Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax.

The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. SIGNIFICANCE: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.

56-year-old man • increased heart rate • weakness • intense sweating • horseradish consumption • Dx?

► Increased heart rate ► Weakness ► Intense sweating ► Horseradish consumption.

Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.

By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

Bioarchaeology of Neolithic Çatalhöyük reveals fundamental transitions in health, mobility, and lifestyle in early farmers.

The transition from a human diet based exclusively on wild plants and animals to one involving dependence on domesticated plants and animals beginning 10,000 to 11,000 y ago in Southwest Asia set into motion a series of profound health, lifestyle, social, and economic changes affecting human populations throughout most of the world. However, the social, cultural, behavioral, and other factors surrounding health and lifestyle associated with the foraging-to-farming transition are vague, owing to an incomplete or poorly understood contextual archaeological record of living conditions. Bioarchaeological investigation of the extraordinary record of human remains and their context from Neolithic Çatalhöyük (7100-5950 cal BCE), a massive archaeological site in south-central Anatolia (Turkey), provides important perspectives on population dynamics, health outcomes, behavioral adaptations, interpersonal conflict, and a record of community resilience over the life of this single early farming settlement having the attributes of a protocity. Study of Çatalhöyük human biology reveals increasing costs to members of the settlement, including elevated exposure to disease and labor demands in response to community dependence on and production of domesticated plant carbohydrates, growing population size and density fueled by elevated fertility, and increasing stresses due to heightened workload and greater mobility required for caprine herding and other resource acquisition activities over the nearly 12 centuries of settlement occupation. These changes in life conditions foreshadow developments that would take place worldwide over the millennia following the abandonment of Neolithic Çatalhöyük, including health challenges, adaptive patterns, physical activity, and emerging social behaviors involving interpersonal violence.

Population density and developmental stress in the Neolithic: A diachronic study of dental fluctuating asymmetry at Çatalhöyük (Turkey, 7,100-5,950 BC).

OBJECTIVES: The transition from foraging to farming is usually associated with unprecedented population densities coupled with an increase in fertility and population growth. However, little is known about the biological effects of such demographic changes during the Neolithic. In the present work, we test the relationship between diachronic changes in population size, relative exposure to developmental stressors, and patterns of dental fluctuating asymmetry in the Neolithic population of Çatalhöyük (Turkey, 7,100-5,950 cal BC). MATERIALS AND METHODS: We calculate fluctuating asymmetry of mesio-distal and bucco-lingual diameters of upper and lower permanent canines and first and second molars on a large (N = 259) sample representing adults of both sexes and various age classes. RESULTS: Results show only a moderate decrease of fluctuating asymmetry during the late phase of occupation of the site, possibly linked to a decrease in population density, and no differences in asymmetry between sexes. DISCUSSION: Though preliminary, our data reflect the presence of developmental stressors throughout the occupation of the site, albeit with a slight improvement in living conditions during the latest periods of occupation. At the same time, these data confirm the key role of diet as buffer against the detrimental effects of fluctuating demographic pressures on the biology of prehistoric human populations.

Event-by-Event Hydrodynamics+Jet Energy Loss: A Solution to the R_{AA}⊗v_{2} Puzzle.

High p_{T}>10 GeV elliptic flow, which is experimentally measured via the correlation between soft and hard hadrons, receives competing contributions from event-by-event fluctuations of the low-p_{T} elliptic flow and event-plane angle fluctuations in the soft sector. In this Letter, a proper account of these event-by-event fluctuations in the soft sector, modeled via viscous hydrodynamics, is combined with a jet-energy-loss model to reveal that the positive contribution from low-p_{T} v_{2} fluctuations overwhelms the negative contributions from event-plane fluctuations. This leads to an enhancement of high-p_{T}>10 GeV elliptic flow in comparison to previous calculations and provides a natural solution to the decade-long high-p_{T} R_{AA}⊗v_{2} puzzle. We also present the first theoretical calculation of high-p_{T} v_{3}, which is shown to be compatible with current LHC data. Furthermore, we discuss how short-wavelength jet-medium physics can be deconvoluted from the physics of soft, bulk event-by-event flow observables using event-shape engineering techniques.

Universal flow-driven conical emission in ultrarelativistic heavy-ion collisions.

The double-peak structure observed in soft-hard hadron correlations is commonly interpreted as a signature for a Mach cone generated by a supersonic jet interacting with the hot and dense medium created in ultrarelativistic heavy-ion collisions. We show that it can also arise due to averaging over many jet events in a transversally expanding background. We find that the jet-induced away-side yield does not depend on the details of the energy-momentum deposition in the plasma, the jet velocity, or the system size. Our claim can be experimentally tested by comparing soft-hard correlations induced by heavy-flavor jets with those generated by light-flavor jets.