESIS: Multicore flower-like iron oxide nanoparticles (IONPs) are among the best candidates for magnetic hyperthermia applications against cancers. However, they are rarely investigated in physiological environments and their efficacy against cancer cells has been even less studied. The combination of magnetic hyperthermia, using multicore IONPs, with selected bioactive molecules should lead to an enhanced activity against cancer cells. EXPERIMENTS: Multicore IONPs were synthesized by a seeded-growth thermal decomposition approach. Then, the cytotoxicity, cell uptake, and efficacy of the magnetic hyperthermia approach were studied with six cancer cell lines: PANC1 (pancreatic carcinoma), Mel202 (uveal melanoma), MCF7 (breast adenocarcinoma), MB231 (triple-negative breast cancer line), A549 (lung cancer), and HCT116 (colon cancer). Finally, IONPs were modified with a chemotherapeutic drug (SN38) and tumor suppressor microRNAs (miR-34a, miR-182, let-7b, and miR-137), to study their activity against cancer cells with and without combination with magnetic hyperthermia. FINDINGS: Two types of multicore IONPs with very good heating abilities under magnetic stimulation have been prepared. Their concentration-dependent cytotoxicity and internalization have been established, showing a strong dependence on the cell line and the nanoparticle type. Magnetic hyperthermia causes significant cell death that is dramatically enhanced in combination with the bioactive molecules.

Observation system for the technical-tactical analysis of judo by the Rio 2016 Olympic champions.

An observational methodology system has been designed which allows the observation and analysis of the technical-tactical behaviour and interaction of judokas during competition. The observation instrument (JUTACTIC) is composed of 8 fixed criteria that provide information related to the competition and the competitors and 13 variable criteria that, throughout the intrasessional monitoring of each combat, allow the behaviour displayed by both judokas and their interaction to be recorded. From an observational sample consisting of matches from the Rio 2016 Olympic champions and the corresponding samples made using the LINCE PLUS software, evidence of validity, reliability, generalizability and applicability of the observation system is provided. The content validity of the observation instrument has been endorsed by a panel of experts (n = 11). Intra and inter-observer reliability has been guaranteed from the results obtained in the Fleiss Kappa and the Krippendorff Alpha. The generalizability analysis with the design structure [Category] [Participants] / [Matches] has confirmed that around seven matches are needed to accurately analyse the behaviour of the competitor under study. The practical application possibilities of the observation instrument has been shown with an example of the results obtained and the regular behaviour structures detected (T-patterns) using the THEME software.

Multifunctional magnetic nanoparticles elicit anti-tumor immunity in a mouse melanoma model.

Immunotherapy has emerged as a promising strategy to eradicate cancer cells. Particularly, the development of cancer vaccines to induce a potent and sustained antigen-specific T cell response has become a center of attention. Herein, we describe a novel immunotherapy based on magnetic nanoparticles (MNP) covalently modified with the OVA254-267 antigen and a CpG oligonucleotide via disulfide bonds. The MNP-CpG-COVA significantly enhances dendritic cell activation and CD8+ T cell antitumoral response against B16-OVA melanoma cells in vitro. Notably, the immune response induced by the covalently modified MNP is more potent and sustained over time than that triggered by the free components, highlighting the advantage of nanoformulations in immunotherapies. What is more, the nanoparticles are stable in the blood after in vivo administration and induce potent levels of systemic tumor-specific effector CD8 + T cells. Overall, our findings highlight the potential of covalently functionalized MNP to induce robust immune responses against mouse melanoma.

Durable benefit after treatment of obstructive benign prostatic hyperplasia with a novel drug-device combination product: 2-year outcomes from the EVEREST-I study.

PURPOSE: To evaluate the safety and efficacy of the Optilume BPH Catheter System for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). METHODS: This open-label, single-arm study enrolled eighty subjects with LUTS secondary to BPH who were treated with the Optilume BPH Catheter System. Symptoms were recorded utilizing the International Prostate Symptom Score (IPSS) and Benign Prostatic Hyperplasia Impact Index (BPH-II). Functional improvement was measured utilizing peak urinary flow rate (Qmax) and post-void residual urine volume (PVR). Adverse events were systematically captured and reported at each follow-up visit. RESULTS: Subjects treated with the Optilume BPH Catheter System experienced a significant improvement in LUTS from baseline through 2 years of follow-up, as measured by IPSS (22.3 vs 8.2, p < 0.001) and BPH-II (6.9 vs 2.3, p < 0.001). Functional improvement was also significant, with Qmax improving from an average of 10.9 mL/s at baseline to 17.2 mL/s at the 2-year follow-up and PVR improving from 63.1 to 45.0 mL. Treatment-related adverse events were typically minor, with none occurring between 1- and 2-year post-treatment. CONCLUSIONS: The Optilume BPH Catheter System is a unique minimally invasive surgical therapy that combines mechanical and pharmaceutical aspects for the treatment of BPH. The functional and symptomatic improvements seen after treatment are significant and have been sustained through 2 years in this early feasibility study. REGISTRATION: NCT03423979, registered February 6, 2018.

Monolayer-to-Mesoscale Modulation of the Optical Properties in 2D CrI_{3} Mapped by Hyperspectral Microscopy.

Magnetic 2D materials hold promise to change the miniaturization paradigm of unidirectional photonic components. However, the integration of these materials in devices hinges on the accurate determination of the optical properties down to the monolayer limit, which is still missing. By using hyperspectral wide-field imaging at room temperature, we reveal a nonmonotonic thickness dependence of the complex optical dielectric function in the archetypal magnetic 2D material CrI_{3} extending across different length scales: onsetting at the mesoscale, peaking at the nanoscale, and decreasing again down to the single layer. These results portray a modification of the electronic properties of the material and align with the layer-dependent magnetism in CrI_{3}, shedding light on the long-standing structural conundrum in this material. The unique modulation of the complex dielectric function from the monolayer up to more than 100 layers will be instrumental for understanding mesoscopic effects in layered materials and tuning light-matter interactions in magnetic 2D materials.

Rhombohedral-stacked bilayer transition metal dichalcogenides for high-performance atomically thin CMOS devices.

Van der Waals coupling with different stacking configurations is emerging as a powerful method to tune the optical and electronic properties of atomically thin two-dimensional materials. Here, we investigate 3R-stacked transition-metal dichalcogenides as a possible option for high-performance atomically thin field-effect transistors (FETs). We report that the effective mobility of 3R bilayer WS2 (WSe2) is 65% (50%) higher than that of 2H WS2 (WSe2). The 3R bilayer WS2 n-type FET exhibits a high on-state current of 480 µA/µm at Vds = 1 V and an ultralow on-state resistance of 1 kilohm·µm. Our observations, together with multiscale simulations, reveal that these improvements originate from the strong interlayer coupling in the 3R stacking, which is reflected in a higher conductance compared to the 2H stacking. Our method provides a general and scalable route toward advanced channel materials in future electronic devices for ultimate scaling, especially for complementary metal oxide semiconductor applications.

Fine Control of In Vivo Magnetic Hyperthermia Using Iron Oxide Nanoparticles with Different Coatings and Degree of Aggregation.

The clinical implementation of magnetic hyperthermia has experienced little progress since the first clinical trial was completed in 2005. Some of the hurdles to overcome are the reliable production of magnetic nanoparticles with controlled properties and the control of the temperature at the target tissue in vivo. Here, forty samples of iron oxide superparamagnetic nanoparticles were prepared by similar methods and thoroughly characterized in terms of size, aggregation degree, and heating response. Selected samples were intratumorally administered in animals with subcutaneous xenografts of human pancreatic cancer. In vivo experiments showed that it is possible to control the rise in temperature by modulating the field intensity during in vivo magnetic hyperthermia protocols. The procedure does not require sophisticated materials and it can be easily implemented by researchers or practitioners working in magnetic hyperthermia therapies.

Synergistic immunomodulatory effect in macrophages mediated by magnetic nanoparticles modified with miRNAs.

In this work, we describe the synthesis of magnetic nanoparticles composed of a maghemite core (MNP) and three different coatings (dextran, D-MNP; carboxymethyldextran, CMD-MNP; and dimercaptosuccinic acid, DMSA-MNP). Their interactions with red blood cells, plasma proteins, and macrophages were also assessed. CMD-MNP was selected for its good biosafety profile and for promoting a pro-inflammatory response in macrophages, which was associated with the nature of the coating. Thus, we proposed a smart miRNA delivery system using CMD-MNP as a carrier for cancer immunotherapy applications. Particularly, we prove that CMD-MNP-miRNA155 and CMD-MNP-miRNA125b nanoparticles can display a pro-inflammatory response in human macrophages by increasing the expression of CD80 and the levels of TNF-α and IL-6. Hence, our proposed miRNA-delivery nanosystem can be exploited as a new immunotherapeutic tool based on magnetic nanoparticles.

Iron oxide-manganese oxide nanoparticles with tunable morphology and switchable MRI contrast mode triggered by intracellular conditions.

Stimuli-responsive nanomaterials are very attractive for biomedical applications. They can be activated through external stimuli or by the physico-chemical conditions present in cells or tissues. Here, we describe the preparation of hybrid iron oxide-manganese oxide core-satellite shell nanostructures that change their contrast mode in magnetic resonance imaging (MRI) from T2 to T1, after being internalized by cells. This occurs by the dissolution of the MnO2 of the shell, preserving intact the iron oxide at the core. First, we study the seeded-growth synthesis of iron oxide-manganese oxide nanoparticles studying the effect of varying the core size of the magnetic seeds and the concentration of the surfactant. This allows tuning the size and shape of the final hybrid nanostructure. Then, we show that the shell can be removed by a redox reaction with glutathione, which is naturally present inside the cells at much higher concentrations than outside the cells. Finally, the dissolution of the MnO2 shell and the change in the contrast mode is confirmed in cell cultures. After this process, the iron oxide nanoparticles at the core remain intact and are still active as heating mediators when an alternating magnetic field is applied.

The Association Between Gastrointestinal Symptoms and Transvaginal Ultrasound Findings in Women Referred for Endometriosis Evaluation: A Prospective Pilot Study.

PURPOSE: To evaluate the relationship between gastrointestinal (GI) symptoms and transvaginal ultrasound (TVUS) findings suggestive of endometriosis. MATERIALS AND METHODS: A prospective design. Women referred for a diagnostic ultrasound due to suspicion of endometriosis completed a Rome III and Pelvic Floor Distress Inventory (PFDI-20) questionnaire for clinical, GI symptoms, before undergoing TVUS. Endometriosis was diagnosed in the presence of endometriomas and/or deeply infiltrative endometriotic (DIE) lesions. Association between lesion sites and GI symptoms was evaluated by univariate and multivariate analysis. RESULTS: The study included 241 women who presented with: dysmenorrhea (89.6 %), dyspareunia (76.3 %), chronic pelvic pain (77.2 %), dyschezia (66 %), hematochezia (15.4 %), subfertility (24.5 %). GI symptoms were present in 25.3-76.8 % and 5.4-55.6 % of Rome III and PFDI-20 questionnaire responses, respectively. TVUS findings were endometriomas (23.2 %), peritoneal adhesions (46.5 %), uterosacral ligament (26.7 %), retrocervical (11.2 %), rectosigmoid (11.2 %), intestinal (4.6 %), and bladder (0.8 %) involvement, and pouch of Douglas (POD) obliteration (15.4 %). There was a high prevalence of peritoneal adhesions, uterosacral ligament involvement, and rectosigmoid and intestinal nodules on TVUS in women with GI symptoms, up to Chi2 = 9.639 (p = 0.013) on univariate and Chi2 = 8.102 (p = 0.005) on multivariate analysis. CONCLUSION: We observed an almost 10-fold increase in DIE lesions in women with GI symptoms. We suggest that the presence of GI symptoms should prompt a referral for endometriosis evaluation and performance of a dedicated TVUS before invasive gastrointestinal procedures.

Smart Modification on Magnetic Nanoparticles Dramatically Enhances Their Therapeutic Properties.

Magnetic nanoparticles (MNP) are employed as nanocarriers and in magnetic hyperthermia (MH) for the treatment of cancers. Herein, a smart drug delivery system composed of MNP functionalized with the cytotoxic drug gemcitabine (MNP-GEM) has been thoroughly evaluated. The linker employed is based on a disulfide bond and allows the controlled release of GEM under a highly reducing environment, which is frequently present in the cytoplasm of tumor cells. The stability, MH, and the interaction with plasma proteins of the nanoparticles are evaluated, highlighting their great potential for biological applications. Their cytotoxicity is assessed in three pancreatic cancer cell lines with different sensitivity to GEM, including the generation of reactive oxygen species (ROS), the effects on the cell cycle, and the mechanisms of cell death involved. Remarkably, the proposed nanocarrier is better internalized than unmodified nanoparticles, and it is particularly effective in PANC-1 cells, resistant to GEM, but not in non-tumoral keratinocytes. Additionally, its combination with MH produces a synergistic cytotoxic effect in all cancer cell lines tested. In conclusion, MNP-GEM presents a promising potential for treating pancreatic cancer, due to multiple parameters, such as reduced binding to plasma proteins, increased internalization, and synergistic activity when combined with MH.

Infrared-Emitting Multimodal Nanostructures for Controlled In Vivo Magnetic Hyperthermia.

Deliberate and local increase of the temperature within solid tumors represents an effective therapeutic approach. Thermal therapies embrace this concept leveraging the capability of some species to convert the absorbed energy into heat. To that end, magnetic hyperthermia (MHT) uses magnetic nanoparticles (MNPs) that can effectively dissipate the energy absorbed under alternating magnetic fields. However, MNPs fail to provide real-time thermal feedback with the risk of unwanted overheating and impeding on-the-fly adjustment of the therapeutic parameters. Localization of MNPs within a tissue in an accurate, rapid, and cost-effective way represents another challenge for increasing the efficacy of MHT. In this work, MNPs are combined with state-of-the-art infrared luminescent nanothermometers (LNTh; Ag2 S nanoparticles) in a nanocapsule that simultaneously overcomes these limitations. The novel optomagnetic nanocapsule acts as multimodal contrast agents for different imaging techniques (magnetic resonance, photoacoustic and near-infrared fluorescence imaging, optical and X-ray computed tomography). Most crucially, these nanocapsules provide accurate (0.2 °C resolution) and real-time subcutaneous thermal feedback during in vivo MHT, also enabling the attainment of thermal maps of the area of interest. These findings are a milestone on the road toward controlled magnetothermal therapies with minimal side effects.

The influence of cation incorporation and leaching in the properties of Mn-doped nanoparticles for biomedical applications.

HYPOTHESIS: Superparamagnetic MnxFe3-xO4 nanoparticles are promising materials for applications in biomedicine and other fields. Small variations in the Mn/Fe ratio have a strong impact on the properties of the nanoparticles. Those variations may be caused by the synthesis itself and by common post-synthesis manipulations like surface modification. EXPERIMENTS: Mn-ferrite nanoparticles have been prepared changing systematically the Mn/Fe ratio of the metal precursors and repeating each reaction three times. Nanoparticles were subjected to surface modification with two different and typical molecules to stabilize them in aqueous media. The discrepancy in the Mn/Fe ratios of the precursors with the ones measured after the synthesis and the surface modification have been studied, as well as its impact on the saturation magnetization, blocking temperature, contrast enhancement for magnetic resonance imaging, magnetic heating, and on the cytotoxicity. FINDINGS: Mn is incorporated in the nanoparticles in a relatively lower amount than Fe and, as this report shows for the first time, both Mn and Fe ions leach out from the nanoparticles during the surface modification step. The blocking temperature decreases exponentially as the Mn/Fe ratio increases. The transverse and longitudinal relaxation times and the magnetic heating ability change appreciably even with small variations in the composition.

Uterine Artery Pseudoaneurysm in a Pregnant Patient with Retrocervical Endometriosis.

A pseudoaneurysm of the uterine artery or its branches is usually a result of vascular trauma during invasive procedures such as a cesarean section, vaginal delivery, myomectomy, hysterotomy, or dilatation and curettage. A uterine artery pseudoaneurysm rupture is a rare, yet life-threatening event. Deep infiltrating endometriosis usually involves a decrease in symptoms and imaging findings throughout pregnancy, with the notable exception of the phenomenon of decidualization. We present the case of a pregnant woman with a recent diagnosis of endometriosis, who conceived spontaneously and presented with disabling pain at 13 weeks' gestation. She was diagnosed with a left, huge (and rapidly growing) retrocervical endometriosis nodule encompassing a uterine artery pseudoaneurysm. Selective transarterial embolization was performed at 22 weeks' gestation owing to enlargement of the pseudoaneurysm sac, and the pseudoaneurysm was obliterated successfully. The patient was followed intensively throughout the pregnancy and the baby was delivered at term by cesarean section. After delivery, the nodule returned to the pregestational size.

An Improved Recombineering Toolset for Plants.

Gene functional studies often rely on the expression of a gene of interest as transcriptional and translational fusions with specialized tags. Ideally, this is done in the native chromosomal contexts to avoid potential misexpression artifacts. Although recent improvements in genome editing have made it possible to directly modify the target genes in their native chromosomal locations, classical transgenesis is still the preferred experimental approach chosen in most gene tagging studies because of its time efficiency and accessibility. We have developed a recombineering-based tagging system that brings together the convenience of the classical transgenic approaches and the high degree of confidence in the results obtained by direct chromosomal tagging using genome-editing strategies. These simple, scalable, customizable recombineering toolsets and protocols allow a variety of genetic modifications to be generated. In addition, we developed a highly efficient recombinase-mediated cassette exchange system to facilitate the transfer of the desired sequences from a bacterial artificial chromosome clone to a transformation-compatible binary vector, expanding the use of the recombineering approaches beyond Arabidopsis (Arabidopsis thaliana). We demonstrated the utility of this system by generating more than 250 whole-gene translational fusions and 123 Arabidopsis transgenic lines corresponding to 62 auxin-related genes and characterizing the translational reporter expression patterns for 14 auxin biosynthesis genes.

Spin Proximity Effects in Graphene/Topological Insulator Heterostructures.

Enhancing the spin-orbit interaction in graphene, via proximity effects with topological insulators, could create a novel 2D system that combines nontrivial spin textures with high electron mobility. To engineer practical spintronics applications with such graphene/topological insulator (Gr/TI) heterostructures, an understanding of the hybrid spin-dependent properties is essential. However, to date, despite the large number of experimental studies on Gr/TI heterostructures reporting a great variety of remarkable (spin) transport phenomena, little is known about the true nature of the spin texture of the interface states as well as their role on the measured properties. Here, we use ab initio simulations and tight-binding models to determine the precise spin texture of electronic states in graphene interfaced with a Bi2Se3 topological insulator. Our calculations predict the emergence of a giant spin lifetime anisotropy in the graphene layer, which should be a measurable hallmark of spin transport in Gr/TI heterostructures and suggest novel types of spin devices.

Pregnancy outcomes in women with endometriosis.

BACKGROUND: The aim of this study was to investigate whether patients with endometriosis who achieved pregnancy have a higher risk for pregnancy complications and adverse perinatal outcomes as compared to patients without endometriosis. METHODS: The study compared obstetrical and perinatal outcomes of women with and without endometriosis who delivered between 1988-2013 at the Soroka University Medical Center. The study population included 504 deliveries divided into the following groups: 1) women with endometriosis (N.=35); and 2) without endometriosis (N.=467). Endometriosis was diagnosed by laparoscopy or laparotomy. Multiple logistic regression models were used to control for confounders. RESULTS: No significant increase in obstetrical complications was noted in the endometriosis group, but significantly higher rates of cesarean sections. Perinatal outcomes were comparable between the groups. CONCLUSIONS: In our population, endometriosis was not found as a risk factor for obstetrical complications or adverse perinatal outcomes. Larger population based cohort studies are needed to clarify the relationship between endometriosis and adverse pregnancy outcomes.

Sonographic Signs of Adenomyosis Are Prevalent in Women Undergoing Surgery for Endometriosis and May Suggest a Higher Risk of Infertility.

OBJECTIVES: To determine the prevalence of ultrasound features suggestive of adenomyosis in women undergoing surgery for endometriosis compared with a control group of healthy women without endometriosis. METHODS: Retrospective case-control study comparing women with intractable pain or infertility, who underwent transvaginal ultrasound and subsequent laparoscopic surgery, with a control group of healthy women without a previous history of endometriosis. A diagnosis of adenomyosis on TVUS was made based on asymmetrical myometrial thickening, linear striations, myometrial cysts, hyperechoic islands, irregular endometrial-myometrial junction, parallel shadowing, and localized adenomyomas and analyzed for one sign and for three or more signs. RESULTS: The study and control groups included 94 and 60 women, respectively. In the study group, women were younger and had more dysmenorrhea and infertility symptoms. The presence of any sonographic feature of adenomyosis, as well as three or more signs, was found to be more prevalent in the study group, which persisted after controlling for age, for all features but linear striations. Women in the study group who had five or more sonographic features of adenomyosis had more than a threefold risk of suffering from infertility (OR = 3.19, p = 0.015, 95% CI; 1.25-8.17). There was no association with disease severity at surgery. CONCLUSIONS: Sonographic features of adenomyosis are more prevalent in women undergoing surgery for endometriosis compared to healthy controls. Women with more than five features had an increased risk of infertility.

Applying a statistical method in transvaginal ultrasound training: lessons from the learning curve cumulative summation test (LC-CUSUM) for endometriosis mapping.

BACKGROUND: Methods available for assessing the learning curve, such as a predefined number of procedures or direct mentoring are lacking. Our aim was to describe the use of a statistical method to identify the minimal training length of an experienced sonographer, newly trained in deep infiltrating endometriosis (DIE) mapping by evaluating the learning curve of transvaginal ultrasound (TVUS) in the preoperative assessment of endometriosis. METHODS: A retrospective study in a tertiary referral center for endometriosis. Reports and stored data from TVUS scans performed by one operator with training in general gynecological ultrasound, but not in endometriosis mapping, were analyzed retrospectively for patients who subsequently underwent laparoscopy, which served as a reference standard. The performance of TVUS was assessed for the following sites: endometriomas, bladder, vagina, pouch of Douglas, bowel and uterosacral ligaments, and correlated with laparoscopic findings. Sensitivity, specificity, PPV, NPV, and accuracy were calculated, and the operator's diagnostic performance was assessed using the learning curve cumulative summation test (LC-CUSUM). RESULTS: Data from 94 women were available for analysis. The learning curve using the LC-CUSUM graph showed that the sonographer reached the predefined level of proficiency in detecting endometriosis lesions after 20, 26, 32, 31, 38, and 44 examinations for endometriomas, bladder nodules, vaginal nodules, pouch of Douglas obliteration, bowel nodules, and uterosacral ligament nodules, respectively. CONCLUSIONS: LC-CUSUM allows monitoring of individual performance during the learning process of new methodologies. This study shows that a sonographer trained in general gynecologic ultrasonography, who devotes time to learn TVUS for DIE mapping, can achieve proficiency for diagnosing the major types of endometriotic lesions after examining less than 50 patients who subsequently undergo surgery in a training setting.