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Supplementary Figure S1. Leukocyte frequencies in breast tissues. Supplementary Figure S2. Genes expressed in T cells. Supplementary Figure S3. Activity status of T cells. Supplementary Figure S4. TCR clonotypes in breast tissues. Supplementary Figure S5. Functional state of T cells. Supplementary Figure S6. Tumor topology. Supplementary Figure S7. Immune-related amplicons in breast cancer.

Supplementary Table S1. List of tissue samples used. Supplementary Table S2. Raw FACS data in each sample. Supplementary Table S3. List of differentially expressed genes. Supplementary Table S4. Results of GSEA analyses. Supplementary Table S5. Gene lists used for functional analyses. Supplementary Table S6. Statistical modeling of ERBB2 and CC co-amplification; and PDL1 amplification. Supplementary Table S7. ERBB2 and 17q12 FISH data. Supplementary Table S8. List of antibodies used.

Supplementary Figure 1. Pro-inflammatory cytokines are elevated in MF mice and reversed with JAK inhibitor treatment. Supplementary Figure 2. Principal component analysis of MF cells. Supplementary Figure 3. Single cell analysis of immunophenotypically-defined subpopulations from MF and control mice. Supplementary Figure 4. Elevated IL8 expression in MF patients. Supplementary Figure 5. Complete removal of Il6 from the mouse system shows only minor effects on MPLW515L disease. Supplementary Figure 6. Peripheral blood and cytometric flow analysis of MPLW515L transplanted mice with and without Stat3 deletion. Supplementary Figure 7. Constitutive activation of STAT3 in the BM of MPLW515L mice and primary MF patients. Supplementary Figure 8. Schematic illustration of bone marrow transplantation experiments using Stat3-deficient mice or littermate control mice as donors. Supplementary Figure 9. Excision of Stat3 post engraftment prolongs survival and reduces leukocytosis. Supplementary Figure 10. Mutant-restricted deletion of Stat3 does not affect disease severity in vivo. Supplementary Figure 11. Single cell analysis of populations from MF and control mice. Supplementary Figure 12. Mutant and non-mutant hematopoietic cells feature a higher percentage of cytokine secreting cells. Supplementary Figure 13. Single cell analysis of populations from Jak2V617F MF and control mice. Supplementary Figure 14. Mutant and non-mutant hematopoietic cells feature a higher percentage of cytokine secreting cells. Supplementary Figure 15. JAK1/2 inhibition reduces cytokine expression from CD45.1-positive wild-type cells and CD45.2-positive mutant cell population. Supplementary Table 1. Primary myelofibrosis patient characteristics. Supplementary Table 2. Genetic alterations of patient PMF#11.

Lipid rafts are small and dynamic membrane compartments that are enriched with cholesterols or sphingolipids. The coalescence of small lipid rafts into a large lipid raft forms a signaling platform at the immunological synapse that plays a crucial role in controlling T cell activation. Cholesterol is a major component for the formation and function of lipid rafts, but the relationship between the spatial configuration of cholesterols and the lipid raft mediated membrane segregation as well as TCR signaling remains poorly understood. Here we used cholesterol conjugated DNA origami nanostructures, cholesterol nano-patch (CNP) to construct lipid rafts on intact live T cells. CNPs are two-dimensional DNA scaffolds that allow controlling the spatial presentation of cholesterols in the plasma membrane. CNPs efficiently bind onto the T cell membrane and rapidly induce large, polarized membrane cap structures which colocalize with flotillin-1. These CNP mediated membrane segregations, which we define as synthetic lipid rafts, drive membrane segregation of key signaling molecules including TCR and CD45, thereby triggering downstream TCR signaling and subsequently functional T cell responses without antigenic challenges. Our work highlights the potential of CNP in uncovering the mechanisms that lipid rafts induced by cholesterols drive membrane protein reorganization and control T cell signaling, and offers valuable insights into the design of antigen-independent immunotherapies.

Adherens junctions (AJs) create spatially and mechanically discrete microdomains at the interfaces of cells. Using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering, and mechanical loading, we report that AJs also organize proteolytic hotspots for γ-secretase with a spatially-regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE-µdomain) to initialize receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP-µdomain). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of cholesterol-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP-µdomains, AJs prevents inappropriate enzyme-substrate interactions and suppresses spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiative expansion of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of large cell-surface receptors like amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis, and disease.

Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering and mechanical loading, we find that AJs also organize proteolytic hotspots for γ-secretase with a spatially regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE microdomains) to initiate receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP microdomains). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP microdomains, AJs prevent inappropriate enzyme-substrate interactions and suppress spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiation of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of other large cell-surface receptors such as amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease.

Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.

Multifunctional magnetic nanoparticles have shown great promise as next-generation imaging and perturbation probes for deciphering molecular and cellular processes. As a consequence of multicomponent integration into a single nanosystem, pre-existing nanoprobes are typically large and show limited access to biological targets present in a crowded microenvironment. Here, we apply organic-phase surface PEGylation, click chemistry, and charge-based valency discrimination principles to develop compact, modular, and monovalent magnetofluorescent nanoparticles (MFNs). We show that MFNs exhibit highly efficient labeling to target receptors present in cells with a dense and thick glycocalyx layer. We use these MFNs to interrogate the E-cadherin-mediated adherens junction formation and F-actin polymerization in a three-dimensional space, demonstrating the utility as modular and versatile mechanogenetic probes in the most demanding single-cell perturbation applications.

To cope with the negative oil futures price caused by the COVID-19 recession, global commodity futures exchanges temporarily switched the option model from Black--Scholes to Bachelier in 2020. This study reviews the literature on Bachelier's pioneering option pricing model and summarizes the practical results on volatility conversion, risk management, stochastic volatility, and barrier options pricing to facilitate the model transition. In particular, using the displaced Black-Scholes model as a model family with the Black-Scholes and Bachelier models as special cases, we not only connect the two models but also present a continuous spectrum of model choices.

This paper studies a continuous-time optimal consumption and portfolio selection problem when an economic agent with recursive utility has stochastic income and liquidity constraints. To tackle this problem, we introduce a transform of the Hamilton-Jacobi-Bellman equation into a free boundary value ODE (ordinary differential equation). This transform is designed to simplify the procedure required for performing a duality method. Then, we characterize the optimal policies by deriving an integral equation with a fixed interval from the free boundary ODE. The integral equation is used to prove the verification theorem and to generate a stable numerical scheme. It is notable that the optimal portfolio depends on the elasticity of intertemporal substitution (EIS) due to liquidity constraints even if the investment opportunity is constant. Furthermore, we perform various analyses to investigate the impact of the borrowing constraints on the optimal policies and the marginal propensity to consume.

Aberrant cleavage of Notch by γ-secretase is implicated in numerous diseases, but how cleavage is regulated in space and time is unclear. Here, we report that cadherin-based adherens junctions (cadAJs) are sites of high cell-surface γ-secretase activity, as well as sites of constrained physical space that excludes γ-secretase substrates having large extracellular domains (ECDs) like Notch. ECD shedding initiates drastic spatial relocalization of Notch to cadAJs, allowing enzyme-substrate interactions and downstream signaling. Spatial mutations by adjusting the ECD size or the physical constraint alter signaling. Dysregulation of this spatial switch promotes precocious differentiation of ventricular zone neural progenitor cells in vivo. We show the generality of this spatial switch for amyloid precursor protein proteolysis. Thus, cadAJs create spatially distinct biochemical compartments regulating cleavage events involving γ-secretase and preventing aberrant activation of receptors.

We consider a consumption, investment, life insurance, and retirement decision problem in which an economic agent is allowed to borrow against only a part of future income. The closed-form solution...

In this paper, we consider variable annuity contracts with guaranteed minimum maturity benefits in which the embedded guarantees can be surrendered any time before the maturity date has been reached. We derive the optimal surrender strategies and the values of three different types of guarantees embedded in VA contracts: (1) constant guarantees, (2) constant guarantees with an up-and-out barrier, and (3) path-dependent guarantees with a lookback feature. The valuation of the embedded guarantees with a surrender option can be formulated as a free boundary problem, and we can obtain a corresponding non-homogeneous partial differential equation (PDE). We apply the Mellin transform to the non-homogeneous PDE in order to obtain an integral equation that produces the value of the embedded guarantee as well as the optimal surrender boundary in a variable annuity contract. We present the properties of the fair fee rate and the optimal surrender strategy with numerical examples.

We investigate a one-period portfolio optimization problem of a cumulative prospect theory (CPT) investor with multiple risky assets and one risk-free asset. The returns of the multiple risky asset...

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098–115. ©2017 AACR. See related commentary by Speiser and Verdeil, p. 1062. This article is highlighted in the In This Issue feature, p. 1047

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells– but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells., Tumor cell proliferation and migration, key drivers of metastasis, can be mechanistically coupled in matrix embedded human sarcoma and carcinoma cells through cell density via a synergistic, paracrine signaling mechanism between Interleukins 6/8. Inhibition of this mechanism significantly decreases metastasis in mouse xenograft models.

This paper studies a model of irreversible investment decisions in which the exercise payoff is endogenously determined by the firm's risk management choice. By obtaining the explicit solution of a non-linear free boundary problem with a stochastic control, we present the implications for the optimal investment timing and the associated optimal risk management strategy. The firm's optimal risk management strategy exhibits risk-seeking: it increases the insurance asset holdings that provide rewards (damages) when there is good (bad) news for the underlying price. As a result of the risk-seeking insurance strategy, in our model, in contrast to the standard models, investment can be hastened as the underlying uncertainty increases, depending on the economic conditions. The main force driving these results is that the firm's risk management is designed to optimize the risk-return tradeoff of the endogenous payoff.

In this article we demonstrate the practical application of standard partial equilibrium, in backward stochastic differential equation (BSDE) framework, to pricing longevity bonds which are essential for functioning of the life market. The market for mortality linked instruments or so-called life market, is experiencing steady progress in its evolution (see Blake et al. (2018)), however, it is regretfully far from reaching its full potential estimated to be of tens of trillions of dollars (see Michaelson and Mulholland (2014)). Highly illiquid and, compared to equity markets, with a relatively very low number of transactions, the life market is comprised of series of negotiated, high monetary value, over-the-counter transactions between few agents that have different risk preferences. To accommodate these realities we demonstrate an application of a partial equilibrium framework for pricing longevity bonds. We do this under the assumption of stochastic mortality intensity that affects the income of economic agents who trade in risky financial security and longevity bond to maximize their monetary utilities. Thus, by rooting ourselves in a foundational economic principle, as a practical contribution, we find the endogenous equilibrium bond price which is numerically computed. In a realistic setting of two agents in a transaction, numerical experiments confirm the expected intuition of price dependence on model parameters. As a theoretical contribution, we prove that our longevity bond completes the market.

This paper focuses on hedging financial risk in variable annuities with guarantees. We show that insurers should incorporate the specificity of the periodic payment of variable annuities fees to best hedge embedded guarantees and should focus on hedging the net liability. We develop a new hedging strategy based on semi-static hedging techniques, which takes into account the periodically collected fees, and confirm that it is more effective than delta-hedging with same rebalancing dates, as well as traditional semi-static hedging strategies that do not consider the specificity of the payments of fees in their optimization. It is also verified that short-selling or using put options as hedging instruments allows more effective hedging.

Co-measurement of multiple omic profiles from the same single cells opens up the opportunity to decode molecular regulation that underlie intercellular heterogeneity in development and disease. Here, we present co-sequencing of microRNAs and mRNAs in the same single cells using a half-cell genomics approach. This method demonstrates good robustness (~95% success rate) and reproducibility (R2=0.93 for both miRNAs and mRNAs), and yields paired half-cell miRNA and mRNA profiles that could be independently validated. Linking the level of miRNAs to the expression of predicted target mRNAs across 19 single cells that are phenotypically identical, we observe that the predicted targets are significantly anti-correlated with the variation of abundantly expressed miRNAs, suggesting that miRNA expression variability alone may lead to non-genetic cell-to-cell heterogeneity. Genome-scale analysis of paired miRNA-mRNA co-profiles further allows us to derive and validate new regulatory relationships of cellular pathways controlling miRNA expression and variability.

We examine how the bequest motive and the incentive affect the consumption, investment, life insurance, and retirement decision of a wage earner with uncertain lifetime. We find, unlike the fixed retirement time model, risky investment prior to retirement decreases as the bequest motive becomes stronger or as the incentive to retire weaker, even though the retirement wealth threshold increases.

Inorganic nanowires are among the most attractive functional materials, which have emerged in the past two decades. They have demonstrated applications in information technology and energy conversion, but their utility in biological or biomedical research remains relatively under-explored. Although nanowire-based sensors have been frequently reported for biomolecular detection, interfacing nanowire arrays and living mammalian cells for the direct analysis of cellular functions is a very recent endeavor. Cell-penetrating nanowires enabled effective delivery of biomolecules, electrical and optical stimulation and recording of intracellular signals over a long period of time. Non-penetrating, high-density nanowire arrays display rich interactions between the nanostructured substrate and the micro/nanoscale features of cell surfaces. Such interactions enable efficient capture of rare cells including circulating tumor cells and trafficking leukocytes from complex biospecimens. It also serves as a platform for probing cell traction force and neuronal guidance. The most recent advances in the field that exploits nanowire arrays (both penetrating and non-penetrating) to perform rapid analysis of cellular functions potentially for disease diagnosis and monitoring are reviewed.

The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. Significance: Our results demonstrate that JAK–STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs. Cancer Discov; 5(3); 316–31. ©2015 AACR. See related commentary by Belver and Ferrando, p. 234 This article is highlighted in the In This Issue feature, p. 213

We report a Mg alloy Mg-2.2Nd-0.1Zn-0.4Zr (wt.%, denoted as JDBM-2) showing great potential in clinical vascular stent application by integrating the advantages of traditional medical stainless steel and polymer. This alloy exhibits high yield strength and elongation of 276 ± 6 MPa and 34.3 ± 3.4% respectively. The JDBM-2 with a stable degradation surface results in a highly homogeneous degradation mechanism and long-term structural and mechanical durability. In vitro cytotoxicity test of the Mg extract via human vascular endothelial cells (HUVECs) indicates that the corrosion products are well tolerated by the tested cells and potentially negligible toxic effect on arterial vessel walls. This alloy also exhibits compromised foreign body response (FBR) determined by human peripheral blood derived macrophage adhesion, foreign body giant cell (FBGC) formation and inflammatory cytokine and chemokine secretion. Finally, vascular stents manufactured from the JDBM-2 were implanted into rabbits for long-term evaluation. The results confirm excellent tissue compatibility and up to 6-month structural and mechanical integrity of the stent in vivo. Thus, the JDBM-2 stent with up to 6-month structural and mechanical integrity and excellent tissue compatibility represents a major breakthrough in this field and a promising alternative to traditional medical stainless steel and polymer for the clinical application.

We report on the rapid and direct quantification of specific cell captures using a micro-patterned streptavidin (STR)-functionalized silicon nanowire (SiNW) platform, which was prepared by Ag-assisted wet chemical etching and a photo-lithography process. This platform operates by high-affinity cell capture rendered by the combination of antibody-epithelial cell surface-binding, biotin-streptavidin binding, and the topologically enhanced cell-substrate interaction on a 3-dimensional SiNWs array. In this work, we developed a micro-patterned nanowire platform, with which we were able to directly evaluate the performance enhancement due to nanotopography. An excellent capture efficiency of ~96.6±6.7%, which is the highest value achieved thus far for the targeting specific A549 cells on a selective area of patterned SiNWs, is demonstrated. Direct comparison between the nanowire region and the planar region on the same substrate indicates dramatically elevated cell-capture efficiency on nanotopological surface identical surface chemistry (

A transient cytosolic delivery system for accurate Cas9 ribonucleoprotein is a key factor for target specificity of the CRIPSR/Cas9 toolkit. Owing to the large size of the Cas9 protein and a long negative strand RNA, the development of the delivery system is still a major challenge. Here, a size-controlled lipopeptide-based nanosome system is reported, derived from the blood-brain barrier-permeable dNP2 peptide which is capable of delivering a hyperaccurate Cas9 ribonucleoprotein complex (HypaRNP) into human cells for gene editing. Each nanosome is capable of encapsulating and delivering ≈2 HypaRNP molecules into the cytoplasm, followed by nuclear localization at 4 h post-treatment without significant cytotoxicity. The HypaRNP thus efficiently enacts endogenous eGFP silencing and editing in human embryonic kidney cells (up to 27.6%) and glioblastoma (up to 19.7% frequency of modification). The lipopeptide-based nanosome system shows superior delivery efficiency, high controllability, and simplicity, thus providing biocompatibility and versatile platform approach for CRISPR-mediated transient gene editing applications.

Single-cell analysis of cytokine production is increasingly recognized as an important method to understand the inflammatory microenvironment and hematopoietic disease state. Certain cytokines are critical to the regulation of lineage specification, and the aberrant production of these cytokines can contribute to lineage reprogramming. Here, we describe of a platform combining subnanoliter microchambers and a high-density antibody barcode array for the study of single-cell cytokine secretions in hematopoietic cancer cell populations.

We study an optimal portfolio and consumption choice problem of a family that combines life insurance for parents who receive deterministic labor income until the fixed time T . We consider utility functions of parents and children separately and assume that parents have an uncertain lifetime. If parents die before time T , children have no labor income and they choose the optimal consumption and portfolio with remaining wealth and life insurance benefit. The object of the family is to maximize the weighted average of utility of parents and that of children. We obtain analytic solutions for the value function and the optimal policies, and then analyze how the changes of the weight of the parents’ utility function and other factors affect the optimal policies.

Most breast tumors display a high degree of intratumor heterogeneity, with many distinct subpopulations of cancer cells present. Elevated diversity within a tumor increases the chance for cellular adaptation, as individual clones may react differently to changes in the tumor microenvironment. Thus, treatment of heterogeneous tumors my lead to selection of a resistant clone, its expansion, and tumor progression. However, the fitness of cancer cells depends not only on their intrinsic properties, but could also be affected through interactions between different subpopulations. These interactions could be the reason for maintenance of minor clones along the major population. Therefore, intratumor heterogeneity may have functional relevance in tumor progression and colonization of metastatic sites. To emulate clonal interactions, we used the previously developed polyclonal breast cancer model of MDA-MB-468 cell line expressing soluble factors, IL-11 and FIGF. The IL-11 and FIGF clones, when present as minor population, support the growth of other clones in vivo. Moreover, polyclonal tumors with minor driving clone population are highly metastatic. Thus, we hypothesized that clonal interactions could not only drive tumor growth, but could also play an important role in metastasis. We have found that polyclonal tumors lead to polyclonal metastases, composed of mixture of neutral and driver clones. To investigate the mechanisms of clonal interactions driving polyclonal metastasis, we performed RNA profiling of subpopulations and stroma from polyclonal tumors. Our results suggest that this cooperation is indirect and that driver clones promote metastasis by altering the tumor microenvironment. We have also found that minor driver clones affect the immune cells within primary tumor, circulating blood, and metastatic site. These systemic changes significantly influence the metastatic progression. We are currently testing whether a treatment targeting this indirect clonal interaction mechanism could prevent polyclonal metastatic spread. Our study shows that the interaction between minor clones and other cancer cells could drive tumor growth and metastasis. Moreover, our results suggest that clonal cooperation in metastatic progression may be indirect and involve modulation of immune microenvironment of the primary tumor and distant organs. This abstract is also being presented as Poster B03. Citation Format: Michalina Janiszewska, Doris P. Tabassum, Andriy Marusyk, Muhammad B. Ekram, Zafira Castaño, Natalie L. Kingston, Yuanbo Qin, Tyler Laszewski, Minsuk Kwak, Kimiyo Nakamura, Rong Fan, Franziska Michor, Sandra S. McAllister, Kornelia Polyak. Minor clones can drive polyclonal metastasis by affecting immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr PR02.

We provide an accurate approximation method for inverting an option price to the implied volatility under arithmetic Brownian motion, which is widely quoted in Fixed Income markets. The maximum error in the volatility is in the order of 10−10 of the given option price and much smaller for the near-the-money options. Thus our approximation can be used as an exact solution without further refinements of iterative methods.

We investigate an optimal portfolio, consumption and retirement decision problem in which an economic agent can determine the discretionary stopping time as a retirement time with constant labor wage and disutility. We allow the preference of the agent to be changed before and after retirement. It is assumed that the agent's coefficient of relative risk aversion becomes higher after retirement. Under a constant relative risk aversion (CRRA) utility function, we obtain the optimal policies in closed-forms using martingale methods and variational inequality methods. We give some numerical results of the optimal policies. We also consider the relation between the level of disutility and the labor wage with the optimal retirement wealth level.

Single-cell analysis of cytokine production is increasingly recognized as an important method to understand the inflammatory microenvironment and hematopoietic disease state. Certain cytokines are critical to the regulation of lineage specification, and the aberrant production of these cytokines can contribute to lineage reprogramming. Here, we describe of a platform combining subnanoliter microchambers and a high-density antibody barcode array for the study of single-cell cytokine secretions in hematopoietic cancer cell populations.

In this paper, we characterize dynamic investment strategies that are consistent with the expected utility setting and more generally with the forward utility setting. Two popular dynamic strategies in the pension funds industry are used to illustrate our results: a constant proportion portfolio insurance (CPPI) strategy and a life-cycle strategy. For the CPPI strategy, we are able to infer preferences of the pension fund's manager from her investment strategy, and to exhibit the specific expected utility maximization that makes this strategy optimal at any given time horizon. In the Black-Scholes market with deterministic parameters, we are able to show that traditional life-cycle funds are not optimal to any expected utility maximizers. We also prove that a CPPI strategy is optimal for a fund manager with HARA utility function, while an investor with a SAHARA utility function will choose a time-decreasing allocation to risky assets in the same spirit as the life-cycle funds strategy. Finally, we suggest howto modify these strategies if the financial market follows a more general diffusion process than in the Black-Scholes market.