A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1high exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I - but not PD-L1 - on tumor cells are strong distinguishing features between these environments

Cancer-associated fibroblast classification in single-cell and spatial proteomics data

Cancer-associated fibroblasts (CAFs) are a diverse cell population within the tumour microenvironment, where they have critical effects on tumour evolution and patient prognosis. To define CAF phenotypes, we analyse a single-cell RNA sequencing (scRNA-seq) dataset of over 16,000 stromal cells from tumours of 14 breast cancer patients, based on which we define and functionally annotate nine CAF phenotypes and one class of pericytes. We validate this classification system in four additional cancer types and use highly multiplexed imaging mass cytometry on matched breast cancer samples to confirm our defined CAF phenotypes at the protein level and to analyse their spatial distribution within tumours. This general CAF classification scheme will allow comparison of CAF phenotypes across studies, facilitate analysis of their functional roles, and potentially guide development of new treatment strategies in the future

Future research directions in injury biomechanics and passive safety research

There has been an increasing trend within the safety environment for funding to be directed towards applied research or towards research developing commercially-exploitable systems. Funding mechanisms such as the EU’s 6th Framework Programme and many national programmes focus on research of likely immediate social benefit, reflecting the use of public finances. These programmes will continue to play an important role in funding safety research, but they typically do not have guidelines specifically directed towards fundamental research questions. Additionally, impartial advice is not always available to help programme managers identify research priorities. This review of biomechanics and passive safety research is intended for use by researchers who may be contemplating research in certain areas and wish independent guidance on specific research questions. It is also intended for use by research funding groups and programme managers who would like impartial guidance on basic research to be supported. It covers engineering research directed at improving vehicles and safety systems for all types of road user. It includes the main research and development tools such as dummy development and humanoid modelling and the important area of crash injury data

A review of cervical fractures and fracture-dislocations without head impacts sustained by restrained occupants

Crash injury reduction via lap-shoulder belt use has been well documented. Like any other interior car component, lap-shoulder belts may be related to injury in certain crashes. Relatively unknown is the fact that cervical fractures or fracture-dislocations to restrained front seat occupants occur where no head contact was evidenced by both medical records and car inspection. A review of the available literature on car crash injuries revealed more than 100 such cases. A review of the National Accident Severity Study (NASS) 80-88 file was also conducted, revealing more examples. Case capsule descriptions from the authors' files are also detailed along with examples of such injuries in infants and children in child restraints. However, cervical fractures or fracture dislocations are rare, as evidenced by the relatively few cases identified in the literature, in the author's files, and by an analysis of NASS 80-90 data that revealed a cervical spine injury frequency of only .4% at the AIS-3 level (Hueike, Morris, and Mackay 1992).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30429/1/0000050.pd

Cervical spine biomechanics: A review of the literature

This article reviews the many clinical and laboratory investigative research reports on the frequency, causes, and biomechanics of human cervical spine impact injuries and tolerances. Neck injury mechanisms have been hypothesized from clinically observed cervical spine injuries without laboratory verification. However, many of the laboratory experiments used static loading techniques of cervical spine segments. Only recently have dynamic impact studies been conducted. Results indicate that crown-of-head impacts can routinely produce compression of the neck with extension or flexion motion. However, the two-dimensional (midsagittal) movement of the head bowing into the chest does not routinely produce flexion/compression type damage to the cervical spine. Flexion/compression damage to the cervical spine can be produced by prepositioning the subject so that upon impact, a three-dimensional motion of the head and neck occurs. Future laboratory research is needed to determine the forces and impact directions required to produce the various known fracture types and dislocations for a clear, accurate description of the cervical spine impact dynamics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50376/1/1100040212_ftp.pd

Side-impact to children in cars: experience from international accident analysis and safety tests

In the ISO TC22/SC12 working group 1 "Child Restraint Systems" the risk of side impacts to children in cars was declared an important working item and an ad hoc group was established to analyze this field. This paper summarizes the first experience and activities of this ad hoc group 'Children in Cars - Side Impact Studies'. The group started in 1993 an international inquiry in accident research unit to cover characteristics and injury patterns of children in cars depending on seating position, age and kind of restraint systems used. The resulting international database covers at present 83 side impacts of children in cars from 0 to 4 years and 56 accidents of children between 5 and 12 years where the children suffered an injury severity of MAIS 2+. Based on the results from the accident data and the sampling of full-scale and sled tests new test onfigurations have been developed. The paper includes suggestions for further work with side impact test procedures, which could be a basis for future safety standards

Measures for increasing passive safety in commercial vehicles: findings from European Research Programs = Massnahmen zur Steigerung der passiven Sicherheit von Nutzfahrzeugen : Erkenntnisse aus europäischen Forschungsprogrammen (Fortsetzung)

The ever increasing ties between European countries on the basis of a common market have long made passive safety in commercial vehicles a Europe-wide issue. Important, harmonized technical stipulations for commercial vehicles are in force within the European Union in the form of EEC directives, and over a broader area, in the form of ECE regulations among the ECE contracting parties. These are continually being improved. The difficulties in arriving at a consensus and implementing passive safety systems when several countries are involved will be demonstrated in this report using past examples. In addition to this, passive safety in commercial vehicles must be improved with regard to protection of both the other aprties involved and the vehicle occupants. In this context, projects and findings in the sphere of current European research programs will be described. In conclusion, the need for international research projects into commercial vehicle safety in the future will be discussed and the research areas outlined. Vehicle dynamics regulators in combination with anti-roll preventing systems for trucks and articulated vehicles show for instance a high safety potential; a reduction uo to 9%of the derious accidents will be expected