Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient's prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, ...we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAF
and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients.
Neoadjuvant stereotactic radiosurgery (NaSRS) of brain metastases has gained importance, but it is not routinely performed. While awaiting the results of prospective studies, we aimed to analyze the ...changes in the volume of brain metastases irradiated pre- and postoperatively and the resulting dosimetric effects on normal brain tissue (NBT).
We identified patients treated with SRS at our institution to compare hypothetical preoperative gross tumor and planning target volumes (pre-GTV and pre-PTV) with original postoperative resection cavity volumes (post-GTV and post-PTV) as well as with a standardized-hypothetical PTV with 2.0 mm margin. We used Pearson correlation to assess the association between the GTV and PTV changes with the pre-GTV. A multiple linear regression analysis was established to predict the GTV change. Hypothetical planning for the selected cases was created to assess the volume effect on the NBT exposure. We performed a literature review on NaSRS and searched for ongoing prospective trials.
We included 30 patients in the analysis. The pre-/post-GTV and pre-/post-PTV did not differ significantly. We observed a negative correlation between pre-GTV and GTV-change, which was also a predictor of volume change in the regression analysis, in terms of a larger volume change for a smaller pre-GTV. In total, 62.5% of cases with an enlargement greater than 5.0 cm
were smaller tumors (pre-GTV < 15.0 cm
), whereas larger tumors greater than 25.0 cm
showed only a decrease in post-GTV. Hypothetical planning for the selected cases to evaluate the volume effect resulted in a median NBT exposure of only 67.6% (range: 33.2-84.5%) relative to the dose received by the NBT in the postoperative SRS setting. Nine published studies and twenty ongoing studies are listed as an overview.
Patients with smaller brain metastases may have a higher risk of volume increase when irradiated postoperatively. Target volume delineation is of great importance because the PTV directly affects the exposure of NBT, but it is a challenge when contouring resection cavities. Further studies should identify patients at risk of relevant volume increase to be preferably treated with NaSRS in routine practice. Ongoing clinical trials will evaluate additional benefits of NaSRS.
Lucent Technologies is defining the next generation base station and mobile switching center (MSC) product architectures to meet anticipated market needs for 1998 and beyond. The goal of the effort ...is to create an infrastructure that can support narrowband and wideband voice, data, and imaging services; multiple radio access technologies; and rapid delivery of low-cost, customizable open-industry products. Achieving these objectives will require particular attention to both software and transport technologies within the network. This paper focuses on a key transport issue, the cost of T-1 or other backhaul transmission facilities between the base station and the MSC in the time division multiple access (TDMA) environment.
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A single bus tightly coupled multiprocessor is a distributed computing system characterized by a single data highway, physically e10se juxtaposition of the processors, and a globally accessible ...memory that is used for interprocessor communication. We present a prioritized hier rchical Markovian queueing model for such a computer organization. This multiprocessor model consists of a set of processing elemelltg (PEs) and single queue/server pair representing the shared memory. Our model takes into count not only global system behavior, but also behavior of tasks on each processing clement and probabilistic tMk migration among the PEs. We show that the prioritization can be masked by reducing each PE submodel to an equivalent queue/server pair whose scrvice rale depends on the numbcr of tMks in this queue; furthermore, under the Msumption of heavy load, this service rate becomes independent of the number of tasks in the server' queue. 8Med on this reduction, an equivalent multiprocessor model is constructed. Global throughput (both exact and limiting) is then obtained based on this reduction.
Purpose: The article is devoted to the research of the issue of the international cooperation between law enforcement agencies of the States and international organizations in the area of combating ...crime and characterization of directions, levels and forms of its implementation. Methodology: The research methodology is based on the results of scientific studies of national (Ukrainian), and European scientists on the issues of the international cooperation in the area of combating crime. The methodological basis of the study is a set of general and special methods of scientific knowledge, such as comparative, statistical, systems analysis, historical and legal, systemically and structural methods. Results: The study allowed determining the directions of international cooperation in the area of crime control, such as the enshrinement of international unlawfulness of crimes; formation of international standards of human rights and freedoms; conclusion of international treaties; investigation of manifestations of international crime; research activity. The levels of international cooperation in the area of crime control such as level of bilateral cooperation and cooperation at the regional and global levels are defined. The forms of international cooperation in the area of combating crime are: international legal assistance, extradition of a person suspected in committing a crime, adoption of criminal proceedings; transfer of convicted to imprisonment for the further execution of a punishment; international search; ensuring the rights and freedoms of citizens during criminal proceedings in another State; information exchange.
The article is devoted to the study of master students’ self-assessment of managerial competence in the context of modern higher education. The relevance of the problem is confirmed from the ...pedagogical, psychological and social points of view. The works of foreign and domestic scholars are analysed, scientific achievements in the field of research are emphasised. It is emphasised that the systematic assessment of managerial competence is a key part of the process of forming professional training of masters, which ensures the compliance of educational and professional and training programmes with modern requirements. The purpose of the article is to develop a model for self-assessment of the level of managerial competence of future education managers by the parameters of «multidisciplinarity» and «multifunctionality» and to allocate the appropriate levels of formation of such competence. The importance of using such parameters for evaluation as «multidisciplinarity» and «multifunctionality» of managerial activity is substantiated. The relevant definitions of these parameters are presented. Their importance for identifying gaps in the knowledge and skills of future educational managers is emphasised. Each of these parameters is described by a certain set of indicators that can be selected by the method of an expert survey. A set of indicators with numerical values from 1 to 6 defines the evaluation criteria. The levels of formation of each indicator of managerial competence are distinguished according to the gradation of its development: «initiation», «comprehension», «execution», «skillfulness», «experience», «authority» Each parameter is described by ten indicators that can be assessed by six levels of development. It has been determined that self-assessment as a tool reflects the personal readiness of master’s students for professional activities in the field of management, which is especially relevant in the context of rapid social change and growing demands on the multifunctionality of education managers. Prospects for further research may include the development of new assessment models, the use of various parameters and the study of the role of the social context of managerial activity. The work is relevant for teachers, researchers and students involved in higher education and management.
The role of germline mutations in BRCA1 and BRCA2 genes in the risk of the development of ovarian cancer is clinically well established. BRCA1/2 testing seems to have increasing role in clinical ...management in patients with advanced ovarian cancer who require treatment with poly(ADP-ribose) polymerase inhibitors.
Between 2002 - 2008, 125 consecutive patients with ovarian cancer were categorized as having three founder mutations in the BRCA1 gene in Poland as: 5382insC exon 20, 4153delA exon 11.17, and 300 T > G exon 5. PFS (progression free survival) and OS (overall survival) were determined by Kaplan-Meier analysis with log rank test, univariate comparisons, and multivariate regression analysis using Cox proportional hazards model.
Of the 125 patients, the founder mutations of BRCA1 were reported in 17 patients (13.6 %). The median OS was longer for BRCA mutated patients (not reached vs 35.6 months, p = 0.041). PFS was similar for both kinds of ovarian cancer. In multivariate analysis, age ≥70 years, suboptimal surgery, and BRCA1 wild type were poor prognostic factors. The BRCA1 mutation reduced the likelihood of death in ovarian cancer by 86 % (HR 0.14; CI: 0.032-0.650, p = 0.012).
In conclusion, we found better overall survival for ovarian cancer patients with BRCA1 germline mutations in comparison with patients without these mutations (sporadic) ovarian cancer. Thus, BRCA1 germline mutations appear to be an independent prognostic factor for ovarian cancer.
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