Markov Random Fields in Cancer Mutation Dependencies

Even though a large amount of evidence would suggest that PP2A serine/threonine protein phosphatase acts as a tumour suppressor the genomics data to support this claim is limited. We fit a sparse binary Markov random field with individual sample's total mutational frequency as an additional covariate to model the dependencies between the mutations occurring in the PP2A encoding genes. We utilize the data from recent large scale cancer genomics studies, where the whole genome from a human tumour biopsy has been analysed. Our results show a complex network of interactions between the occurrence of mutations in our twenty examined genes. According to our analysis the mutations occurring in the genes PPP2R1A, PPP2R3A, and PPP2R2B are identified as the key mutations. These genes form the core of the network of conditional dependency between the mutations in the investigated twenty genes. Additionally, we note that the mutations occurring in PPP2R4 seem to be more influential in samples with higher number of total mutations. The mutations occurring in the set of genes suggested by our results has been shown to contribute to the transformation of human cells. We conclude that our evidence further supports the claim that PP2A acts as a tumour suppressor and restoring PP2A activity is an appealing therapeutic strategy.Siirretty Doriast

Leadership in Swedish Public Organizations: A Research Review in Education and Care

This article is a review of recent Swedish leadership research in two large public-sector areas: education and care. By comparing and contrasting research in these areas, we unveil the specifics and commonalities of research in public-sector leadership. We reviewed research articles from 2018 to 2020 and analyzed theories used, data-gathering methods employed, and topics researched. The results show some fundamental differences between the two areas. Compared to research on education, research on care is to a larger extent non-theoretical and is often focused on change management, quality assurance, and leaders’ roles in employee health. Conversely, studies on education are theory driven and mostly focused on leaders’ roles in learning and shared leadership. We discuss the state of Swedish public leadership research and make suggestions for mutual learning and moving forward in this research field

How do different extracorporeal circulation systems affect metoprolol bioavailability in coronary artery bypass surgery patients

Purpose Cardiac surgery and conventional extracorporeal circulation (CECC) impair the bioavailability of drugs administered by mouth. It is not known whether miniaturized ECC (MECC) or off-pump surgery (OPCAB) affect the bioavailability in similar manner. We evaluated the metoprolol bioavailability in patients undergoing CABG surgery with CECC, MECC, or having OPCAB. Methods Thirty patients, ten in each group, aged 44-79 years, scheduled for CABG surgery were administered 50 mg metoprolol by mouth on the preoperative day at 8-10 a.m. and 8 p.m., 2 h before surgery, and thereafter daily at 8 a.m. and 8 p.m. Blood samples were collected up to 12 h after the morning dose on the preoperative day and on first and third postoperative days. Metoprolol concentration in plasma was analyzed using liquid chromatography-mass spectrometry. Results The absorption of metoprolol was markedly reduced on the first postoperative day in all three groups, but recovered to the preoperative level on the third postoperative day. The geometric means (90% confidence interval) of AUC(0-12) on the first and third postoperative days versus the preoperative day were 44 (26-74)% and 109 (86-139)% in the CECC-group, 28 (16-50)% and 79 (59-105)% in the MECC-group, and 26 (12-56)% and 96 (77-119)% in the OPCAB-group, respectively. Two patients in the CECC-group and two in the MECC-group developed atrial fibrillation (AF). The bioavailability and the drug concentrations of metoprolol in patients developing AF did not differ from those who remained in sinus rhythm. Conclusion The bioavailability of metoprolol by mouth was markedly reduced in the early phase after CABG with no difference between the CECC-, MECC-, and OPCAB-groups.Peer reviewe

Методическая система обучения математике студентов фармацевтических факультетов

МАТЕМАТИКАОБУЧЕНИЕ /МЕТОДЫМЕТОДИКА ПРЕПОДАВАНИЯСТУДЕНТЫ МЕДИЦИНСКИХ УЧЕБНЫХ ЗАВЕДЕНИЙФАРМАЦЕВТИЧЕСКИЕ ФАКУЛЬТЕТЫОБРАЗОВАТЕЛЬНЫЙ ПРОЦЕССЛИЧНОСТНО-ОРИЕНТИРОВАННЫЙ ПОДХОДМЕТОДИЧЕСКИЕ СИСТЕМЫПРЕПОДАВАНИЕ МАТЕМАТИК

Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia

The prevalence and functional impact of somatic mutations in nonleukemic T cells is not well characterized, although clonal T-cell expansions are common. In immune-mediated aplastic anemia (AA), cytotoxic T-cell expansions are shown to participate in disease pathogenesis. We investigated the mutation profiles of T cells in AA by a custom panel of 2533 genes. We sequenced CD4+ and CD8+ T cells of 24 AA patients and compared the results to 20 healthy controls and whole-exome sequencing of 37 patients with AA. Somatic variants were common both in patients and healthy controls but enriched to AA patients' CD8+ T cells, which accumulated most mutations on JAK-STAT and MAPK pathways. Mutation burden was associated with CD8+ T-cell clonality, assessed by T-cell receptor beta sequencing. To understand the effect of mutations, we performed single-cell sequencing of AA patients carrying STAT3 or other mutations in CD8+ T cells. STAT3 mutated clone was cytotoxic, clearly distinguishable from other CD8+ T cells, and attenuated by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation of their role in the pathogenesis of AA.Peer reviewe

Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence

Background Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)National Human Genome Research Institute (U.S.) (Grant U54 HG003067)National Human Genome Research Institute (U.S.) (Grant R01 HG006855)Stanley Center for Psychiatric ResearchAlexander and Margaret Stewart TrustNational Institute of Mental Health (U.S.) (Grant R01 MH 077139)National Institute of Mental Health (U.S.) (Grant RC2 MH089905)Sylvan C. Herman Foundatio

The Victorian Newsletter (Fall 1959)

The Victorian Newsletter is edited for the English X Group of the Modern Language Association by William E. Buckler, 737 East Building, New York University, New York 3, New York.Some pages are missing from this record

Pathway using WUDAPT's Digital Synthetic City tool towards generating urban canopy parameters for multi-scale urban atmospheric modeling

The WUDAPT (World Urban Database and Access Portal Tools project goal is to capture consistent information on urban form and function for cities worldwide that can support urban weather, climate, hydrology and air quality modeling. These data are provided as urban canopy parameters (UCPs) as used by weather, climate and air quality models to simulate the effects of urban surfaces on the overlying atmosphere. Information is stored with different levels of detail (LOD). With higher LOD greater spatial precision is provided. At the lowest LOD, Local Climate Zones(LCZ) with nominal UCP ranges is provided (order 100 m or more). To describe the spatial heterogeneity present in cities with great specificity at different urban scales we introduce the Digital Synthetic City (DSC) tool to generate UCPs at any desired scale meeting the fit-for-purpose goal of WUDAPT. 3D building and road elements of entire city landscapes are simulated based on readily available data. Comparisons with real-world urban data are very encouraging. It is customized (C-DSC) to incorporate each city's unique building morphologies based on unique types, variations and spatial distribution of building typologies, architecture features, construction materials and distribution of green and pervious surfaces. The C-DSC uses crowdsourcing methods and sampling within city Testbeds from around the world. UCP data can be computed from synthetic images at selected grid sizes and stored such that the coded string provides UCP values for individual grid cells

The Victorian Newsletter (Spring 1960)

The Victorian Newsletter is edited for the English X Group of the Modern Language Association by William E. Buckler, 737 East Building, New York University, New York 3, New York