Explore the vast range of titles available.

This Article presents findings from the most comprehensive empirical study to date on how the federal courts of appeals have applied Chevron deference—the doctrine under which courts defer to a federal agency's reasonable interpretation of an ambiguous statute that it administers. Based on 1,558 agency interpretations the circuit courts reviewed from 2003 through 2013 (where they cited Chevron), we found that the circuit courts overall upheld 71% of interpretations and applied Chevron deference 77% of the time. But there was nearly a twenty-five-percentage-point difference in agency-win rates when the circuit courts applied Chevron deference than when they did not. Among many other findings, our study reveals important differences across circuits, agencies, agency formats, and subject matters as to judicial review of agency statutory interpretations. Based on prior empirical studies of judicial deference at the Supreme Court, however, our findings suggest that there may be a Chevron Supreme and a Chevron Regular: whereas Chevron may not have much of an effect on agency outcomes at the Supreme Court, Chevron deference seems to matter in the circuit courts. That there is a Chevron Supreme and a Chevron Regular may suggest that, in Chevron, the Supreme Court has an effective tool to supervise lower courts' review of agency statutory interpretations. To render Chevron more effective in creating uniformity throughout the circuit courts, the Supreme Court needs to send clearer signals on how courts should apply the deference standard.

The Constitution vests all legislative powers in Congress, yet Congress grants expansive lawmaking authority to federal agencies. As positive political theorists have long explored, Congress intends for federal agencies to faithfully exercise their delegated authority, but ensuring fidelity to congressional wishes is difficult due to asymmetries in information, expertise, and preferences that complicate congressional control and oversight. Indeed, this principal-agent problem has a democratic and constitutional dimension, as the legitimacy of administrative governance may well depend on whether the unelected bureaucracy is a faithful agent of Congress. Despite the predominance of lawmaking by regulation and the decades-long application of principal-agent theory to the regulatory state, we know very little about how federal agencies interpret statutes. This Article looks inside the black box of agency statutory interpretation in the rulemaking context. The Article reports the findings of a 195-question survey of agency rule drafters at seven executive departments (Agriculture, Commerce, Energy, Homeland Security, Health and Human Services, Housing and Urban Development, and Transportation) and two independent agencies (the Federal Communications Commission and the Federal Reserve). Of the 411 officials sent the survey, 128 responded, and their answers shed considerable light on the tools and approaches they use to interpret statutes and draft regulations. The findings uncovered challenge some theories on agency interpretation while reinforcing others. As Congress, courts, and scholars gain more insight into how federal agencies use the canons, legislative history, and judicial deference doctrines in agency statutory interpretation, the relationship between Congress and federal agencies should improve, as should the judicial branch's ability to monitor and faithfully constrain lawmaking by regulation.

Federal agencies are deeply involved in both the foreground and shadows of legislative drafting. In the foreground, agencies draft the substantive legislation the Administration desires to submit to Congress. In the shadows, agencies provide confidential \"technical drafting assistance\" on legislation that originates with congressional staffers. This technical drafting assistance provides Congress with agency expertise on the subject matter, which helps Congress avoid considering legislation that would unnecessarily disrupt the current statutory scheme. It also allows the agency to play an active—yet opaque—role in drafting legislation from the very early stages. In fact, the empirical findings presented in this Article, based on extensive interviews and surveys at some twenty federal agencies, suggest that agencies provide technical drafting assistance on the vast majority of proposed legislation that directly affects them and on most legislation that gets enacted. The underexplored yet widespread practice of legislating in the shadows has important implications for administrative law theory and doctrine, as well as the conventional principal–agent bureaucratic model. On one hand, this phenomenon perhaps supports the growing scholarly call that agencies should be allowed to engage in more purposivist interpretation (than their judicial counterparts) because of their expertise in legislative history and purpose as well as their role in statutory drafting. On the other, this phenomenon may cast some doubt on the foundations for judicial deference to agency statutory interpretations. Agencies are usually intimately involved in drafting legislation that ultimately delegates—to themselves—the authority to interpret that very legislation. In other words, many of the criticisms of agency self-delegation raised against Auer deference could apply with some force to Chevron deference as well. At the very least, scholars should consider more closely the administrative state's role in drafting legislation—especially drafting legislation in the shadows—when evaluating the level of deference courts should give to agency statutory interpretations. Such reconsideration is particularly warranted given the lack of transparency implicated by legislating in the shadows.

Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1 -mutated ( NPM1 mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1 mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts. LncRNAs at the HOX gene locus are increased in expression in NPM1 mutant acute myeloid leukemia. In this study, the authors show that one such lncRNA, HOX3B-AS3, has a role in regulating gene transcription and protein synthesis in leukemia cells.

In 1946, the Administrative Procedure Act (APA) set forth the criteria for “formal” adjudication, requiring an administrative law judge to make the initial determination and the agency head to have the final word. That is the lost world. Today, the vast majority of agency adjudications Congress has created are not paradigmatic “formal” adjudications as set forth in the APA. It turns out that there is great diversity in the procedures by which federal agencies adjudicate. This new world involves a variety of less-independent administrative judges, hearing officers, and other agency personnel adjudicating disputes. But, like in the lost world, the agency head retains final decision-making authority. In 2011, Congress created yet another novel agency tribunal—the Patent Trial and Appeal Board (PTAB)—to adjudicate patent validity disputes between private parties. Questions abound concerning the PTAB’s proper place in the modern administrative state, as its features depart from the textbook accounts of APA-governed “formal” adjudication. Many of these questions are working their way through the Federal Circuit and to the Supreme Court. Indeed, the Supreme Court recently held in Oil States Energy Services that PTAB adjudication does not unconstitutionally strip parties of their property rights in issued patents—while expressly leaving open many questions concerning the limits of administrative adjudication. This Article situates PTAB adjudication within administrative law’s larger landscape of agency adjudication. By surveying this new world of agency adjudication, we find that PTAB adjudication is not extraordinary. But we also identify one core feature of modern agency adjudication that is absent at the PTAB: the Director of the Patent and Trademark Office lacks final decision-making authority. To be sure, the Director has some power to influence outcomes: in the past, she has ordered rehearing of cases and stacked the board with administrative patent judges who share her substantive vision. But these second-best means of agency-head control raise problems of their own, including constitutional questions and inefficiencies in agency performance. This Article concludes by exploring alternative mechanisms that would remedy the lack of agency-head review at the PTAB.

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.

The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression--but not activity--of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.

Targeted mutation assessment of 81 genes in 1021 adults with de novo acute myeloid leukemia (AML) identified recurrent mutations in the neurofibromin 1 (NF1) gene in 52 (5.1%) patients, including 36 (5.2%) younger and 16 (4.8%) older patients, which suggests NF1 belongs to the 20 most frequently mutated genes in adult AML. NF1 mutations were found throughout the gene, and comprised missense, frameshift, and nonsense mutations. One mutation hotspot, at amino acid threonine 676 (Thr676), was found in 27% of AML patients with NF1 mutations. NF1-mutated patients belonged more often to the adverse European LeukemiaNet (ELN) risk category than NF1 wild-type patients. Among patients aged <60 years, the presence of NF1 Thr676 mutations was associated with lower complete remission (CR) rates (P = 0.04) and shorter overall survival (OS; P = 0.01), as was the presence of any NF1 mutation in patients in the adverse ELN risk category (CR, P = 0.05; OS, P < 0.001). CR rates were also lower in NF1-mutated patients aged ≥60 years compared with NF1 wild-type patients (P = 0.001). In summary, our findings provide novel insights into the frequency of NF1 mutations in AML, and are suggestive of an adverse prognostic impact in patients treated with standard chemotherapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS (ULMS) is an aggressive tumor with poor prognosis and a high risk of recurrence and death, regardless of the stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that reversibly binds to exportin 1 (XPO1), thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. In this study, we evaluated the effects of selinexor in combination with doxorubicin and eribulin in the LMS tumor model in vitro and in vivo. Treatment of selinexor combined with eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 LMS-derived xenografts. Immunohistochemical assessment of the tumor tissues showed a significantly reduced expression of proliferation (Ki67) and XPO1 markers following combination therapy compared to the control group. Global transcriptome analyses on tumor tissue revealed that the combination therapy regulates genes from several key cancer-related pathways that are differentially expressed in ULMS tumors. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of selinexor and eribulin in vivo. Results from this study further warrant clinical testing a combination of chemotherapy agents with selinexor to reduce the morbidity and mortality from ULMS.