Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

The Karst Information Portal: A Virtual Tool to Facilitate Research and Collaboration in Paleontological Speleology

Data access, management, and evaluation challenge the progress of speleology. Crucial information is both scattered throughout specialty mainstream journals and buried in the gray literature. The karst-information problem is exacerbated in paleontological speleology due to overlaps into other disciplines, such as geology, biology, paleoclimatology, and hydrology. Important patterns and relationships can easily be overlooked, especially when no geographic or cultural connections are known between archeological sites. The Karst Information Portal (KIP) is a solution to these paleontological research problems. Conceived in 2005 and launched in June 2007, KIP developed as a partnership between the International Union of Speleology, National Cave and Karst Research Institute, University of New Mexico, and University of South Florida. Like other virtual research portals, KIP will grow as existing and future partners contribute information and plug websites and databases into the network. KIP will not duplicate existing databases but will serve to more efficiently access and process them with superior tools. A cave archeology bibliography is under development but additional partners are needed to fulfill KIP’s potential in revolutionizing archeological speleology through its advanced and collaborative integration of data and ideas

Superior Karst Management Through Superior Data Management: The Karst Information Portal

Effective stewardship of caves and karst areas requires access to and efficient analysis of a diverse range of information. Vital data are scattered throughout specialty mainstream journals, which even for a single project could include fields such as ecology, hydrogeology, contaminant transport, toxicology, engineering geology and law. Additionally, volumes of crucial information often lie in diffi­cult-to-find gray literature. Management recommendations and decisions should be based on assessments of state-of-the-art information, but fall short when im­portant patterns and relationships are overlooked. The Karst Information Portal (KIP) offers a solution to these problems. Con­ceived in 2005 and launched in June 2007, KIP grew as a partnership among the International Union of Speleology, National Cave and Karst Research Institute, University of New Mexico, and University of South Florida. Key features com­plete or in development include: federated searches of Web sites for more efficient and reliable location of key research papers and information; a searchable database of multidisciplinary karst information; a library of on-line karst papers, reports and theses; and a collaborative international on-line workspace to post and evaluate im­ages, maps, databases, and other published and unpublished information. Like other virtual research portals, KIP will continue to grow as existing and future partners contribute information by plugging Web sites and databases into the network. KIP will not duplicate existing databases but will more efficiently access and process them with superior tools. Additional partners can help fulfill KIP’s potential in revolutionizing cave and karst stewardship through advanced and collaborative integration of data and ideas

The Karst Information Portal (KIP): Developing a Network of Geographic and Geologic Karst Information

The difficulty of sharing geologic and geographic karst information is well documented. While there is a significant body of internationally accessible literature, important works are largely unknown or inaccessible. Some of the more difficult documents to access include maps, databases, technical reports, graduate theses or dissertations, images, video, and government publications. Also, karst related documents published in lessaccessible languages are hard to access or find—especially those published prior to the information age. In order to address this issue, the Karst Information Portal (KIP) was formed in 2005 and launched in 2007. KIP is an evolving international community of scientists, information specialists, and other researchers seeking to promote information sharing and access to published and unpublished research in order to advance karst, cave, and aquifer research and stewardship. The portal is a searchable database of a variety of karst information that is accessible anywhere in the world. Like other well-known portals, such as Chronos, the KIP will continue to grow as users and developers bring more information within the network. We seek to expand KIP by developing partners in to populate the portal with pertinent databases, maps, gray literature, and other information of interest to the geoscience community. The KIP has the potential to transform geologic and geographic research in karst by creating new knowledge through the integration of international information in the discipline

Enhancing Communication and Knowledge Discovery Among Karst Biospeleologists: The Role of the Karst Information Portal (KIP)

Speleology is an intrinsically multidisciplinary field of study that draws upon a substantial grey literature (for exapmle, agency research reports) that is poorly indexed, difficult to access, and generated in many different languages. The creation and implementation of the Karst Information Portal (KIP) beginning in 2005 addresses these and other information access and management problems by focusing on providing a global portal that will provide a gateway to the Web for karst information and services. Digital versions of many karst resources will be available through KIP. Databases, datasets, bibliographies, images, grey literature, and the like. that have been created by karst scientists worldwide will be accessible through KIP federated searching (simultaneous search of multiple data sources) of identified karst sites on the Internet. The core idea is not to recreate databases that have been developed by others but to make those that exist (or are being developed now and in the future) more universally available and provide advanced tools for using them. In June 2007, an enhanced KIP was launched that includes The Guide to Speleological Literature database, a scanning electron micrograph repository, and links to key electronic karst resources. Knowledge discovery, commenting by users, and collaborative workspaces are being tested through the SEM (scanning electron microscopy) database in a joint project with Los Alamos National Laboratory. Biospeleology partners are needed to create and maintain databases of information and resources pertaining to biospeleology that can be linked to KIP

Enhancing Communication and Knowledge Discovery Among Karst Scientists: The Role of the Karst Information Portal (KIP)

Karst science is an intrinsically multidisciplinary field of study that is poorly indexed and difficult to access. While much of the significant body of international literature is accessible, many important works remain largely unknown or inaccessible. Some of the more difficult and essential documents to access are what is characterized as gray literature, which includes maps, databases, technical reports, graduate theses or dissertations, images, video, and government publications. Also, karst-related documents published in less-accessible languages are hard to access or find. The creation and implementation of the Karst Information Portal (KIP) beginning in 2005 addresses these and other information access and management problems by focusing on providing a global portal to provide a gateway to the Web for karst information and services. Digital versions of many karst resources will be available through KIP. Databases, datasets, bibliographies, images, grey literature, etc. that have been created world-wide by karst scientists, explorers, and educators will be accessible through KIP federated searching (i.e. simultaneous search of multiple data sources) identified karst sites on the Internet. In June 2007, an enhanced KIP was launched that includes The Guide to Speleological Literature database, a scanning electron micrograph repository, and links to key electronic karst resources. Like other well-known portals, such as Chronos, the KIP will continue to grow as users and developers bring more information within the network. We seek to expand KIP by developing partnerships to populate the portal with pertinent databases, maps, gray literature, and other information of interest to the geoscience community. Knowledge discovery, commenting by users, and collaborative workspaces (collaboratoria) are being tested through an image database of scanning electron micrographs in a joint project with Los Alamos National Laboratory. The KIP has the potential to transform geologic, biological, paleontological, archaeological, and historical research in karst by creating knew knowledge through the integration of international information in the discipline

CMS Physics Technical Design Report: Addendum on High Density QCD with Heavy Ions

This report presents the capabilities of the CMS experiment to explore the rich heavy-ion physics programme offered by the CERN Large Hadron Collider (LHC). The collisions of lead nuclei at energies $\sqrt{s_{NN}}= 5.5\,{\rm TeV}$ , will probe quark and gluon matter at unprecedented values of energy density. The prime goal of this research is to study the fundamental theory of the strong interaction \u2014 Quantum Chromodynamics (QCD) \u2014 in extreme conditions of temperature, density and parton momentum fraction (low- x ). This report covers in detail the potential of CMS to carry out a series of representative Pb-Pb measurements. These include "bulk" observables, (charged hadron multiplicity, low p T inclusive hadron identified spectra and elliptic flow) which provide information on the collective properties of the system, as well as perturbative probes such as quarkonia, heavy-quarks, jets and high p T hadrons which yield "tomographic" information of the hottest and densest phases of the reaction