A novel preclinical model of craniospinal irradiation in pediatric diffuse midline glioma demonstrates decreased metastatic disease

BackgroundDiffuse midline glioma (DMG) is an aggressive pediatric central nervous system tumor with strong metastatic potential. As localized treatment of the primary tumor improves, metastatic disease is becoming a more important factor in treatment. We hypothesized that we could model craniospinal irradiation (CSI) through a DMG patient-derived xenograft (PDX) model and that CSI would limit metastatic tumor.MethodsWe used a BT245 murine orthotopic DMG PDX model for this work. We developed a protocol and specialized platform to deliver craniospinal irradiation (CSI) (4 Gy x2 days) with a pontine boost (4 Gy x2 days) and compared metastatic disease by pathology, bioluminescence, and MRI to mice treated with focal radiation only (4 Gy x4 days) or no radiation.ResultsMice receiving CSI plus boost showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only or no radiation.ConclusionIn a DMG PDX model, CSI+boost minimizes tumor dissemination compared to focal radiation. By expanding effective DMG treatment to the entire neuraxis, CSI has potential as a key component to combination, multimodality treatment for DMG designed to achieve long-term survival once novel therapies definitively demonstrate improved local control

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Historical Development of the Angeline Elizabeth Kirby Memorial Health Center

The neighborhood Health Center is to some extent an outgrowth of the experience with what is known as a settlement”. The settlement house originated in England, in the late nineteenth century and the movement subsequently spread throughout the world. Samuel A. Barnett, and his pupil, Arnold Toynbee, considered the pioneer settlement worker was intimately associated with the development of the first settlement, Toynbee Hall, which opened in London on Christmas Eve, 1884 and which became the source of inspiration and information for the subsequent settlements in Europe and America. The first settlements in America were developed in New York and Chicago. Settlements were usually in poorer communities and in neighborhoods where a large part of the population were foreigners. The people of the community came to the settlement houses for information and advice regarding various troubles. Because these centers were organized in response to the need of these people they became important in promoting their adjustment and consequently a constructive force in the life of the community. In some places the residents were trained in the care of sick and such settlements soon became headquarters for dispersing aid in time of illness and injury as well as the neighborhood Center for mothers\u27 clubs, behavior classes, milk stations, pre-school and maternity clinics, kindergarten work. In some first aid room care and tuberculosis services were included. In general, neighborhood health services in the settlement houses were mostly preventive and educational, although some settlements maintained treatment and diagnostic clinics. As part of these preventive and educational programs, exhibits were given on various subjects, such as the protection and handling of food in markets and in the homes, baby clinics services, proper clothing and bedding for children. Small instruction groups were organized to supplement exhibits, dealing with first aid and care of the sick, personal and family hygiene. This addition of small groups with specialized functions supplemented the mark of the existing staff and made it possible for the organization to offer a variety of services at a central point for the people of a particular district or community. In many cities this marked a transition from the earlier settlement idea, to a Health Center program. The Health Center gathered under one head a group of services, which in greater or less degree had been undertaken in the past by the settlement

Random-effects meta-analysis for systematic reviews of phase I clinical trials: Rare events and missing data.

Phase I trials aim to establish appropriate clinical and statistical parameters to guide future clinical trials. With individual trials typically underpowered, systematic reviews and meta-analysis are desired to assess the totality of evidence. A high percentage of zero or missing outcomes often complicate such efforts. We use a systematic review of pediatric phase I oncology trials as an example and illustrate the utility of advanced Bayesian analysis. Standard random-effects methods rely on the exchangeability of individual trial effects, typically assuming that a common normal distribution sufficiently describes random variation among the trial level effects. Summary statistics of individual trial data may become undefined with zero counts, and this assumption may not be readily examined. We conduct Bayesian semi-parametric analysis with a Dirichlet process prior and examine the assumption. The Bayesian semi-parametric analysis is also useful for visually summarizing individual trial data. It provides alternative statistics that are computed free of distributional assumptions about the shape of the population of trial level effects. Outcomes are rarely entirely missing in clinical trials. We utilize available information and conduct Bayesian incomplete data analysis. The advanced Bayesian analyses, although illustrated with the specific example, are generally applicable. © 2016 The Authors. Research Synthesis Methods Published by John Wiley & Sons Ltd

Random‐effects meta‐analysis for systematic reviews of phase I clinical trials: Rare events and missing data

Phase I trials aim to establish appropriate clinical and statistical parameters to guide future clinical trials. With individual trials typically underpowered, systematic reviews and meta‐analysis are desired to assess the totality of evidence. A high percentage of zero or missing outcomes often complicate such efforts. We use a systematic review of pediatric phase I oncology trials as an example and illustrate the utility of advanced Bayesian analysis. Standard random‐effects methods rely on the exchangeability of individual trial effects, typically assuming that a common normal distribution sufficiently describes random variation among the trial level effects. Summary statistics of individual trial data may become undefined with zero counts, and this assumption may not be readily examined. We conduct Bayesian semi‐parametric analysis with a Dirichlet process prior and examine the assumption. The Bayesian semi‐parametric analysis is also useful for visually summarizing individual trial data. It provides alternative statistics that are computed free of distributional assumptions about the shape of the population of trial level effects. Outcomes are rarely entirely missing in clinical trials. We utilize available information and conduct Bayesian incomplete data analysis. The advanced Bayesian analyses, although illustrated with the specific example, are generally applicable. © 2016 The Authors. Research Synthesis Methods Published by John Wiley & Sons Ltd