Targeting Chemotherapy to Decondensed H3K27me3-Marked Chromatin of AML Cells Enhances Leukemia Suppression.

Despite treatment with intensive chemotherapy, acute myelogenous leukemia (AML) remains an aggressive malignancy with a dismal outcome in most patients. We found that AML cells exhibit an unusually rapid accumulation of the repressive histone mark H3K27me3 on nascent DNA. In cell lines, primary cells and xenograft mouse models, inhibition of the H3K27 histone methyltransferase EZH2 to decondense the H3K27me3-marked chromatin of AML cells enhanced chromatin accessibility and chemotherapy-induced DNA damage, apoptosis, and leukemia suppression. These effects were further promoted when chromatin decondensation of AML cells was induced upon S-phase entry after release from a transient G1 arrest mediated by CDK4/6 inhibition. In the p53-null KG-1 and THP-1 AML cell lines, EZH2 inhibitor and doxorubicin cotreatment induced transcriptional reprogramming that was, in part, dependent on derepression of H3K27me3-marked gene promoters and led to increased expression of cell death-promoting and growth-inhibitory genes.In conclusion, decondensing H3K27me3-marked chromatin by EZH2 inhibition represents a promising approach to improve the efficacy of DNA-damaging cytotoxic agents in patients with AML. This strategy might allow for a lowering of chemotherapy doses, with a consequent reduction of treatment-related side effects in elderly patients with AML or those with significant comorbidities. SIGNIFICANCE: Pharmacological inhibition of EZH2 renders DNA of AML cells more accessible to cytotoxic agents, facilitating leukemia suppression with reduced doses of chemotherapy.See related commentary by Adema and Colla, p. 359.

Toward understanding the impact of artificial intelligence on labor.

Rapid advances in artificial intelligence (AI) and automation technologies have the potential to significantly disrupt labor markets. While AI and automation can augment the productivity of some workers, they can replace the work done by others and will likely transform almost all occupations at least to some degree. Rising automation is happening in a period of growing economic inequality, raising fears of mass technological unemployment and a renewed call for policy efforts to address the consequences of technological change. In this paper we discuss the barriers that inhibit scientists from measuring the effects of AI and automation on the future of work. These barriers include the lack of high-quality data about the nature of work (e.g., the dynamic requirements of occupations), lack of empirically informed models of key microlevel processes (e.g., skill substitution and human-machine complementarity), and insufficient understanding of how cognitive technologies interact with broader economic dynamics and institutional mechanisms (e.g., urban migration and international trade policy). Overcoming these barriers requires improvements in the longitudinal and spatial resolution of data, as well as refinements to data on workplace skills. These improvements will enable multidisciplinary research to quantitatively monitor and predict the complex evolution of work in tandem with technological progress. Finally, given the fundamental uncertainty in predicting technological change, we recommend developing a decision framework that focuses on resilience to unexpected scenarios in addition to general equilibrium behavior.

ß1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation.

Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (ß1wt /TRAMP) mice as well as in mice carrying a conditional ablation of ß1 integrins in the prostatic epithelium (ß1pc-/- /TRAMP). Since JNK is known to be suppressed by ß1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in ß1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in ß1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of ß1wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the ß1/IGF-IR crosstalk and report that ß1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that ß1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.

Do Extraordinary Claims Require Extraordinary Evidence?

In 1979 astronomer Carl Sagan popularized the aphorism "extraordinary claims require extraordinary evidence" (ECREE). But Sagan never defined the term "extraordinary." Ambiguity in what constitutes "extraordinary" has led to misuse of the aphorism. ECREE is commonly invoked to discredit research dealing with scientific anomalies, and has even been rhetorically employed in attempts to raise doubts concerning mainstream scientific hypotheses that have substantive empirical support. The origin of ECREE lies in eighteenth-century Enlightenment criticisms of miracles. The most important of these was Hume's essay On Miracles. Hume precisely defined an extraordinary claim as one that is directly contradicted by a massive amount of existing evidence. For a claim to qualify as extraordinary there must exist overwhelming empirical data of the exact antithesis. Extraordinary evidence is not a separate category or type of evidence--it is an extraordinarily large number of observations. Claims that are merely novel or those which violate human consensus are not properly characterized as extraordinary. Science does not contemplate two types of evidence. The misuse of ECREE to suppress innovation and maintain orthodoxy should be avoided as it must inevitably retard the scientific goal of establishing reliable knowledge.

School Choice, School Quality and Postsecondary Attainment.

We study the impact of a public school choice lottery in Charlotte-Mecklenburg schools on college enrollment and degree completion. We find a significant overall increase in college attainment among lottery winners who attend their first choice school. Using rich administrative data on peers, teachers, course offerings and other inputs, we show that the impacts of choice are strongly predicted by gains on several measures of school quality. Gains in attainment are concentrated among girls. Girls respond to attending a better school with higher grades and increases in college-preparatory course-taking, while boys do not.

For-profit colleges.

For-profit, or proprietary, colleges are the fastest-growing postsecondary schools in the nation, enrolling a disproportionately high share of disadvantaged and minority students and those ill-prepared for college. Because these schools, many of them big national chains, derive most of their revenue from taxpayer-funded student financial aid, they are of interest to policy makers not only for the role they play in the higher education spectrum but also for the value they provide their students. In this article, David Deming, Claudia Goldin, and Lawrence Katz look at the students who attend for-profits, the reasons they choose these schools, and student outcomes on a number of broad measures and draw several conclusions. First, the authors write, the evidence shows that public community colleges may provide an equal or better education at lower cost than for-profits. But budget pressures mean that community colleges and other nonselective public institutions may not be able to meet the demand for higher education. Some students unable to get into desired courses and programs at public institutions may face only two alternatives: attendance at a for-profit or no postsecondary education at all. Second, for-profits appear to be at their best with well-defined programs of short duration that prepare students for a specific occupation. But for-profit completion rates, default rates, and labor market outcomes for students seeking associate's or higher degrees compare unfavorably with those of public postsecondary institutions. In principle, taxpayer investment in student aid should be accompanied by scrutiny concerning whether students complete their course of study and subsequently earn enough to justify the investment and pay back their student loans. Designing appropriate regulations to help students navigate the market for higher education has proven to be a challenge because of the great variation in student goals and types of programs. Ensuring that potential students have complete and objective information about the costs and expected benefits of for-profit programs could improve postsecondary education opportunities for disadvantaged students and counter aggressive and potentially misleading recruitment practices at for-profit colleges, the authors write.