Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

An Optical-Fiber-Based Airborne Particle Sensor.

A new optical-fiber-based airborne particle counter is reported. Unlike traditional light-scatter-based techniques, the particle is detected through the drop in optical fiber coupling efficiency as the particle disrupts the electromagnetic mode of the optical beam. The system is simple, substantially smaller than traditional systems, and does not require high power laser input. This makes it attractive for wearable air quality monitors where size is a premium. There is close agreement between theoretical model and experimental results for solid and liquid particles in the 1 to 10 µm range.

VO(2) based waveguide-mode plasmonic nano-gratings for optical switching.

In this paper, we present one dimensional plasmonic narrow groove nano-gratings, covered with a thin film of VO(2) (Vanadium Dioxide), as novel optical switches. These narrow groove gratings couple the incident optical radiation to plasmonic waveguide modes leading to high electromagnetic fields in the gaps between the nano-gratings. Since VO(2) changes from its semiconductor to its metallic phase on heating, on exposure to infra-red light, or on application of voltage, the optical properties of the underlying plasmonic grating also get altered during this phase transition, thereby resulting in significant switchability of the reflectance spectra. Moreover, as the phase transition in VO(2) can occur at femto-second time-scales, the VO(2)-coated plasmonic optical switch described in this paper can potentially be employed for ultrafast optical switching. We aim at maximizing this switchability, i.e., maximizing the differential reflectance (DR) between the two states (metallic and semiconductor) of this VO(2) coated nano-grating. Rigorous Coupled Wave Analysis (RCWA) reveals that the switching wavelengths - i.e., the wavelengths at which the values of the differential reflectance between VO(2) (S) and VO(2) (M) phases are maximum - can be tuned over a large spectral regime by varying the nano-grating parameters such as groove width, depth of the narrow groove, grating width, and thickness of the VO(2) layer. A comparison of the proposed ideal nano-gratings with various types of non-ideal nano-gratings - i.e., nano-gratings with non-parallel sidewalls - has also been carried out. It is found that significant switchability is also present for these non-ideal gratings that are easy to fabricate. Thus, we propose highly switchable and wide-spectra VO(2) based narrow groove nano-gratings that do not have a complex structure and can be easily fabricated.

Simulating channel losses in an underwater optical communication system.

A Monte Carlo numerical simulation for computing the received power for an underwater optical communication system is discussed and validated. Power loss between receiver and transmitter is simulated for a variety of receiver aperture sizes and fields of view. Additionally, pointing-and-tracking losses are simulated.

Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia.

Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy. The efficacy of an investigational dual-affinity retargeting antibody (DART) molecule (CD123 × CD3; MGD006 or flotetuzumab) was assessed in two distinct patient-derived xenograft (PDX) models of pediatric AML. MGD006 simultaneously binds to CD123 on target cells and CD3 on effector T cells, thereby activating T cells and redirecting them to induce cytotoxicity in target cells. The concurrent treatment of cytarabine and MGD006 was performed to determine the effect of cytarabine on T-cell counts and MGD006 activity. Treatment with MGD006 along with an allogeneic human T-cell infusion to act as effector cells induced durable responses in both PDX models, with CD123 positivity. This effect was sustained in mice treated with a combination of MGD006 and cytarabine in the presence of T cells. MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.

Modulated pulse laser with pseudorandom coding capabilities for underwater ranging, detection, and imaging.

Optical detection, ranging, and imaging of targets in turbid water is complicated by absorption and scattering. It has been shown that using a pulsed laser source with a range-gated receiver or an intensity modulated source with a coherent RF receiver can improve target contrast in turbid water. A blended approach using a modulated-pulse waveform has been previously suggested as a way to further improve target contrast. However only recently has a rugged and reliable laser source been developed that is capable of synthesizing such a waveform so that the effect of the underwater environment on the propagation of a modulated pulse can be studied. In this paper, we outline the motivation for the modulated-pulse (MP) concept, and experimentally evaluate different MP waveforms: single-tone MP and pseudorandom coded MP sequences.

Effect of scattering albedo on attenuation and polarization of light underwater.

Recent work on underwater laser communication links uses polarization discrimination to improve system performance [Appl. Opt.48, 328 (2009)] [in Proceedings of IEEE Oceans 2009 (IEEE, 2009), pp. 1-4]. In the laboratory, Maalox antacid is commonly used as a scattering agent. While its scattering function closely mimics that of natural seawaters, its scattering albedo can be much higher, as Maalox particles tend to be less absorbing. We present a series of experiments where Nigrosin dye is added to Maalox in order to more accurately recreate real-world absorption and scattering properties. We consider the effect that scattering albedo has on received power and the degree of depolarization of forward-scattered light in the context of underwater laser communication links.

TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML.

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.

Backscatter suppression for underwater modulating retroreflector links using polarization discrimination.

Free space optical links underwater have the potential to enable short range (<100 m) high-bandwidth (megabits per second) data links that have a low probability of detection and interception. The use of a retroreflecting free space optical link in water has the added advantage of allowing much of the weight and power burden of the link to remain at one end. While modulating retroreflectors have been successfully implemented in above-water links, the underwater environment introduces new challenges. The focus of this paper is to address these challenges and to investigate techniques for minimizing their effect on the link performance.

A Wearable Hydration Sensor with Conformal Nanowire Electrodes.

A wearable skin hydration sensor in the form of a capacitor is demonstrated based on skin impedance measurement. The capacitor consists of two interdigitated or parallel electrodes that are made of silver nanowires (AgNWs) in a polydimethylsiloxane (PDMS) matrix. The flexible and stretchable nature of the AgNW/PDMS electrode allows conformal contact to the skin. The hydration sensor is insensitive to the external humidity change and is calibrated against a commercial skin hydration system on an artificial skin over a wide hydration range. The hydration sensor is packaged into a flexible wristband, together with a network analyzer chip, a button cell battery, and an ultralow power microprocessor with Bluetooth. In addition, a chest patch consisting of a strain sensor, three electrocardiography electrodes, and a skin hydration sensor is developed for multimodal sensing. The wearable wristband and chest patch may be used for low-cost, wireless, and continuous monitoring of skin hydration and other health parameters.

Low-Power Wearable Systems for Continuous Monitoring of Environment and Health for Chronic Respiratory Disease.

We present our efforts toward enabling a wearable sensor system that allows for the correlation of individual environmental exposures with physiologic and subsequent adverse health responses. This system will permit a better understanding of the impact of increased ozone levels and other pollutants on chronic asthma conditions. We discuss the inefficiency of existing commercial off-the-shelf components to achieve continuous monitoring and our system-level and nano-enabled efforts toward improving the wearability and power consumption. Our system consists of a wristband, a chest patch, and a handheld spirometer. We describe our preliminary efforts to achieve a submilliwatt system ultimately powered by the energy harvested from thermal radiation and motion of the body with the primary contributions being an ultralow-power ozone sensor, an volatile organic compounds sensor, spirometer, and the integration of these and other sensors in a multimodal sensing platform. The measured environmental parameters include ambient ozone concentration, temperature, and relative humidity. Our array of sensors also assesses heart rate via photoplethysmography and electrocardiography, respiratory rate via photoplethysmography, skin impedance, three-axis acceleration, wheezing via a microphone, and expiratory airflow. The sensors on the wristband, chest patch, and spirometer consume 0.83, 0.96, and 0.01 mW, respectively. The data from each sensor are continually streamed to a peripheral data aggregation device and are subsequently transferred to a dedicated server for cloud storage. Future work includes reducing the power consumption of the system-on-chip including radio to reduce the entirety of each described system in the submilliwatt range.

3D printing of free standing liquid metal microstructures.

This paper describes a method to direct-write 3D liquid metal microcomponents at room temperature. The thin oxide layer on the surface of the metal allows the formation of mechanically stable structures strong enough to stand against gravity and the large surface tension of the liquid. The method is capable of printing wires, arrays of spheres, arches, and interconnects.

Custom visible to infrared, multi-wavelength light emitters for pulse oximeter applications.

Compact multi-wavelength light sources have been developed to provide flexibility in pulse oximeter device design. Advantages of these light sources include emitting light of multiple wavelengths with a constant ratio of intensity, and a co-linear light propagation path through tissue. These devices can function as normal pulse oximeter to determine oxygen saturation and pulse rate, but this approach potentially reduces circuit complexity, reduces motion artifacts and enables multi-wavelength sensing of different forms of hemoglobin or other blood products.

Patterned hybrid nanohole array surfaces for cell adhesion and migration.

We report the fabrication of hybrid nanohole array surfaces to study the role of the surface nanoevironment on cell adhesion and cell migration. We use polystyrene beads and reactive ion etching to control the size and the spacing between nanoholes on a tailored self-assembled monolayer inert gold surface. The arrays were characterized by scanning electron microscopy and brightfield microscopy. For cell adhesion studies, cells were seeded to these substrates to study the effect of ligand spacing on cell spreading, stress fiber formation, and focal adhesion structure and size. Finally, comparative cell migration rates were examined on the various nanohole array surfaces using time-lapse microscopy.

Plasmon resonances of gold nanoparticles incorporated inside an optical fibre matrix.

Metallic nanoparticles were incorporated into the core of standard telecommunication grade optical fibres. This creates a simple, yet robust, platform which can be used to investigate the properties of nanoparticles, for sensing, spectroscopy, and optical switching applications. The optical response of gold nanoparticles embedded in the optical fibre matrix was evaluated as a function of temperature and the use of the structure as an inline fibre-optic temperature sensor is described. A redshift in the localized surface plasmon (LSP) resonance related peak, as well as broadening of the plasmon resonance, was observed upon increasing the temperature of the nanoparticle containing fibre. The shift and broadening of the plasmon resonance were attributed to the temperature dependence of dielectric constants of metallic nanoparticles and the silica matrix and to plasmon-phonon interactions.

Mortality in a long-term open cohort of prostitute women.

In this study, the authors estimated overall and cause-specific mortality among prostitute women. They recorded information on prostitute women identified by police and health department surveillance in Colorado Springs, Colorado, from 1967 to 1999. The authors assessed cause-specific mortality in this open cohort of 1,969 women using the Social Security Death Index and the National Death Index, augmented by individual investigations. They identified 117 definite or probable deaths and had sufficient information on 100 to calculate a crude mortality rate (CMR) of 391 per 100,000 (95% confidence interval (CI): 314, 471). In comparison with the general population, the standardized mortality ratio (SMR), adjusted for age and race, was 1.9 (95% CI: 1.5, 2.3). For the period of presumed active prostitution only, the CMR was 459 per 100,000 (95% CI: 246, 695) and the SMR was 5.9 (95% CI: 3.2, 9.0). Violence and drug use were the predominant causes of death, both during periods of prostitution and during the whole observation period. The CMR for death by homicide among active prostitutes was 229 per 100,000 (95% CI: 79, 378), and the SMR was 17.7 (95% CI: 6.2, 29.3). Deaths from acquired immunodeficiency syndrome occurred exclusively among prostitutes who admitted to injecting drug use or were inferred to have a history of it.