MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma

Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.Glioma cells diffusely infiltrate the brain and intermingle with neural cells in the surrounding brain tissue, resulting in a complex mixture that includes variable proportions of glioma cells, neurons, and various lineages of reactive or recruited glia. At the infiltrative margins of glioblastoma (GBM), the nonneoplastic brain cells can far outnumber the glioma cells and, therefore, will have a significant effect on the molecular features of the tissue. Expression profiling and whole genome sequencing from hundreds of GBM specimens by The Cancer Genome Atlas (TCGA) has revealed a broad spectrum of genetic alterations and discrete expression signatures or subtypes that stratify the majority of patients (1, 2). These studies analyzed tumor samples that were removed during surgery, but were not radiographically localized and, therefore, do not address the question of how the molecular signature may vary across different regions of a tumor. Recent studies have sampled multiple regions within a GBM and shown that more than one molecular subtype can coexist within a single tumor (3). However, the effect of varying cellular composition on GBM subtype, particularly the contribution of nonneoplastic cells, has not been addressed.GBM typically appears as a contrast-enhancing mass, which represents the highly cellular core of the tumor with vascular proliferation and blood–brain barrier breakdown. This contrast-enhancing (CE) region is typically surrounded by a diffuse, nonenhancing (NE) region of abnormal T2/FLAIR signal, which represents edematous brain tissue with varying numbers of infiltrating glioma cells. The primary treatment of GBM is surgical resection, during which the surgeon removes as much of the CE mass as possible. Thus, molecular and genetic profiling of GBM, including the TCGA effort, has predominantly used samples from the CE regions of tumor. However, it is the NE regions of glioma that are left behind after surgery, which neurooncologists must treat and which inevitably give rise to recurrence. Thus, there is immense prognostic and therapeutic significance to understanding the cellular and molecular features of the NE regions of tumor, yet often these areas are not resected and, therefore, have not been directly studied.There are two major obstacles to this goal. The first is the surgical challenge of radiographically localized sampling of the NE tumor margins. The second is the issue of the complex cellular composition that characterizes these regions of diffuse infiltration. In this study, we have addressed both challenges, and associated distinct molecular and cellular features of the NE regions of GBM with the molecular subtype, as defined by the resected CE regions of the tumor.     

Malnutrition Diagnoses in Hospitalized Patients

Malnutrition is common among hospitalized patients in the United States, and its coded prevalence is increasing. Malnutrition is known to be associated with increased morbidity, mortality and healthcare costs. Although national data indicate that the number of malnutrition diagnoses among hospital discharges has been steadily rising, an in‐depth examination of the demographic and clinical characteristics of these patients has not been conducted. We examined data from the 2010 Healthcare Cost and Utilization Project (HCUP), the most recent nationally‐representative data describing U.S. hospital discharges. Using ICD‐9 codes, we constructed a composite variable indicating a diagnosis of malnutrition. Based on our definition, 3.2% of all U.S. hospital discharges in 2010 had this diagnosis. Relative to patients without a malnutrition diagnosis, those with the diagnosis were older, had longer lengths of stay and incurred higher costs. These patients were more likely to have 27 of 29 comorbidities assessed in HCUP. Finally, discharge to home care was twice as common among malnourished patients, and a discharge of death was more than 5 times as common among patients with a malnutrition diagnosis. Taken together, these nationally representative, cross‐sectional data indicate that hospitalized patients discharged with a diagnosis of malnutrition are older and sicker and their inpatient care is more expensive than their counterparts without this diagnosis.     

Child safety from the perspective of essential needs

OBJECTIVE:

to characterize the maternal care for children under one year of age with a view to child health promotion at home.

METHOD:

exploratory study with qualitative data analysis, thematic mode, based on the conceptual framework of the essential needs of children, based on interviews recorded with 16 mothers.

RESULTS:

the analysis of the maternal narratives showed elements that facilitate the promotion of child safety: presence and involvement of the parents, constant surveillance for physical and emotional protection, experiences to stimulate child development, support networks for childcare at home; and inhibiting elements of child safety: limited perception of characteristics of child development and of children''s singularities, overprotection and difficulties to set limits.

CONCLUSION:

the study enhances the understanding of home care in child health promotion, directing professional actions to guarantee ongoing nurturing relationships, protection, respect for individual differences, experiences appropriate to child development, limit setting and construction of stable and supportive social networks. In addition, the relevance of considering the maternal perspective in child health care is considered, as a strategy to apprehend aspects related to the attendance of the growth and development needs, particularly for child health promotion at home.     

Father–child interaction: associations with self-control and aggression among 4.5-year-olds

Examined correlates of positive father caregiving and harsh control among 721 (350 girls) four-year-old children through analysis of NICHD Study of Early Child Care data and 7050 (3450 girls) four-year-old children through analysis of Early Childhood Longitudinal Study – Birth Cohort data. Findings from both samples suggest that, for both boys and girls, father positive care is associated with lower levels of impulsivity and higher ratings of inhibitory control. For girls, father positive care is associated with lower ratings of aggression. For boys, these findings suggest self-regulation moderates associations between father positive care and aggression. Some support was obtained for models of both moderation and mediation in the prediction of children's peer-based behaviour.     

Rheumatoid factors from patients with rheumatoid arthritis react with tryptophan 60 and 95, lysine 58, and arginine 97, on human β2-microglobulin

Objective. To define precise epitopes on human β₂-microglobulin (β₂m) reacting with polyclonal IgM rheumatoid factors (RF) from patients with rheumatoid arthritis (RA). Methods. Ten polyclonal RF were tested for their human β₂m epitope–binding specificities using the entire 99–amino acid sequence synthesized as overlapping 7-mers in an enzyme-linked immunosorbent assay. Glycine substitution for each residue within RF-reacting linear regions was employed to define major reactive sites. Results and Conclusion. Major β₂m residues contributing to RF reactivity were tryptophans at positions 60 and 95, lysine at 58, and arginine at position 97.