Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25+ NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25+ NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy

The Diffusion of Doctrinal Innovations in Tort Law

This Article examines the spread of “successful” common-law doctrinal innovations in the law of torts. Its analysis reveals recurring influences upon and tendencies within the diffusion of novel tort doctrines across the states. The studied diffusion patterns also document a trend toward common-law doctrinal “stabilization” over the past quarter-century. As detailed herein, this stabilization owes in part to altered adoption dynamics associated with the ongoing shrinkage and fragmentation of the common-law tort dockets entertained by state supreme courts. Prevailing conditions will make it difficult, this Article concludes, for even well-received common-law doctrinal innovations of the future to match the rapid diffusion rates associated with tort-law innovations that spread during the 1960s, 1970s, and 1980s

Facilitating Crimes: An Inquiry Into the Selective Invocation of Offenses Within the Continuum of Criminal Procedures

Conventional wisdom holds that all crimes run a gauntlet of procedures that begins with an investigation and arrest, leads to charging and arraignment, and culminates (at least in successful prosecutions) with a conviction and the application of punishment. The reality is more nuanced. As this article\u27s empirical study of the invocation and utilization of specific crimes contained within the United States Code indicates, there exist “detention crimes,” “charging crimes,” and “pleading crimes,” three types of offenses that, as applied, tend to implicate only portions of this sequence. This article examines the three categories of “facilitating crimes” and the benefits and drawbacks associated with their use. On the one hand, these offenses may reflect the more sensitive criminalization of specific misconduct; on the other, the failure of these crimes to engage the entire procedural continuum may compromise their legitimacy. The article concludes that while facilitating crimes and the practices that produce these offenses raise significant concerns, a species of pleading crime that categorically could not form the basis for an arrest or an initial charge, but could provide grounds for a negotiated plea bargain, might be considered as a replacement for some conventional crimes

Study protocol for a randomised controlled trial of invasive versus conservative management of primary spontaneous pneumothorax

INTRODUCTION: Current management of primary spontaneous pneumothorax (PSP) is variable, with little evidence from randomised controlled trials to guide treatment. Guidelines emphasise intervention in many patients, which involves chest drain insertion, hospital admission and occasionally surgery. However, there is evidence that conservative management may be effective and safe, and it may also reduce the risk of recurrence. Significant questions remain regarding the optimal initial approach to the management of PSP

A Moment in the The Times: Law Professors and the Court-Packing Plan

When Franklin Roosevelt unveiled his court-packing plan, law professors found themselves in an unfamiliar position. For perhaps the first time ever, their professional opinions were being sought by journalists and politicians, for consumption by the general public. In faculty meetings and private correspondence, law professors considered the propriety of taking a stand for or against the President\u27s plan. Ultimately, some professors chose to go public with their support (or opposition); others considered such commentary as a form of advocacy that was incompatible with their job descriptions. This article relates and examines the debate among law professors over both the court-packing proposal and their proper role, if any, in the public sphere

Sorry Seems to be the Hardest Word: The Fair Sentencing Act of 2010, Crack, and Methamphetamine

This Essay considers the circumstances that led to the enactment of the Fair Sentencing Act of 2010, which increased the quantities of crack cocaine necessary to implicate mandatory minimum prison sentences for federal drug trafficking crimes, and considers whether the Act might facilitate re-evaluation of the penalty scheme applicable to methamphetamine