Extracellular Vesicles: Messengers of p53 in Tumor–Stroma Communication and Cancer Metastasis

Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor–stroma crosstalk is instructed by the genetic alterations of the tumor cells—the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor–stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor–host communication within the entire organism so as to promote metastatic tumor cell dissemination.     

IV-Controlling in einem Systemhaus

This paper analyses the characteristics of software houses as service providers. The tasks of internal IT-services are determined from these characteristics and a reporting system for the IT-controlling is outlined. The concept results from the analysis of one of the 25 largest German software houses. The paper concludes with a case study of the fiscal year 2000 IT-controlling report of the above-mentioned firm.     

Ein stochastisches,schadensmechanisches Versagensmodell für Komposite

A stochastic damage mechanics failure model of composites This paper focuses on the theoretical simulation of strength and failure of specimens with nonlocal damage. A concept is proposed for quantitative interpretation and prediction of nonlinear. nominal stress-strain curves of damaged materials like fine ceramics or intermetallic alloys. For that reason methods of damage mechanics and of probability theory are combined.     

On-line H NMR spectroscopic investigation of hydrogen bonding in supercritical and near critical CO2–methanol up to 35 MPa and 403 K

On-line NMR spectroscopy can beneficially be applied to studies of supercritical and near-critical fluids as an alternative to optical spectroscopy. Up to now high pressure NMR experiments are predominantly accomplished using custom made NMR batch reactors. The authors present a novel high pressure cell with displacement plunger for on-line NMR experiments on compressible fluids which can be used in conjunction with commercially available SCF NMR flow probes. The on-line technique offers advantages compared to stopped flow techniques such as enhanced control of mixture composition and reaction parameters as well as the facility of engagement into the reaction. The new apparatus is used for NMR studies on hydrogen bonding of methanol in near critical and supercritical carbon dioxide up to 403 K and 35 MPa for which data on the chemical shift of the hydroxyl group and methyl group are reported and interpreted.     

In Google We Trust: Users' Decisions on Rank, Position, and Relevance

An eye tracking experiment revealed that college student users have substantial trust in Google's ability to rank results by their true relevance to the query. When the participants selected a link to follow from Google's result pages, their decisions were strongly biased towards links higher in position even if the abstracts themselves were less relevant. While the participants reacted to artificially reduced retrieval quality by greater scrutiny, they failed to achieve the same success rate. This demonstrated trust in Google has implications for the search engine's tremendous potential influence on culture, society, and user traffic on the Web.     

Cataract surgery and YAG-laser capsulotomy following vitrectomy for diabetic retinopathy

The present study was initiated to assess time-course and risk factors for the development of cataract and posterior-capsule opacification as well as complications of cataract surgery and YAG-laser capsulotomy following vitrectomy for diabetic retinopathy. The charts of all patients undergoing vitrectomy for diabetic retinopathy during a 5-year period in a university eye hospital were retrospectively reviewed. The course of 306 consecutive eyes in which the lens was retained during vitrectomy was analyzed for subsequent cataract surgery and YAG-laser capsulotomy. The first 6 months after cataract or YAG-laser surgery were examined for the occurrence of complications. Data were analyzed with regard to the time course using Kaplan-Meier life-table analysis. The proportion of eyes that underwent cataract surgery after vitrectomy increased nearly linearly with time, approaching 75% after 5 years. Silicone tamponade (relative risk 1.9; P = 0.0005) and transscleral retinal cryotherapy (relative risk 1.4; P = 0.003) were risk factors for subsequent cataract surgery. No significant cataractogenous effect of intravitreal gas as compared with balanced salt solution was found. YAG-laser capsulotomy was performed in 60% of vitrectomized diabetic eyes within 2 years but in only 10% of nondiabetic controls (P < 0.0001). Within 6 months of extracapsular cataract surgery with implantation of an intraocular lens (IOL) in 54 eyes, no serious complication was observed. After YAG-laser capsulotomy, vitreous hemorrhage occurred within 6 months in 6 of 21 eyes. In conclusion, cataract surgery was performed in 75% of the phakic eyes within 5 years of vitrectomy for diabetic retinopathy. Posterior capsular opacification is particularly common in this subset of eyes. No serious complication was observed after extracapsular cataract surgery with IOL implantation, but YAG-laser capsulotomy was associated with an increased risk for vitreous hemorrhage.     

Spatially resolved X-ray diffraction phase mapping and α → β → α transformation kinetics in the heat-affected zone of commercially pure titanium arc welds

Spatially resolved X-ray diffraction (SRXRD) is used to map the α → β → α phase transformation in the heat-affected zone (HAZ) of commercially pure titanium gas tungsten arc welds. In situ SRXRD experiments were conducted using a 180-μm-diameter X-ray beam at the Stanford Synchrotron Radiation Laboratory (SSRL) (Stanford, CA) to probe the phases present in the HAZ of a 1.9 kW weld moving at 1.1 mm/s. Results of sequential linear X-ray diffraction scans made perpendicular to the weld direction were combined to construct a phase transformation map around the liquid weld pool. This map identifies six HAZ microstructural regions between the liquid weld pool and the base metal: (1) α-Ti that is undergoing annealing and recrystallization; (2) completely recrystallized α-Ti; (3) partially transformed α-Ti, where α-Ti and β-Ti coexist; (4) single-phase β-Ti; (5) back-transformed α-Ti; and (6) recrystallized α-Ti plus back-transformed α-Ti. Although the microstructure consisted predominantly of α-Ti, both prior to and after the weld, the crystallographically textured starting material was altered during welding to produce different α-Ti textures within the resulting HAZ. Based on the travel speed of the weld, the α → β transformation was measured to take 1.83 seconds during heating, while the β → α transformation was measured to take 0.91 seconds during cooling. The α → β transformation was characterized to be dominated by long-range diffusional growth on the leading (heating) side of the weld, while the β → α transformation was characterized to be predominantly massive on the trailing (cooling) side of the weld, with a massive growth rate on the order of 100 μm/s.     

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.