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Court-related fines and fees are widely levied on criminal defendants who are frequently poor and have little capacity to pay. Such financial obligations may produce a criminalization of poverty, where later court involvement results not from crime but from an inability to meet the financial burdens of the legal process. We test this hypothesis using a randomized controlled trial of court-related fee relief for misdemeanor defendants in Oklahoma County, Oklahoma. We find that relief from fees does not affect new criminal charges, convictions, or jail bookings after 12 months. However, control respondents were subject to debt collection efforts at significantly higher rates that involved new warrants, additional court debt, tax refund garnishment, and referral to a private debt collector. Despite significant efforts at debt collection among those in the control group, payments to the court totaled less than 5 percent of outstanding debt. The evidence indicates that court debt charged to indigent defendants neither caused nor deterred new crime, and the government obtained little financial benefit. Yet, fines and fees contributed to a criminalization of low-income defendants, placing them at risk of ongoing court involvement through new warrants and debt collection.

Multiple myeloma (MM) is a hematologic malignancy that is characterized by the accumulation of abnormal plasma cells (PCs) in the bone marrow (BM). Patient outcome may be improved with BiTE (bispecific T-cell engager) molecules, which redirect T cells to lyse tumor cells. B-cell maturation antigen (BCMA) supports PC survival and is highly expressed on MM cells. A half-life extended anti-BCMA BiTE molecule (AMG 701) induced selective cytotoxicity against BCMA-expressing MM cells (average half-maximal effective concentration, 18.8 ± 14.8 pM), T-cell activation, and cytokine release in vitro. In a subcutaneous mouse xenograft model, at all doses tested, AMG 701 completely inhibited tumor formation (P < .001), as well as inhibited growth of established tumors (P ≤ .001) and extended survival in an orthotopic MM model (P ≤ .01). To evaluate AMG 701 bioactivity in cynomolgus monkeys, a PC surface phenotype and specific genes were defined to enable a quantitative digital droplet polymerase chain reaction assay (sensitivity, 0.1%). Dose-dependent pharmacokinetic and pharmacodynamic behavior was observed, with depletion of PC-specific genes reaching 93% in blood and 85% in BM. Combination with a programmed cell death protein 1 (PD-1)–blocking antibody significantly increased AMG 701 potency in vitro. A model of AMG 701 binding to BCMA and CD3 indicates that the distance between the T-cell and target cell membranes (ie, the immunological synapse) is similar to that of the major histocompatibility complex class I molecule binding to a T-cell receptor and suggests that the synapse would not be disrupted by the half-life extending Fc domain. These data support the clinical development of AMG 701.

Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34+ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development.

Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 may present with fever, elevated inflammatory markers, and multiorgan involvement. Although the gastrointestinal system is commonly affected in MIS-C patients, associated necrotizing pancreatitis is rare. We present an 11-year-old boy with B-cell acute lymphoblastic leukemia in remission undergoing maintenance chemotherapy presenting with acute necrotizing pancreatitis. He developed fevers, fluid and electrolyte imbalance, respiratory distress, cytopenias, and coagulopathy, and was found to have markedly elevated inflammatory markers and positive SARS-CoV-2 antibodies. The patient met criteria for MIS-C and was treated with intravenous immunoglobulin with significant clinical improvement. This is the first known reported case of a child with B-cell acute lymphoblastic leukemia who met criteria for MIS-C presenting as acute pancreatitis, and highlights the importance of considering a broader differential for pancreatitis in children given the current SARS-CoV-2 pandemic.

Mattering, one’s sense of the difference one makes in the world, has been variously described in psychological and philosophical literatures. We propose the experience of mattering is tied to the p...

Poor endometrial development during in vitro fertilization remains challenging. Indeed, no broadly accepted definition of poor endometrial development exists, and no treatment has shown any improve...

Acute myeloid leukemia is a grievous illness. BiTE® (bispecific T cell engager) molecules redirect T cells by engaging CD3 and a tumor-associated antigen (TAA). These molecules have shown clinical efficacy but one mechanism of resistance is loss of a single TAA. We hypothesized that a BiTE® molecule targeting >1 TAA could reduce relapse frequency. FLT3 and CD123, were selected for a dual-targeting BiTE® (dBiTE࣪) molecule.A half-life extended (HLE) CD123-FLT3 dBiTE࣪ molecule was evaluated in vitro, in mouse xenografts, and in non-human primate (NHP) tolerability studies. The molecule had nM affinity for human and NHP FLT3, CD123, and CD3, and pM efficacy in cytotoxicity assays using human T cells or NHP PBMCs. The molecule achieved 100% killing against single-positive (sp) cells (CRISPR-generated isogenic cell lines) at potencies like those of double-positive (dp) cells (7.4 ±. 4.1 pM FLT3sp, 7.1 ±. 3.8 pM CD123sp and 3.4 ±. 1.5 pM dp, n=3). In a mouse xenograft model, the molecule induced significant activity and extended survival > 3 weeks (1.0, 0.1, and 0.01 mg/kg (p ≤ 0.001)). In mice with sp tumors, survival benefit could not be calculated due to high survival, demonstrating that both arms of the molecule are active. In NHP, the molecule had a half-life of 52 hours (0.3 or 3 µg/kg). FLT3 mRNA levels, a marker of FLT3-expressing cells, decreased in blood following dosing. Repeat dosing was not tolerated, and cytokine release was observed. Some cytokines were reduced while others increased. CD123 is reportedly expressed on endothelial cells (ECs), with increased expression in inflammatory conditions. An immunohistochemical survey found that CD123 is expressed on human and NHP monocyte/macrophages and ECs with limited distribution in lymphoid tissues and lamina propria of the gut. We hypothesized that cytokine release following administration may result in increased CD123 expression and in turn, further increased cytokine levels with repeat dosing. CD123 was detected on primary human umbilical vein ECs (HUVECs). In co-cultures of HUVECs and T cells, a CD123 BiTE® molecule induced expression of CD123 on HUVEC cells at concentrations that elicited redirected lysis (12.5 pM), T cell activation, and cytokine secretion. To better understand BiTE®-induced upregulation of CD123 on ECs, HUVECs were cultured with supernatants (SN) from a TDCC assay or recombinant IL-3, IL-6, TNFα, or IFNγ. Assay SN and TNFα induced >2-fold CD123 expression on HUVECs, but not on CD123-negative primary human pulmonary microvascular ECs. These data demonstrate that CD123 expression on ECs was increased upon exposure to a CD123 mono-targeting BiTE® molecule, potentially through BiTE®-induced secretion of TNFα. Additional studies are ongoing.In sum, a CD123-FLT3 HLE dBiTE࣪ molecule was active against both dp- and sp-positive target cells in vitro and in vivo. Careful selection of TAA for dBiTE࣪ molecules is necessary to increase efficacy and maintain safety. Citation Format: Rebecca Goldstein, Christine Karbowski, Anja Henn, Petra Deegen, Joachim Wahl, Katja Matthes, Christoph Dahlhoff, Brooke Rock, Sabrina Benchaar, Katie Hsu, Brandy Alexander, Matthias Friedrich, Joan Lane, Xiaoting Wang, Jonas Anlahr, Markus Muenz, Tobias Raum, Tara L. Arvedson. Evaluation of a dual CD123-FLT3 BiTE molecule for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6313.

Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes from Gram-positive bacteria are secreted virulence factors that aid in downregulating host immunity. These PI-PLCs are minimalist peripheral membrane enzymes with a distorted (βα)8 TIM barrel fold offering a conserved and stable scaffold for the conserved catalytic amino acids while membrane recognition is achieved mostly through variable loops. Decades of experimental and computational research on these enzymes have revealed the subtle interplay between molecular mechanisms of catalysis and membrane binding, leading to a semiquantitative model for how they find, bind, and cleave their respective substrates on host cell membranes. Variations in sequence and structure of their membrane binding sites may correlate with how enzymes from different Gram-positive bacteria search for their particular targets on the membrane. Detailed molecular characterization of protein–lipid interactions have been aided by cutting-edge methods ranging from 31P fiel...

A growing body of evidence indicates that local police departments are being used to provide revenue for municipalities by imposing and collecting fees, fines, and asset forfeitures. We examine whether revenue collection activities compromise the criminal investigation functions of local police departments. We find that police departments in cities that collect a greater share of their revenue from fees solve violent and property crimes at significantly lower rates. The effect on violent crime clearance is more salient in smaller cities where police officers’ assignments tend not to be highly specialized. We find that this relationship is robust to a variety of empirical strategies, including instrumenting for fines revenue using commuting time. Our results suggest that institutional changes—such as decreasing municipal government reliance on fines and fees for revenue—are important for changing police behavior and improving the provision of public safety.

Summary The role of microenvironment-mediated biophysical forces in human lymphomas remains elusive. Diffuse large B cell lymphomas (DLBCLs) are heterogeneous tumors, which originate from highly proliferative germinal center B cells. These tumors, their associated neo-vessels, and lymphatics presumably expose cells to particular fluid flow and survival signals. Here, we show that fluid flow enhances proliferation and modulates response of DLBCLs to specific therapeutic agents. Fluid flow upregulates surface expression of B cell receptors (BCRs) and integrin receptors in subsets of ABC-DLBCLs with either CD79A/B mutations or WT BCRs, similar to what is observed with xenografted human tumors in mice. Fluid flow differentially upregulates signaling targets, such as SYK and p70S6K, in ABC-DLBCLs.By selective knockdown of CD79B and inhibition of signaling targets, we provide mechanistic insights into how fluid flow mechanomodulates BCRs and integrins in ABC-DLBCLs. These findings redefine microenvironment factors that regulate lymphoma-drug interactions and will be critical for testing targeted therapies., Graphical abstract Apoorva et al. report a lymphoma micro-reactor to understand biophysical factors that regulate lymphoma growth and their therapeutic responses. They describe the role of fluid forces, from lymphatics and neo-vessels, in mechanomodulation of integrin and B cell receptor signaling. These insights shed light on the heterogeneous nature of lymphomas and may allow faster translation of therapeutics.

The complexity of cancer signaling networks limits the efficacy of most single-agent treatments and brings about challenges in identifying effective combinatorial therapies. In this study, we used chronic active B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma as a model system to establish a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex cross-talk between the NFκB, ERK, and AKT pathways and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model, we predicted viability responses of many single drug and drug combinations in agreement with experimental data. Under this framework, we exhaustively predicted and ranked the efficacy and synergism of all possible combinatorial inhibitions of eleven currently targetable kinases in the BCR signaling network. Ultimately, our work establishes a detailed kinetic model of the core BCR signaling network and provides the means to explore the large space of possible drug combinations. Cancer Res; 77(8); 1818–30. ©2017 AACR.

Individual cities are active interest groups in lobbying the federal government, and yet the dynamics of this intergovernmental lobbying are poorly understood. We argue that preference incongruence between a city and its parent state government leads to underprovision of public goods, and cities need to appeal to the federal government for additional resources. We provide evidence for this theory using a data set of over 13,800 lobbying disclosures filed by cities with populations over 25,000 between 1999 and 2012. Income inequality and ethnic fragmentation are also highly related to federal lobbying activities. Using an instrumental variables analysis of earmark and Recovery Act grant data, we show that each dollar a city spends on lobbying generates substantial returns.

In recent decades, advocates for police reform on the political left and right have proposed numerous changes to how street-level policing operates. One such proposed reform, which has been adopted in jurisdictions nationwide, is “proactive policing,” that is, policing strategies based on the notion that by proactively regulating minor offenses, the police can reduce both serious crime and fear of crime in the community. Yet, as with many proposed police reforms, researchers have not undertaken a through benefit-cost analysis of proactive policing. This article lays out strategies for estimating the impacts of proactive policing, including direct, indirect, and distributional impacts. First, I describe quasi-experimental approaches, which entail partnerships between researchers and police departments and would be particularly useful when a municipality is considering a move to proactive policing in the first instance, expansion of small-scale proactive policing to a larger area, or the introduction of particular new tactics. Second, I describe nonexperimental retrospective approaches, including conventional regression analysis, which can also allow researchers to estimate the effects of proactive policing. I discuss potential threats to validity for both strategies. I close by describing the data that researchers wishing to engage in benefit-cost analysis of proactive policing would need in order to do so.

MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction–targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway–targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy.

Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T-cell Engager (BiTE) molecules, which redirect patient T cells to lyse tumor cells, are a clinically validated modality for hematologic malignancies. Due to broad AML expression and limited normal tissue expression, fms-related tyrosine kinase 3 (FLT3) is proposed to be an optimal BiTE molecule target. Expression profiling of FLT3 was performed in primary AML patient samples and normal hematopoietic cells and nonhematopoietic tissues. Two novel FLT3 BiTE molecules, one with a half-life extending (HLE) Fc moiety and one without, were assessed for T-cell–dependent cellular cytotoxicity (TDCC) of FLT3-positive cell lines in vitro, in vivo, and ex vivo. FLT3 protein was detected on the surface of most primary AML bulk and leukemic stem cells but only a fraction of normal hematopoietic stem and progenitor cells. FLT3 protein detected in nonhematopoietic cells was cytoplasmic. FLT3 BiTE molecules induced TDCC of FLT3-positive cells in vitro, reduced tumor growth and increased survival in AML mouse models in vivo. Both molecules exhibited reproducible pharmacokinetic and pharmacodynamic profiles in cynomolgus monkeys in vivo, including elimination of FLT3-positive cells in blood and bone marrow. In ex vivo cultures of primary AML samples, patient T cells induced TDCC of FLT3-positive target cells. Combination with PD-1 blockade increased BiTE activity. These data support the clinical development of an FLT3 targeting BiTE molecule for the treatment of AML.

Previous literature reports have shown that single crystals of 1,2-bis(9-anthryl)acetylene (1), in which the molecule is essentially planar, can be fabricated as organic field effect transistors. We have identified a new conformational polymorph of 1 in which the two anthracene moieties are twisted out of plane by more than 60°. Occasionally, both the planar (1α) and twisted (1β) polymorphic forms crystallize out together representing a rare example of concomitant conformational polymorphism in a pure hydrocarbon. The two polymorphic forms also show distinctly different colours and morphologies – the planar form (1α) grows as long orange-red needles whereas the twisted form (1β) appears as yellow blocks. Furthermore, a variety of electronic structure-based calculations show that the planar molecule forms the more stable polymorph (1α), despite the conformation being close to the maximum in conformational energy. This may be attributed to 1α being stabilized by greater intermolecular dispersion forces as the planar conformation allows a denser packing. The new polymorph (1β) is a long-lived metastable structure, because of the marked difference in crystal packing. Since the conformation in 1β is more stable in isolation, and probably in solution state, this discovery raises questions about the control of crystallization of anthracene-based functional materials and the assumptions about conformational polymoprhism commonly made in crystal structure prediction studies.

MALT1 inhibition is a promising strategy against B-cell receptor (BCR)-dependent lymphomas including ABC DLBCL, CLL and MCL. MALT1 is downstream of the most frequently mutated genes in the BCR and Toll-like receptor (TLR) pathways. MALT1 inhibitors are active in Ibrutinib-resistant BTK and PLCγ2 mutant CLL or CARD11 mutant ABC DLBCL. Therefore, MALT1 inhibitors, which recently began first in man clinical testing, have the potential to cover a larger patient population than drugs against more upstream targets in the BCR pathway including BTK inhibitors. However, activity of inhibitors targeting signaling mediators can be limited by feedback mechanisms counteracting and/or bypassing the need for a specific pathway. MALT1 is central to NF-κB activation downstream of the BCR. Therefore, activation of alternative pathways leading to full or partial activation of the BCR program or other pro-survival pathways might enable cell survival and set off MALT1i resistance. In order to map the landscape of resistance/sensitivity to MALT1 inhibition in ABC DLBCL and assist design of combinatorial regimens, we carried out a loss-of-function screen in HBL-1 (MALT1i sensitive) with or without MI-2 (small molecule irreversible inhibitor of MALT1) to identify genes capable of modulating response to MALT1 inhibition. Our analyses showed that loss of BCR and PI3K activators enhanced sensitivity, while loss of negative regulators of these pathways promoted MALT1i resistance. These findings were validated by knockdown of individual genes with two independent hairpins against activators CD79B, CARD11, BTK or the negative regulator TNFAIP3. Next, we carried out a combinatorial drug screen anchored in MALT1 inhibition by MI-2 or C3 (irreversible substrate-mimetic MALT1 inhibitor) and focused on inhibitors against signaling hubs in the BCR/PI3K pathways in 4 MALT1i sensitive cell lines. This combinatorial screen confirmed that concurrent inhibition of MALT1 and other BCR and PI3K pathways' proteins is additive (0.9>CI (combination index) In depth analysis of proliferation and cell death by CFSE dilution and Annexin V staining revealed that both MALT1/PI3K-i and MALT1/MTORC1-i combinations significantly enhanced growth inhibition and apoptosis in TMD8 and HBL-1 compared to individual agents. Results with MI-2 and C3 were comparable. Short exposure to MI-2 or C3 increased MTORC1 activity as assessed by S6K-Thr389 and S6-Ser235/6 phosphorylation in TMD8 and HBL-1 indicating that MALT1 protease activity modulates MTORC1 activation. MTOR activation is tumorigenic and can mediate chemotherapy resistance. Increased p-S6 following MALT1 inhibition (FC=1.4-2) was blocked by Idelalisib (PI3Ki). However, only Rapamycin, an MTORC1 inhibitor, reduced p-S6 levels relative to vehicle, FC=-5 alone or in combination. In vivo, MALT1/PI3K-i (MI-2/Idelalisib) significantly delayed tumor progression compared to single treatments (p MALT1/MTORC1-i regimens were also highly synergistic in 2 patient-derived xenografted (PDX) ABC DLBCL ex vivo. PDXs were cultured in gelatin/silicate nanoparticle hydrogel 3-D organoids and co-cultured with CD40L expressing cells. Compound pairs were assayed for synergy using 4x4 matrices and growth inhibition evaluated by flow cytometry. Synergy ZIP δ-score ranged 7-14 in 2 specimens for 2 MALT1i. Combined, these results suggest that: 1) MTORC1 activation constitutes a survival feedback mechanism activated after MALT1i treatment that might be leveraged by tumoral cells to evade MALT1 inhibition and, 2) that simultaneous targeting of MTORC1 could improve response and prevent resistance to MALT1 inhibitors. Disclosures Melnick: Constellation: Consultancy; Janssen: Research Funding; Epizyme: Consultancy.