Neoplastic cells are a rare component in human glioblastoma microvasculature

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance

Heart Rate Responses during Simulated Fire Ground Scenarios among Full-Time Firefighters

International Journal of Exercise Science 13(2): 374-382, 2020. Simulated fire ground scenarios (SFGS) provide firefighters with an opportunity to maintain skills, receive feedback, and optimize performance. Although there is extensive research on heart rate (HR) changes in the firefighter population, few examine the differences between positions. Firefighters are primarily responsible for fire suppression and control (23), officers for emergency operations and organizational management, paramedics for providing on-scene emergency medical care, and drivers are responsible for driving the fire apparatus. Utilizing HR analysis to quantify the physical demands of SFGS among firefighting crews by position. Sixty-seven male (age: 38.97 ± 9.17; ht: 177.99 ± 6.45 cm. wt: 88.83 ± 13.55 kg) firefighters (FF) participated in this investigation. FF crews performed two SFGS involving the suppression and control of a structural fire. Participants were outfitted with heart rate (HR) monitors and average heart rate (HRavg) and maximum heart rate (HRmax) data were collected for each of the two SFGS. Significant differences were observed for Age (P = 0.01), APMHR (P = 0.01), HRmax1(P = 0.04), and HRmax2(P = 0.04) in which firefighters had higher values for Age-predicted maximal heart rate (APMHR), HRmax1, HRmax2compared to the officers. SFGS can be very physically demanding events that may elicit maximal or near maximal HR responses regardless of position. Based on the metabolic demands of these events and the individual firefighter’s capabilities, this information can be used to develop resistance training and conditioning programs that optimize performance at maximal or near maximal heart rates

Association between frequency of telephonic contact and clinical testing for a large, geographically diverse diabetes disease management population

Diabetes disease management (DM) programs strive to promote healthy behaviors, including obtaining hemoglobin A1c (A1c) and low-density lipoprotein (LDL) tests as part of standards of care. The purpose of this study was to examine the relationship between frequency of telephonic contact and A1c and LDL testing rates. A total of 245,668 members continuously enrolled in diabetes DM programs were evaluated for performance of an A1c or LDL test during their first 12 months in the programs. The association between the number of calls a member received and clinical testing rates was examined. Members who received four calls demonstrated a 24.1% and 21.5% relative increase in A1c and LDL testing rates, respectively, compared to members who received DM mailings alone. Response to the telephonic intervention as part of the diabetes DM programs was influenced by member characteristics including gender, age, and disease burden. For example, females who received four calls achieved a 27.7% and 23.6% increase in A1c and LDL testing, respectively, compared to females who received mailings alone; by comparison, males who were called achieved 21.2% and 19.9% relative increase in A1c and LDL testing, respectively, compared to those who received mailings alone. This study demonstrates a positive association between frequency of telephonic contact and increased performance of an A1c or LDL test in a large, diverse diabetes population participating in DM programs. The impact of member characteristics on the responsiveness to these programs provides DM program designers with knowledge for developing strategies to promote healthy behaviors and improve diabetes outcomes

Remote physiological monitoring: Clinical, financial, and behavioral outcomes in a heart failure population

This article reports on the outcomes associated with remote physiological monitoring (RPM) conducted as part of a heart failure disease management program. Claims data, medical records, data transmission records, and survey results for 91 individuals ages 50–92 (mean 74 years) successfully completing a heart failure RPM program were analyzed for time periods before, during, and after the monitoring intervention. The program was associated with significant reductions in per member per month costs and emergency room and hospital utilization. More detailed analyses were performed for specific gender and age subgroups. Participant surveys indicated high levels of satisfaction, and improvements in self-perceived health status, self-efficacy, and self-management behaviors. This study is the first to assess the impact of a RPM program following removal of the monitoring equipment. The results indicate that RPM, as a component of a traditional disease management program, has a sustained, beneficial effect on participants’ lifestyles after the monitoring period has ended

Alternative lengthening of telomeres, ATRX loss and H3â K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fiftyâ seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3â 75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomereâ specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3â K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRXâ (20/24, 83%) or ALTâ /ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3â K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PAâ A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3â K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147190/1/bpa12646_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147190/2/bpa12646.pd

Oncogenic KRAS promotes malignant brain tumors in zebrafish

BACKGROUND: Zebrafish have been used as a vertebrate model to study human cancers such as melanoma, rhabdomyosarcoma, liver cancer, and leukemia as well as for high-throughput screening of small molecules of therapeutic value. However, they are just emerging as a model for human brain tumors, which are among the most devastating and difficult to treat. In this study, we evaluated zebrafish as a brain tumor model by overexpressing a human version of oncogenic KRAS (KRAS[superscript G12V]). METHODS: Using zebrafish cytokeratin 5 (krt5) and glial fibrillary acidic protein (gfap) gene promoters, we activated Ras signaling in the zebrafish central nervous system (CNS) through transient and stable transgenic overexpression. Immunohistochemical analyses were performed to identify activated pathways in the resulting brain tumors. The effects of the MEK inhibitor U0126 on oncogenic KRAS were evaluated. RESULTS: We demonstrated that transient transgenic expression of KRAS[superscript G12V] in putative neural stem and/or progenitor cells induced brain tumorigenesis. When expressed under the control of the krt5 gene promoter, KRAS[superscript G12V] induced brain tumors in ventricular zones (VZ) at low frequency. The majority of other tumors were composed mostly of spindle and epithelioid cells, reminiscent of malignant peripheral nerve sheath tumors (MPNSTs). In contrast, when expressed under the control of the gfap gene promoter, KRAS[superscript G12V] induced brain tumors in both VZs and brain parenchyma at higher frequency. Immunohistochemical analyses indicated prominent activation of the canonical RAS-RAF-ERK pathway, variable activation of the mTOR pathway, but no activation of the PI3K-AKT pathway. In a krt5-derived stable and inducible transgenic line, expression of oncogenic KRAS resulted in skin hyperplasia, and the MEK inhibitor U0126 effectively suppressed this pro-proliferative effects. In a gfap-derived stable and inducible line, expression of oncogenic KRAS led to significantly increased mitotic index in the spinal cord. CONCLUSIONS: Our studies demonstrate that zebrafish could be explored to study cellular origins and molecular mechanisms of brain tumorigenesis and could also be used as a platform for studying human oncogene function and for discovering oncogenic RAS inhibitors.Keywords: gfap, krt5, Oncogenic KRAS (KRAS[superscript G12V]), Zebrafish, Drug screening, Brain tumor