Design of an Optical Blood Pressure Sensor for Noninvasive monitoring of blood pressure

In modern society, patients often have access to a wealth of electronic data concerning their social networks and surroundings, but have little personalized insight into their own health. Our plan is to distribute a small handheld device with an array of biometric sensors to collect data about a user’s body. With the patient’s current and past data, we can give the patients a pre-diagnosis (outlining symptoms and possible sickness) using machine learning techniques to create a general summary of the patient’s symptoms and potential treatment while collaborating with physicians to reach a final consensus of the patient’s health status before the patient is aware of his/her illness. We want to empower users with basic knowledge of their vital signs and help them be more proactive in disease prevention while relying less on frequent primary care physician office visits

Registered report: IDH mutation impairs histone demethylation and results in a block to cell differentiation

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from “IDH mutation impairs histone demethylation and results in a block to cell differentiation” by Lu and colleagues, published in Nature in 2012 (Lu et al., 2012). The experiments that will be replicated are those reported in Figures 1B, 2A, 2B, 2D and 4D. Lu and colleagues demonstrated that expression of mutant forms of IDH1 or IDH2 caused global increases in histone methylation and increased levels of 2 hydroxyglutarate (Figure 1B). This was correlated with a block in differentiation (Figures 2A, B and D). This effect appeared to be mediated by the histone demethylase KDM4C (Figure 4D). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Scienceand Science Exchange, and the results of the replications will be published by eLife. DOI: http://dx.doi.org/10.7554/eLife.10860.00

cIMPACT‐NOW update 7: advancing the molecular classification of ependymal tumors

Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT‐NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT‐NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162791/2/bpa12866_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162791/1/bpa12866.pd

ATRX loss in pediatric glioma results in epigenetic dysregulation of G2/M checkpoint maintenance and sensitivity to ATM inhibition

ATRX is a histone chaperone protein recurrently mutated in pediatric glioma. The mechanism which mediates the proliferative advantage of ATRX loss in pediatric glioma remains unexplained. Recent data revealed a distinct pattern of DNA binding sites of the ATRX protein using ChIP-seq in mouse neuronal precursor cells (mNPCs). Using the ATRX peaks identified in p53-/- mNPCs, we confirmed that ATRX binding sites were significantly enriched in gene promoters (p \u3c 0.0001) and CpG islands (p \u3c 0.0001) compared with random regions. Gene set enrichment (GSE) analysis identified that cell cycle and regulation of cell cycle were among the most significantly enriched gene sets (p=2.52e-16 and 1.61e-9, respectively). We found that ATRX loss resulted in dysfunction of G2/M checkpoint maintenance: (1) ATRX-deficient pediatric glioblastoma (GBM) cells exhibited a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation, and (2) murine GBM cells with ATRX knockdown demonstrated impaired pChk1 signaling on western blot at multiple time points after radiation compared to controls (p=0.0187). Notably, the ATM signaling (pChk2) remained intact in those cells, suggesting a potential therapeutic target. ATRX-deficient mouse cells were uniquely sensitive to ATM inhibitors at 1 uM alongside 8 Gy radiation compared to controls with intact ATRX (AZD0156: p=0.0027 and AZD01390: p=0.0436). Mice intra-cranially implanted with ATRX-deficient GBM cells showed improved survival (n=10, p=0.0018) when treated with AZD0156 combined with radiation. Our findings suggest that ATRX loss in glioma results in unique sensitivity to ATM inhibition via epigenetic dysregulation of G2/M checkpoint maintenance

A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas

Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-014-1338-3) contains supplementary material, which is available to authorized users

Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases

Neuroinflammation is a process characterised by drastic changes in microglial morphology and by marked upregulation of the 18-kDa translocator protein (TSPO) on the mitochondria. The continual increase in incidence of neuroinflammation and neurodegenerative diseases poses a major health issue in many countries, requiring more innovative diagnostic and monitoring tools. TSPO expression may constitute a biomarker for brain inflammation that could be monitored by using TSPO tracers as neuroimaging agents. From medical imaging perspectives, this review focuses on the current concepts related to the TSPO, and discusses briefly on the status of its PET imaging related to neuroinflammation and neurodegenerative diseases in humans

Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry

Abstract With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3–3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4–17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.https://deepblue.lib.umich.edu/bitstream/2027.42/145180/1/40478_2018_Article_570.pd