An antibody-interleukin 2 fusion protein overcomes tumor heterogeneity by induction of a cellular immune response.

Antibody-based therapies for cancer rely on the expression of defined antigens on neoplastic cells. However, most tumors display heterogeneity in the expression of such antigens. We demonstrate here that antibody-targeted interleukin 2 delivery overcomes this problem by induction of a host immune response. Immunohistochemical analysis demonstrated that the antibody-interleukin 2 fusion protein-induced eradication of established tumors is mediated by host immune cells, particularly CD8+ T cells. Because of this cellular immune response, antibody-directed interleukin 2 therapy is capable to address established metastases displaying substantial heterogeneity in expression of the targeted antigen. This effector mechanism further enables the induction of partial regressions of large subcutaneous tumors that exceeded more than 5% of the body weight. These observations indicate that antibody-directed cytokine delivery offers an effective new tool for cancer therapy.

Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers.

5'-Deoxy-5'-methylthioadenosine phosphorylase (methylthioadeno-sine: ortho-phosphate methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism and in the regulation of transmethylation reactions. MTAP is abundant in normal cells but is deficient in many cancers. Recently, the genes for the cyclin-dependent kinase inhibitors p16 and p15 have been localized to the short arm of human chromosome 9 at band p21, where MTAP and interferon alpha genes (IFNA) also map. Homozygous deletions of p16 and p15 are frequent malignant cell lines. However, the order of the MTAP, p16, p15, and IFNA genes on chromosome 9p is uncertain, and the molecular basis for MTAP deficiency in cancer is unknown. We have cloned the MTAP gene, and have constructed a topologic map of the 9p21 region using yeast artificial chromosome clones, pulse-field gel electrophoresis, and sequence-tagged-site PCR. The MTAP gene consists of eight exons and seven introns. Of 23 malignant cell lines deficient in MTAP protein, all but one had complete or partial deletions. Partial or total deletions of the MTAP gene were found in primary T-cell acute lymphoblastic leukemias (T-ALL). A deletion breakpoint of partial deletions found in cell lines and primary T-ALL was in intron 4. Starting from the centromeric end, the gene order on chromosome 9p2l is p15, p16, MTAP, IFNA, and interferon beta gene (IFNB). These results indicate that MTAP deficiency in cancer is primarily due to codeletion of the MTAP and p16 genes.

Characterization of immature thymocyte lines derived from T-cell receptor or recombination activating gene 1 and p53 double mutant mice.

The T-cell receptor (TCR) beta chain is instrumental in the progression of thymocyte differentiation from the CD4-CD8- to the CD4+CD8+ stage. This differentiation step may involve cell surface expression of novel CD3-TCR complexes. To facilitate biochemical characterization of these complexes, we established cell lines from thymic lymphomas originating from mice carrying a mutation in the p53 gene on the one hand and a mutation in TCR-alpha, TCR-beta, or the recombination activating gene 1 (RAG-1) on the other hand. The cell lines were CD4+CD8+ and appeared to be monoclonal. A cell line derived from a RAG-1 x p53 double mutant thymic lymphoma expressed low levels of CD3-epsilon, -gamma, and -delta on the surface. TCR-alpha x p53 double mutant cell lines were found to express complexes consisting of TCR-beta chains associated with CD3-epsilon, -gamma, and -delta chains and CD3-zeta zeta dimers. These lines will be useful tools to study the molecular structure and signal transducing properties of partial CD3-TCR complexes expressed on the surface of immature thymocytes.

The Future Direction of Delaware Law (Including a Brief Exegesis on Fee Shifting Bylaws)

Delaware sets the governance standards for most public companies. The ability to attract corporations could not be explained solely by the existence of a favorable statutory regime. Delaware was not invariably the first or the only state to implement management friendly provisions. Given the interpretive gaps in the statute and the critical importance of the common law in the governance process, courts played an outsized role in setting legal standards. The management friendly nature of the Delaware courts contributed significantly to the state’s attraction to public corporations. A current example of a management friendly trend in the case law had seen the recent decisions setting out the board’s authority to adopt bylaws under Section 109 of the Delaware General Corporation Law (DGCL), particularly those involving the shifting of fees in litigation against the corporation or its directors. The DGCL allows bylaws that address “the business of the corporation, the conduct of its affairs, and its rights or powers or the rights or powers of its stockholders, directors, officers or employees.” The broad parameters are, however, subject to limits. Bylaws cannot be inconsistent with the certificate of incorporation or “the law.” Law includes the common law. The Delaware courts have used the limitations imposed by “the law” to severely restrict the reach of shareholder inspired bylaws. The courts have not used the same principles to impose similar restraints on bylaws adopted by the board of directors. This can be seen with respect to bylaws that restrict or even eliminate the right of shareholders to bring actions against management and the corporation. In ATP Tour, Inc. v. Deutscher Tennis Bund the court approved a fee shifting bylaw that had littl relationship to the internal affairs of the corporation. The decision upheld the bylaw as facially valid.The decision ignored a number of obvious legal infirmities. Among other things, the decision did not adequately address the requirement in Section 109(b) that bylaws be consistent with “the law.” The decision obliquely acknowledged that the provisions would “by their nature, deter litigation” but otherwise made no effort to assess the impact of this deterrence on shareholders causes of action. The provision in fact had the practical effect of restricting, if not eliminating, litigation rights granted by the DGCL and the common law. Perhaps most significantly, however, the bylaws significantly limited common law rights of shareholders to bring actions against the corporation and the board. Given the high dismissal rates for these actions, fee shifting bylaws imposed a meaningful risk of liability on plaintiffs. Moreover, because judgments in derivative suits were paid to the corporation, shareholders serving as plaintiffs confronted the risk of liability without any offsetting direct benefit. By preventing suits in this area, the bylaw effectively insulated the behavior of boards from legal challenge. The ATP decision was poorly reasoned and overstepped acceptable boundaries. The management friendly decision threatened the preeminent role of Delaware in the development of corporate law. The decision raised the specter of federal intervention and the potential for meaningful competition from the states. Because the opinion examined the bylaw in the context of non-stock companies, the reasoning may remain applicable only to those entities and never make the leap to for-profit stock corporations. Nonetheless, the analysis reflects a management friendly approach that does not adequately take into account the impact of the provision on the rights of shareholders.

Evolution of the last koninckinids (Athyridida, Koninckinidae), a precursor signal of the early Toarcian mass extinction event in the Western Tethys

Koninckinids are a suitable group to shed light on the biotic crisis suffered by brachiopod fauna in the Early Jurassic. Koninckinid fauna recorded in the late Pliensbachian–early Toarcian from the easternmost Subbetic basin is analyzed and identified as a precursor signal for one of the most conspicuous mass extinction events of the Phylum Brachiopoda, a multi-phased interval with episodes of changing environmental conditions, whose onset can be detected from the Elisa–Mirabile subzones up to the early Toarcian extinction boundary in the lowermost Serpentinum Zone (T-OAE). The koninckinid fauna had a previously well-established migration pattern from the intra-Tethyan to the NW-European basins but a first phase with a progressive warming episode in the Pliensbachian–Toarcian transition triggered a koninckinid fauna exodus from the eastern/central Tethys toward the westernmost Mediterranean margins. A second stage shows an adaptive response to more adverse conditions in the westernmost Tethyan margins and finally, an escape and extinction phase is detected in the Atlantic areas from the mid-Polymorphum Zone onwards up to their global extinction in the lowermost Serpentinum Zone. This migration pattern is independent of the paleogeographic bioprovinciality and is unrelated to a facies-controlled pattern. The anoxic/suboxic environmental conditions should only be considered as a minor factor of partial control since well-oxygenated habitats are noted in the intra-Tethyan basins and this factor is noticeable only in the second westward migratory stage (with dwarf taxa and oligotypical assemblages). The analysis of cold-seep proxies in the Subbetic deposits suggests a radiation that is independent of methane releases in the Subbetic basin.

Abstracts of legislation relating to Harvard College governance (manuscript notebook), ca. 1723

Octavo-sized notebook containing handwritten abstracts of Massachusetts General Court legislation between 1650 and August 24, 1723 related to Harvard governance. The volume contains informal notes with extracts and summaries of legislation that established or amended the makeup and power of the Harvard Corporation. The authors of the volume are unidentified, but the notes appear to be in two different hands. The volume was presumably created during the fellowship controversy that erupted in the early 1720s after tutors Henry Flynt, Nicholas Sever, and Thomas Robie presented a memorial to the Board of Overseers calling for the tutors' right of fellowship in the Corporation.

The future of the Eurozone and the role of the German Constitutional Court. Research Papers in Law, 05/2012

[Introduction.] Necessary reforms towards a deepened and increased European shaped economic, financial and budgetary policy, paraphrased with the term “fiscal union”, could possibly reach constitutional limits. In its EFSF judgment1, the German Constitutional Court, following the Lisbon judgment in which certain government tasks were determined as being part of the “constitutional identity”2, connected the budget right of the parliament via the principle of democracy to the eternity clause of Art. 79 para 3 Basic Law. A transfer of essential parts of the budget right of the German Bundestag, which would be in conflict with the German constitution, is said to exist when the determination of the nature and amount of the tax affecting the citizens is largely regulated on the supranational level and thereby deprived of the Bundestag’s right to disposition. A reform of the Economic and Monetary Union that touches the core of the budget right can, according to the German Federal Court, with regard to Art. 79 (3) of the Basic Law only be realized by way of Art. 146 of the Basic Law, thus with a new constitution given by the people that replaces the Basic Law.3

The Member States’ Initiatives: An Inter-Institutional Turf War after the Treaty of Lisbon

With the introduction of the Treaty of Lisbon came the possibility for Member States to launch an initiative under the Ordinary Legislative Procedure. This came into being as the scope of co-decision was expanded to cover the more sensitive issues of the third pillar (such as judicial cooperation in criminal matters and police cooperation). It was considered necessary that Member States have a shared right of initiative with the European Commission. One case in which the right of initiative was invoked was the Initiative for a European Protection Order (EPO). This dossier is one of the first and few cases in which the Member States’ Initiative after the Treaty of Lisbon was used. It resulted in a turf war between the Presidency and the Commission regarding the scope of the Member States’ Initiatives. This article looks into the Member States’ Initiative as it was introduced after the Treaty of Lisbon and the debate that took place on the EPO.

l bilanciamento tra le libertà economiche e i diritti sociali collettivi operato dalla Corte di Giustizia è un contemperamento tra diritti equiordinati?* = The balance between economic freedoms and collective social rights and actions; Court of Justice is a choice between rights equiordinati? Actions by the Court of Justice. WP C.S.D.L.E. “Massimo D’Antona”.INT – 98/2012

In the Viking and Laval judgments and more recently in the Comm. v. Germany ruling, the Court of Justice applied the proportionality test to collective rights, setting a series of restrictions to the exercise of the right to strike and the right to collective bargaining. The way the ECJ balances the economic freedoms and the social rights is indeed very different from that of the Italian Constitutional Court. Unlike the European Union Treaties, the Italian Constitution recognizes an important role to the right to take collective action which has to be connected with article 3, paragraph 2, consequently the right of strike is more protected than the exercise of economic freedoms.

Freedom of movement of persons - the building block of European growth. CHALLENGE EUROPE Issue 22 - Challenges and new beginnings: Priorities for the EU's new leadership, September 2014.

The European integration project is founded on values and principles which are simple, equal, and advantageous for all. Freedom of movement of persons is one of the main cornerstones of EU success. It is a fundamental, cherished right of EU citizens. Thanks to this liberty, European citizenship is real, concrete and attractive. Moreover, it spurs economic growth and technological development. But because freedom of movement has become an obvious feature of our day-to-day lives, some of us tend to underestimate its consequences. Important recent developments mean that we must renew our commitment to defend this building-block of a Europe whole and free.

Citizenship in the discourse of Egyptian political parties. EUSpring Working Paper No. 6, June 2015 [also Citizenship Report no. 3]

The concept of citizenship is one of the most complicated in political and social sciences. Its long process of historical development makes dealing with it particularly complicated. Citizenship is by nature a multi-dimensional concept: there is a legal citizenship, referring first to the equal legal status of individuals, for instance the equality between men and women. Legal citizenship also refers to a political dimension, the right to start and/or join political parties, or political participation more broadly. Thirdly, it has a religious dimension relating to the right of all religious groups to equally and freely practice their religious customs and rituals. Finally, legal citizenship possesses a socio-economic dimension related to the non-marginalisation of different social categories, for instance women. All of these dimensions, far from being purely objects of legal texts and codifications, are emerging as an arena of political struggle within the Egyptian society. Citizenship as a concept has its roots in European history and, more specifically, the emergence of the nation state in Europe and the ensuing economic and social developments in these societies. These social developments and the rise of the nation state have worked in parallel, fostering the notion of an individual citizen bestowed with rights and obligations. This gradual interaction was very different from what happened in the context of the Arab world. The emerging of the nation state in Egypt was an outcome of modernisation efforts from the top-down; it coercively redesigned the social structure, by eliminating or weakening some social classes in favour of others. These efforts have had an impact on the state-society relation at least in two respects. First, on the overlapping relation between some social classes and the state, and second, on the ability of some social groups to self-organise, define and raise their demands. This study identifies how different political parties in Egypt envision the multi-dimensional concept of citizenship. We focus on the following elements: Nature of the state (identity, nature of the regime) Liberties and rights (election laws, political party laws, etc.) Right to gather and organise (syndicates, associations, etc.) Freedom of expression and speech (right to protest, sit in, strike, etc.) Public and individual liberties (freedom of belief, personal issues, etc.) Rights of marginalised groups (women, minorities, etc.)

Geochemistry of basalts from ODP Leg 49, North Atlantic Ocean

The geochemistry of basalts recovered from seven sites in the North Atlantic is described with particular reference to minor elements. Three sites (407, 408, and 409) along the same mantle flow line, transverse to the Reykjanes Ridge at about 63°N, provide information on the composition of basalts erupted over a 34-m.y. interval between 2.3 and 36 m.y. ago. At Site 410, at 45°N, penetration into 10 m.y.-old crust west of the ridge axis permits comparisons with young basalts dredged from the median valley at 45°N. Three sites in the FAMOUS area at about 36°N provided material from very young (1 m.y.) basaltic crust (Site 411), and material to test the geochemical coherence of basalts of different ages (1.5 and 3.5 m.y.) on either side of a fracture zone (Sites 412 and 413). These sites complement earlier data from dredged and drilled sites (Leg 37) in the FAMOUS area. At Site 407, four geochemically distinct basalt units occur, with different normative and rare-earth element (REE) characteristics, and there is a clear correlation with magnetic stratigraphy. Yet there is a remarkable consistency in incompatible element ratios between these units, indicating derivation from an essentially similar mantle source. The basalts from the younger sites, 408 and 409, show a similar range of normative and REE variation, but incompatible element ratios are identical to those at Site 407, indicating that basalts at all three sites were produced from a mantle source which was geochemically relatively uniform. Rare-earth differences between the basalts can be interpreted in terms of variations in the degree and depth of partial melting causing HREE (+Y) retention in the source, although there may be some inter-site differences with respect to REE. A similar picture is presented at 45°N. Apparently a range of tholeiitic, transitional, and alkalic basalts were being erupted 10 m.y. ago, which have almost identical geochemical characteristics to those recently erupted in the median valley at 45°N. Incompatible element ratios are markedly different from those recorded at the Reykjanes Ridge. Basalts recovered from the FAMOUS sites are geochemically similar to previous samples recovered from the FAMOUS area, and their incompatible element ratios are similar, but not identical, to those at 45°N. However, total trace element levels are consistently lower than in 45°N basalts, which might imply smaller degrees of partial melting and/or greater depths of magma generation at 45°N, or higher trace element levels in the mantle source at 45°N. Few of the basalts recovered on Leg 49 have the geochemical characteristics of typical "MORB" (e.g., Nazca Plate, Leg 34). The data strongly support models invoking geochemical inhomogeneity in the source regions of basalts produced at the Mid-Atlantic Ridge. However, the data also introduce an additional time factor into such models and demonstrate the uniformity of the mantle source at a particular ridge sector (over periods in excess of 30 m.y.), while emphasizing the marked differences along the ridge. Mixing models invoking "depleted" and "enriched" mantle sources would seem to be inadequate to account for the observed variations.

An evaluation of the 1979 Texas law (V.C.S., Sec. 73.A.) which requires frontage road traffic to yield at freeway ramps. Interim report.

Texas State Department of Highways and Public Transportation, Transportation Planning Division, Austin

Amending the Financial institutions regulatory and interest rate control act : hearing before the Subcommittee on Financial Institutions Supervision, Regulation and Insurance of the Committee on Banking, Finance and Urban Affairs, House of Representatives, Ninety-sixth Congress, first session, on H.R. 1903 ... February 21, 1979.

"Serial 96-27."

Application of law on search and seizures to police procedures /

"A transcript of lectures and discussions relative to the law of search and seizures and its effect on law enforcement, conducted by the U.S. Attorney's Office of the District of Columbia in cooperation with the Metropolitan Police Department, Washington, D.C."