Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.     

Facile Microwave Assisted Synthesis of Silver Nanostars for Ultrasensitive Detection of Biological Analytes by SERS

We report a very simple, rapid and reproducible method for the fabrication of anisotropic silver nanostars (AgNS) that can be successfully used as highly efficient SERS substrates for different bioanalytes, even in the case of a near-infra-red (NIR) excitation laser. The nanostars have been synthesized using the chemical reduction of Ag⁺ ions by trisodium citrate. This is the first research reporting the synthesis of AgNS using only trisodium citrate as a reducing and stabilizing agent. The key elements of this original synthesis procedure are rapid hydrothermal synthesis of silver nanostars followed by a cooling down procedure by immersion in a water bath. The synthesis was performed in a sealed bottom flask homogenously heated and brought to a boil in a microwave oven. After 60 s, the colloidal solution was cooled down to room temperature by immersion in a water bath at 35 °C. The as-synthesized AgNS were washed by centrifugation and used for SERS analysis of test molecules (methylene blue) as well as biological analytes: pharmaceutical compounds with various Raman cross sections (doxorubicin, atenolol & metoprolol), cell lysates and amino acids (methionine & cysteine). UV-Vis absorption spectroscopy, (Scanning) Transmission Electron Microscopy ((S)TEM) and Atomic Force Microscopy (AFM) have been employed for investigating nanostars’ physical properties.     

Genetics and Epigenetics of Spontaneous Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a complex and heterogeneous disease, and there is no effective treatment. Spontaneous ICH represents the final manifestation of different types of cerebral small vessel disease, usually categorized as: lobar (mostly related to cerebral amyloid angiopathy) and nonlobar (hypertension-related vasculopathy) ICH. Accurate phenotyping aims to reflect these biological differences in the underlying mechanisms and has been demonstrated to be crucial to the success of genetic studies in this field. This review summarizes how current knowledge on genetics and epigenetics of this devastating stroke subtype are contributing to improve the understanding of ICH pathophysiology and their potential role in developing therapeutic strategies.     

Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma

Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence.     

Nutritional Calcium Supply Dependent Calcium Balance,Bone Calcification and Calcium Isotope Ratios in Rats

Serum calcium isotopes (δ^44/42Ca) have been suggested as a non-invasive and sensitive Ca balance marker. Quantitative δ^44/42Ca changes associated with Ca flux across body compartment barriers relative to the dietary Ca and the correlation of δ^44/42Ca_Serum with bone histology are unknown. We analyzed Ca and δ^44/42Ca by mass-spectrometry in rats after two weeks of standard-Ca-diet (0.5%) and after four subsequent weeks of standard- and of low-Ca-diet (0.25%). In animals on a low-Ca-diet net Ca gain was 61 ± 3% and femur Ca content 68 ± 41% of standard-Ca-diet, bone mineralized area per section area was 68 ± 15% compared to standard-Ca-diet. δ^44/42Ca was similar in the diets, and decreased in feces and urine and increased in serum in animals on low-Ca-diet. δ^44/42Ca_Bone was higher in animals on low-Ca-diet, lower in the diaphysis than the metaphysis and epiphysis, and unaffected by gender. Independent of diet, δ^44/42Ca_Bone was similar in the femora and ribs. At the time of sacrifice, δ^44/42Ca_Serum inversely correlated with intestinal Ca uptake and histological bone mineralization markers, but not with Ca content and bone mineral density by µCT. In conclusion, δ^44/42Ca_Bone was bone site specific, but mechanical stress and gender independent. Low-Ca-diet induced marked changes in feces, serum and urine δ^44/42Ca in growing rats. δ^44/42Ca_Serum inversely correlated with markers of bone mineralization.     

玛丽蒂姆会议酒店,柏林,德国

立面、周边环境以及对所在街区的一系列回应,是玛丽蒂姆酒店的设计要点。这个占地约1.2万m2的酒店基地紧邻文化中心（Kulturforum）和著名的文物保护建筑贝壳屋（Shellhaus,建筑师：Emil Fahrenkamp）,且距国家美术馆和波茨坦广场不远。     

Finite multidimensional behaviors

We study finitely generated and finite systems defined by linear partial difference equations with constant coefficients in a Noetherian ring. The two notions coincide for finite rings, and we show that all finite systems exhibit certain periodicity properties. For the particular case of systems over the ring of integers modulo m?>?1, which is important in coding theory, a method is given for determining the number of trajectories, using Gr?bner basis techniques.     

Covalent Adaptable Microstructures via Combining Two-Photon Laser Printing and Alkoxyamine Chemistry: Toward Living 3D Microstructures

Manufacturing programmable materials, whose mechanical properties can be adapted on demand, is highly desired for their application in areas ranging from robotics, to biomedicine, or microfluidics. Herein, the inclusion of dynamic and living bonds, such as alkoxyamines, in a printable formulation suitable for two-photon 3D laser printing is exploited. On one hand, taking advantage of the dynamic covalent character of alkoxyamines, the nitroxide exchange reaction is investigated. As a consequence, a reduction of the Young´s Modulus by 50%, is measured by nanoindentation. On the other hand, due to its “living” characteristic, the chain extension becomes possible via nitroxide mediated polymerization. In particular, living nitroxide mediated polymerization of styrene results not only in a dramatic increase of the volume (≈8 times) of the 3D printed microstructure but also an increase of the Young's Modulus by two orders of magnitude (from 14 MPa to 2.7 GPa), while maintaining the shape including fine structural details. Thus, the approach introduces a new dimension by enabling to create microstructures with dynamically tunable size and mechanical properties.     

Nanocasting of Mesoporous In‐TM (TM = Co,Fe, Mn) Oxides: Towards 3D Diluted‐Oxide Magnetic Semiconductor Architectures

Transition metal (Co, Fe, Mn)‐doped In₂O_3?y mesoporous oxides are synthesized by nanocasting using mesoporous silica as hard templates. 3D ordered mesoporous replicas are obtained after silica removal in the case of the In‐Co and In‐Fe oxide powders. During the conversion of metal nitrates into the target mixed oxides, Co, Fe, and Mn ions enter the lattice of the In₂O₃ bixbyite phase via isovalent or heterovalent cation substitution, leading to a reduction in the cell parameter. In turn, non‐negligible amounts of oxygen vacancies are also present, as evidenced from Rietveld refinements of the X‐ray diffraction patterns. In addition to (In_1?xTM_x)₂O_3?y, minor amounts of Co₃O₄, α‐Fe₂O₃, and Mn_xO_y phases are also detected, which originate from the remaining TM cations not forming part of the bixbyite lattice. The resulting TM‐doped In₂O_3?y mesoporous materials show a ferromagnetic response at room temperature, superimposed on a paramagnetic background. Conversely, undoped In₂O_3?y exhibits a mixed diamagnetic‐ferromagnetic behavior with much smaller magnetization. The influence of the oxygen vacancies and the doping elements on the magnetic properties of these materials is discussed. Due to their 3D mesostructural geometrical arrangement and their room‐temperature ferromagnetic behavior, mesoporous oxide‐diluted magnetic semiconductors may become smart materials for the implementation of advanced components in spintronic nanodevices.