Functional aortic valve area differs significantly between sexes: A phase-contrast cardiac MRI study in patients with severe aortic stenosis.

Background: Aortic stenosis (AS) is one of the most prevalent valvular heart-diseases in Europe. Currently, diagnosis and classification are not sex-sensitive; however, due to a distinctly different natural history of AS, further investigations of sex-differences in AS-patients are needed. Thus, this study aimed to detect sex-differences in severe AS, especially concerning flow-patterns, via phase-contrast cardiac magnetic resonance imaging (PC-CMR). Methods: Forty-four severe AS-patients (20 women, 45 % vs. 24 men, 55 %) with a median age of 72 years underwent transthoracic echocardiography (TTE), cardiac catheterization (CC) and CMR. Aortic valve area (AVA) and stroke volume (SV) were determined in all modalities, with CMR yielding geometrical AVA via cine-planimetry and functional AVA via PC-CMR, the latter being also used to examine flow-properties. Results: Geometrical AVA showed no sex-differences (0.91 cm2, IQR: 0.61-1.14 vs. 0.94 cm2, IQR: 0.77-1.22, p = 0.322). However, functional AVA differed significantly between sexes in all three modalities (TTE: p = 0.044; CC/PC-CMR: p < 0.001). In men, no significant intermethodical biases in functional AVA-measurements between modalities were found (p = 0.278); yet, in women the particular measurements differed significantly (p < 0.001). Momentary flowrate showed sex-differences depending on momentary opening-degree (at 50 %, 75 % and 90 % of peak-AVA, all p < 0.001), with men showing higher flowrates with increasing opening-area. In women, flowrate did not differ between 75 % and 90 % of peak-AVA (p = 0.191). Conclusions: In severe AS-patients, functional AVA showed marked sex-differences in all modalities, whilst geometrical AVA did not differ. Inter-methodical biases were negligible in men, but not in women. Lastly, significant sex-differences in flow-patterns fit in with the different pathogenesis of AS.

Albumin-based nanoparticles: small, uniform and reproducible.

Nanomedicine carries the hope of precisely identifying and healing lesion sites in vivo. However, the reproducible synthesis of monodisperse protein nanoparticles smaller than 50 nm in diameter and up-scalable to industrial production still poses challenges to researchers. In this report, we describe nanoparticles, so called Absicles, based on an albumin matrix and prepared by a procedure developed by the authors. These Absicles are monodisperse with tunable diameters ranging from 15 nm to 70 nm respectively. They exhibit long term stability against decomposition and aggregation, exceeding many months. The synthesis of Absicles shows exceptionally high reproducibility concerning size, and is simple and cost-effective for up-scaling. Absicles, bearing appropriate targeting groups, bind with high specificity to colon carcinoma tissue ex vivo; they present an attractive platform for further development towards drug delivery applications.

Complement and Fungal Dysbiosis as Prognostic Markers and Potential Targets in PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is still hampered by a dismal prognosis. A better understanding of the tumor microenvironment within the pancreas and of the factors affecting its composition is of utmost importance for developing new diagnostic and treatment tools. In this context, the complement system plays a prominent role. Not only has it been shown to shape a T cell-mediated immune response, but it also directly affects proliferation and apoptosis of the tumor cells, influencing angiogenesis, metastatic spread and therapeutic resistance. This makes complement proteins appealing not only as early biomarkers of PDAC development, but also as therapeutic targets. Fungal dysbiosis is currently the new kid on the block in tumorigenesis with cancer-associated mycobiomes extracted from several cancer types. For PDAC, colonization with the yeast Malassezia seems to promote cancer progression, already in precursor lesions. One responsible mechanism appears to be complement activation via the lectin pathway. In the present article, we review the role of the complement system in tumorigenesis, presenting observations that propose it as the missing link between fungal dysbiosis and PDAC development. We also present the results of a small pilot study supporting the crucial interplay between the complement system and Malassezia colonization in PDAC pathogenesis.

Targeting Drug Delivery in the Elderly: Are Nanoparticles an Option for Treating Osteoporosis?

Nanoparticles bearing specific targeting groups can, in principle, accumulate exclusively at lesion sites bearing target molecules, and release therapeutic agents there. However, practical application of targeted nanoparticles in the living organism presents challenges. In particular, intravasally applied nanoparticles encounter physical and physiological barriers located in blood vessel walls, blocking passage from the blood into tissue compartments. Whereas small molecules can pass out of the blood, nanoparticles are too large and need to utilize physiological carriers enabling passage across endothelial walls. The issues associated with crossing blood-tissue barriers have limited the usefulness of nanoparticles in clinical applications. However, nanoparticles do not encounter blood-tissue barriers if their targets are directly accessible from the blood. This review focuses on osteoporosis, a disabling and common disease for which therapeutic strategies are limited. The target sites for therapeutic agents in osteoporosis are located in bone resorption pits, and these are in immediate contact with the blood. There are specific targetable biomarkers within bone resorption pits. These present nanomedicine with the opportunity to treat a major disease by use of simple nanoparticles loaded with any of several available effective therapeutics that, at present, cannot be used due to their associated side effects.

Molecular imaging with nanoparticles: the dwarf actors revisited 10 years later.

We explore present-day trends and challenges in nanomedicine. Creativity in the laboratories continues: the published literature on novel nanoparticles is now vast. Nanoagents are discussed here which are composed entirely of strongly photoluminescent materials, tunable to desired optical properties and of inherently low toxicity. We focus on "quantum nanoparticles" prepared from allotropes of carbon. The principles behind strong, tunable photoluminescence are quantum mechanical: we present them in simple outline. The major industries racing to develop these materials can offer significant technical guidance to nanomedicine, which could help to custom-design strongly signalling nanoagents specifically for stated clinical applications. Since such agents are small, they can be targeted easily, making active targeting possible. We consider it timely now to study the interactions nanoparticles undergo with tissue components in living animals and to learn to understand and overcome the numerous barriers the organism interposes between the blood and targets in or on parenchymal cells. As the near infra-red spectrum opens up, detection of glowing nanoparticles several centimeters deep in a living human subject becomes calculable and we present a simple way to do this. Finally, we discuss the slow-fuse and resource-inefficient entry of nanoparticles into clinical application. A first possible reason is failure to target across the body's barriers, see above. Second, in the sparse translational landscape funding and support gaps yawn widely between academic research and subsequent development. We consider the agendas of the numerous "stakeholders" participating in this sad landscape and point to some faint glimmers of hope for the future.

Screening and identification of molecular targets for cancer therapy.

In recent decades, targeted therapeutics have significantly improved therapy results in patients with malignant tumors of different origins. However, malignant diseases characterized by aggressiveness and increased capacity for metastatic spread still require basic researchers and clinicians to direct enormous efforts toward the development of novel therapeutic targets. Potential targets should be selected with the clinical endpoint in view; targeted therapeutics can be developed: for use in combination with currently existing therapeutic approaches in order to improve their efficacy; to overcome the treatment resistance of tumor cells and thus protect the patient from recurrence; to repress molecular mechanisms related to immune escape of cancer cells; and to combat the metastatic dissemination of carcinoma cells. Taking into account the specific clinical aim that should be achieved, different strategies and techniques can be proposed to identify the most promising candidate molecules for further development as therapeutic targets. Since cellular membranes contain a large number of druggable molecules, evaluation of the membrane protein profiles of carcinoma cells having different properties can provide a basis for further development of therapeutic targets. This review considers how cellular membranes obtained from different pre-clinical and clinical samples can be used in screening and to identify targets for cancer therapy.

Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles.

PURPOSE: Liposomes have been proposed to be a means of selectively targeting cancer sites for diagnostic and therapeutic applications. The focus of this work was the evaluation of radiolabeled PEGylated liposomes derivatized with varying amounts of a cyclic arginyl-glycyl-aspartic acid (RGD) peptide. RGD peptides are known to bind to α(v)ß(3) integrin receptors overexpressed during tumor-induced angiogenesis. METHODS: Several liposomal nanoparticles carrying the RGD peptide targeting sequence (RLPs) were synthesized using a combination of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, cholesterol, diethylenetriaminepentaacetic acid-derivatized lipids for radiolabeling, a polyethylene glycol (PEG) building block, and a lipid-based RGD building block. Relative amounts of RGD and PEG building blocks were varied. In vitro binding affinities were determined using isolated α(v)ß(3) integrin receptors incubated with different concentrations of RLPs in competition with iodine-125-labeled cyclo-(-RGDyV-). Binding of the indium-111-labeled RLPs was also evaluated. Biodistribution and micro single photon emission computed tomography/computed tomography imaging studies were performed in nude mice using different tumor xenograft models. RESULTS: RLPs were labeled with indium-111 with high radiochemical yields. In vitro binding studies of RLPs with different RGD/PEG loading revealed good binding to isolated receptors, which was dependent on the extent of RGD and PEG loading. Binding increased with higher RGD loading, whereas reduced binding was found with higher PEG loading. Biodistribution showed increased circulating time for PEGylated RLPs, but no dependence on RGD loading. Both biodistribution and micro single photon emission computed tomography/computed tomography imaging studies revealed low, nonspecific tumor uptake values. CONCLUSION: In this study, RLPs for targeting angiogenesis were described. Even though good binding to α(v)ß(3) integrin receptors was found in vitro, the balance between PEGylation and RGD loading clearly requires optimization to achieve targeting in vivo. These data form the basis for future development and provide a platform for the investigation of multimodal approaches.