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Background Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs). Methods Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs). Results Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60). Conclusions The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM.

We present a novel, to the best of our knowledge, remote gas detection and identification technique based on correlation spectroscopy with a piezoelectric tunable fiber-optic Fabry–Perot filter. We show that the spectral correlation amplitude between the filter transmission window and gas absorption features is related to the gas absorption optical depth, and that different gases can be distinguished from one another using their correlation signal phase. Using a previously captured telluric-corrected high-resolution near-infrared spectrum of Venus, we show that the radial velocity of Venus can be extracted from the phase of higher order harmonic lock-in signals. This correlation spectroscopy technique has applications in the detection and radial velocity determination of weak spectral features in astronomy and remote sensing. We experimentally demonstrate a remote C O 2 detection system using a lock-in amplifier, fiber-optic Fabry–Perot filter, and single channel avalanche photodiode.

We show how existing iterative methods can be used to efficiently and accurately calculate Bloch periodic solutions of Maxwell’s equations in arbitrary geometries. This is carried out in the complex-wavevector domain using a commercial frequency-domain finite-element solver that is available to the general user. The method is capable of dealing with leaky Bloch mode solutions, and is extremely efficient even for 3D geometries with non-trivial material distributions. We perform independent finite-difference time-domain simulations of Maxwell’s equations to confirm our results. This comparison demonstrates that the iterative mode finder is more accurate, since it provides the true solutions in the complex-wavevector domain and removes the need for additional signal processing and fitting. Due to its efficiency, generality and reliability, this technique is well suited for complex and novel design tasks in integrated photonics, and also for a wider range of photonics problems.

The absorption spectra of distant targets can be used for remote gas detection. However, the detection of very faint absorption features is difficult since noise can dominate the molecular signal in the acquired spectrum. Rather than using typical dispersive spectroscopy, high sensitivity remote gas sensing is possible by correlation spectroscopy using a spectral matching filter. In this work, we use a thermo-optically tunable nanophotonic silicon waveguide ring resonator as an integrated spectral filter to obtain a correlation signal proportional to the absorption spectrum of a specific gas. We demonstrate the ability to resolve very small absorption depth changes using integrated photonics at the level required for the characterization of exoplanet atmospheres during transits of their host stars., 2021 Photonics North (PN), May 31 - June 2, 2021, Toronto, ON, Canada

We present fully apodized and perfectly vertical surface grating couplers in 300 nm silicon waveguides. We achieve ultrahigh coupling efficiency of -0.35 dB at 1550 nm for an optical fiber with 10.4 µm mode-fiber-diameter. To this end, we followed a two stage process in which, we first optimized a pool of periodic grating couplers using machine learning techniques, and then apodized them over 100 parameters using the gradient based adjoint- method. Using a simple fabrication tolerance analysis, we also show that segment variations mostly causes a wavelength shift for the maximum coupling efficiency of the apodized grating couplers, similar to those typically observed for periodic grating couplers., Integrated Optics: Devices, Materials, and Technologies XXV, March 6-12, 2021, Online Only, United States, Series: Proceedings of SPIE

Modern design of photonic devices is quickly and steadily departing from classical geometries to focus more and more on non-trivial structures and metamaterials. These devices are governed by a multitude of parameters and the optimal design requires to simultaneously consider different figure of merits. In this invited talk we will present our recent work on the application of machine learning tools to the multi-objective optimization of multi-parameter photonic devices. In particular, we will demonstrate the potentiality of dimensionality reduction for the analysis of the complex design space of subwavelength metamaterials devices.

Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.

Exoplanetary biosignatures, molecular compounds which indicate a likelihood of extraterrestrial life, can be detected by highly sensitive spectroscopy of starlight which passes through the atmospheres of exoplanets towards the Earth. Such sensitive measurements can only be accomplished with the next generation of telescopes, leading to a corresponding increase in cost and complexity spectrometers. Integrated astrophotonic instruments are well-suited to address these challenges through their low-cost fabrication and compact geometries. We propose and characterize an integrated photonic gas sensor which detects the correlation between the near-infrared quasi-periodic vibronic absorption line spectrum of a gas and a silicon waveguide ring resonator transmittance comb. This technique enables lock-in amplification detection for real-time detection of faint biosignatures for reduced observation timescales and rapid exoplanetary atmosphere surveys using highly compact instrumentation.

Absorption spectroscopy is widely used in sensing and astronomy to understand molecular compositions on microscopic to cosmological scales. However, typical dispersive spectroscopic techniques require multichannel detection, fundamentally limiting the ability to detect extremely weak signals when compared to direct photometric methods. We report the realization of direct spectral molecular detection using a silicon nanophotonic waveguide resonator, obviating dispersive spectral acquisition. We use a thermally tunable silicon ring resonator with a transmission spectrum matched and cross-correlated to the quasi-periodic vibronic absorption lines of hydrogen cyanide. We show that the correlation peak amplitude is proportional to the number of overlapping ring resonances and gas lines, and that molecular specificity is obtained from the phase of the correlation signal in a single detection channel. Our results demonstrate on-chip correlation spectroscopy that is less restricted by the signal-to-noise penalty of other spectroscopic approaches, enabling the detection of faint spectral signatures.

We present an integrated photonic correlation filter for the detection of remote HCN gas. We demonstrate sensing of absorption due to HCN using thermo-optic tuning of the drop port transmission spectrum in a silicon waveguide ring resonator., 2020 IEEE Photonics Conference (IPC), September 28 - October 1, 2020, Vancouver, BC, Canada

We study the fabrication tolerance of two types of grating antennas featuring U-shape and L-shape structures. The L-shape design is found to be more fabrication tolerant, showing performance degradation of less than 2% assuming common fabrication imperfections, making it promising for optical phased array applications., 2020 IEEE Photonics Conference (IPC), September 28 - October 1, 2020, Vancouver, BC, Canada

Subwavelength engineered metamaterial waveguides and devices are considered as fundamental building blocks for the next generation of integrated photonic circuits. Here we present an overview of recent advances in this surging field.

The optimization of complex high-dimensional photonic structures is often limited by computational resources. Current techniques based on global optimization algorithms or shape/topology inverse design treat design variables as entirely independent. However, there is often correlation between the input variables and patterns in the design outcomes. We review our strategy of using machine learning pattern recognition for building the performance map of a high-dimensional design space, thereby quickly guiding the search to a small region of interest and significantly improving the computational efficiency. This strategy is found beneficial in both forward and inverse design process flow., 2020 Photonics North (PN), May 26-28, 2020, Niagara Falls, Ontario, Series: Photonics North

We present the design of integrated astrophotonic instruments for high background atmospheric gas detection. Such instruments can be fibre-coupled to long focal length space telescopes as compact, flexure-free, instruments., Conference on Lasers and Electro-Optics/Pacific Rim 2020, August 3-5, 2020, Sydney Australia

Compact and efficient optical antennas are fundamental components for many applications, including high-density fiber-chip coupling and optical phased arrays. Here we present the design of grating-based micro-antennas with perfectly vertical emission in the 300-nm silicon-on-insulator platform. We leverage a methodology combining adjoint optimization and machine learning dimensionality reduction to efficiently map the multiparameter design space of the antennas, analyse a large number of relevant performance metrics, carry out the required multi-objective optimization, and discover high performance designs. Using a one-step apodized grating we achieve a vertical upward diffraction efficiency of almost 92% with a 3.6 $\mu {}$ m-long antenna. When coupled with an ultra-high numerical aperture fiber, the antenna exhibits a coupling efficiency of more than 81% (−0.9 dB) and a 1-dB bandwidth of almost 158 nm. The reflection generated by the perfectly vertical antenna is smaller than −20 dB on a 200-nm bandwidth centered at $\lambda$ = 1550 nm.

We report a novel and simple fabrication process to realize vertically tapered spot size converters (SSC) on InP photonic integrated circuits. The vertical tapering was achieved via a linewidth controlled local optical dose variation, leading to a grey tone photoresist profile. The fabricated SSCs are compact, polarization insensitive and demonstrate a very high mode conversion efficiency of 95%. Integrated SSCs improved the overall loss by 5 dB giving a coupling loss as low as 1.3 dB/facet, for a lensed fibre with a mode field diameter of 3.0 µm. A good agreement was found between the fibre-to-fibre optical loss measurements and those predicted from simulations.

Spectral pattern recognition is used to measure temperature and generate calibrated wavelength/frequency combs using a single silicon waveguide ring resonator. The ring generates two incommensurate interleaving TE and TM spectral combs that shift independently with temperature to create a spectral pattern that is unique at every temperature. Following an initial calibration, the ring temperature can be determined by recognizing the spectral resonance pattern, and as a consequence the wavelength of every resonance is also known. Two methods of pattern based temperature retrieval are presented. In the first method, the ring is locked to a previously determined temperature set-point defined by the coincidence of only two specific TE and TM cavity modes. Based on a prior calibration at the set-point, the ring temperature and hence all resonance wavelengths are then known and the resulting comb can be used as a wavelength calibration reference. In this configuration, all reference comb wavelengths have been reproduced within a 5 pm accuracy across an 80 nm range by using an on-chip micro-heater to tune the ring. For more general photonic thermometry, a spectral correlation algorithm is developed to recognize a resonance pattern across a 30 nm wide spectral window and thereby determine ring temperature continuously to 50 mK accuracy. The correlation method is extended to simultaneously determine temperature and to identify and correct for wavelength calibration errors in the interrogating light source. The temperature and comb wavelength accuracy is limited primarily by the linewidth of the ring resonances, with accuracy and resolution scaling with the ring quality factor., Comment: 15 pages, 11 figures

Subwavelength metamaterial structures in silicon waveguides open new degrees of freedom to control on-chip light propagation. They have been applied to many silicon photonic devices such as fiber-chip couplers, waveguide crossings, microspectrometers, ultra-fast optical switches, athermal waveguides, evanescent field sensors, polarization rotators and colorless interference couplers [1]. Here we report a demonstration of a metamaterial coupler and an InAs-on-InP quantum dash buried heterostructure laser optimized for mutual integration by direct facet-to-facet coupling with -1.2 dB coupling efficiency, coupled laser relative intensity noise (RIN) of -150 dB/Hz and 152 kHz linewidth. We further demonstrate the design of multi-line spectral notch filters based on narrow linewidth metamaterial Bragg filters synthesized using the layer-peeling method., 2020 Photonics North (PN), May 26-28, 2020, Niagara Falls, ON, Canada

Absorption spectroscopy is a powerful technique for characterizing remote gas composition where direct interaction with a target it not possible. While dispersive spectroscopy is typically used to acquire a spectrum with which the gas presence is determined, correlation spectroscopy can directly detect such spectral features in a single detection channel. Here we present a novel integrated photonics correlation technique on an integrated photonic platform which uses real-time spectral processing to generate a multiline gas specific detection signal., 2020 Photonics North (PN), May 26-28, 2020, Niagara Falls, ON, Canada

Sarcopenia, defined as loss of muscle mass, can occur with aging. We conducted a single-center retrospective analysis to evaluate the impact of muscle quality in multiple myeloma (MM), a hematologic cancer of older adults, undergoing autologous hematopoietic cell transplantation (autoHCT). Healthy muscle was quantified by measuring the percent of high-density muscle within the L3 psoas muscle using a novel computed tomography method in 142 eligible patients. Early post-transplant complications were assessed in the first 100 days after transplant. Sarcopenia, defined as ≤80% high-density muscle, was found in 72 (51%) patients. Sarcopenic obesity, defined as sarcopenia and a BMI ≥ 30, was found in 32 (23%) patients. One or more early complications occurred in 22 (16%) patients. Cardiovascular events accounted for 36% of all complications. Patients with sarcopenia had more cardiac complications (12.5%) than patients without (2.9%, p = 0.03). Multivariate analysis revealed increased BMI at transplant, but not sarcopenia, was associated with worse OS (hazard ratio: 1.11, 95% confidence interval: 1.02–1.22, p = 0.02). Our analysis suggests that sarcopenia is prevalent in MM and associated with increased early post-transplant cardiovascular complications in MM. Obesity, regardless of sarcopenia, is associated with worse survival in MM. Our study generates hypothesis-generating data to risk-stratify patients being considered for autoHCT.

In recent years photonic thermometers - temperature sensors based on optical frequency measurement which exploit the thermo-optic effect to translate thermal changes into frequency shifts - are gaining popularity as a possible alternative to their electrical counterparts: platinum resistance thermometers and thermocouples. In this work, we report our results of testing photonic thermometers based on silica fiber-Bragg-grating technology supplied by a commercial company, as well as preliminary testing results of a silicon ring-resonator thermometer developed at the National Research Council of Canada. The main purpose of showing these two examples is to highlight some of the challenges that need to be addressed if photonic thermometers are to replace thermocouples or platinum resistance thermometers in metrology laboratories and other environments where high accuracy and stability are required, namely the influence of packaging on the sensor's performance and the need for rigorous testing to be done in a temperature metrology lab.

Enabled by technological improvements, photonic devices and circuits are becoming increasingly more complex. Non-trivial geometries are designed to reduce device footprint, improve performance, and introduce novel functionalities. However, the number of design variables required to properly represent these geometries quickly grows, limiting the effectiveness of classical design approaches. Moreover, parameters are often strongly interdependent, restricting the use of sequential optimizations or independent parameter sweeps. Although several optimization techniques can be effective for multi-parameter design, they commonly allow to optimize for a single or a handful designs and the optimization process needs to be repeated if new performance criteria are introduced. In contrast to classical design approaches, the influences of the design parameters remain hidden as well as the general behavior of the design space. In this paper we present an extension of our recent work on the application of machine learning pattern recognition to the design of multi-parameter photonic devices. In particular, we propose using a combination of local optimization based on the adjoint method and the use of dimensionality reduction. Adjoint optimization is used multiple times to generate a small set of different designs with high performance. Dimensionality reduction is applied to analyze the relationship between these degenerate designs and identify a lower-dimensional design sub-space that includes all alternative good designs. This sub-space can be mapped for any performance criteria thus enabling informed decisions based on the relative priorities of all relevant performance specifications. As a proof of concept, we demonstrate a ten-parameter design of an integrated photonic power splitter using silicon-on-insulator technology. We identify a region of possible high performance design solutions and select two design candidates either maximizing the splitter efficiency or minimizing back-reflection., Integrated Photonics Platforms: Fundamental Research, Manufacturing and Applications, April 6-10, 2020, Online Only, France, Series: Proceedings of SPIE

Introduction: Anti-myeloma BCMA-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising new treatment strategy, with high response rates observed in the early stages of therapy. However, the responses are not durable. One known mechanism of relapse has been traced to the loss of BCMA expression following long-term CAR-T therapy. Another potential reason is that while BCMA CAR-T cells eliminate the bulk of BCMA-positive MM cells, a small subset of BCMA-negative, very drug-resistant MM cells, such as tumor-initiating cells (TICs) survive and seed relapses. There is a strong correlation between the presence of MM TICs with minimal residual disease, acquired drug resistance and relapse. This suggests that TIC-targeted therapies could improve outcomes. We have previously demonstrated that MM cells expressing CD24 also exhibit features of TICs, e.g. self-renewal, increased expression of embryonic stem cell genes and drug resistance. We have generated bispecific CAR-T cells which recognize both BCMA and CD24 antigens and have tested their therapeutic efficacy in MM cells in vitro and in vivo models. Methods: We constructed a bispecific BCMA-CD24 CAR vector, with 2 complete CAR units: BCMA CAR and CD24 CAR. P2A was inserted between these two CARs. The BCMA CAR contains a safety switch in the hinge region, and a CD28 co-activation domain with CD3ζ. The CD24 CAR contained a 4-1BB co-activation domain with CD3ζ. To decrease the risk of severe immunological side effects, we integrated RQR8, an immunological safety switch with epitopes for CD34 and CD20 as a suicide molecule into the hinge region. Lentivirus particles were used to transduce primary human T cells. CAR-T cells were detected on day 7 by flow cytometry using antibodies to CD34. We performed co-culture killing assays, detected the T cell activation marker CD69 and measured the cytokines in the supernatant. We determined whether BCMA-CD24 CAR-T cells targeted the TIC population by flow cytometry and microscopy. The NOD. Cg-Prkdc scidIl2rg tm1Wjl/SzJ (NSG) xenograft mouse model was used for in vivo studies. 8-week-old NSG mice were administered 2 × 10 6 MM cells by intravenous injection. On day 7 after MM cells injection, 1 × 10 6 CAR-T cells were administered. Mice were weighed and monitored for signs of distress every two days. Bioluminescence images were acquired 10 min after D-luciferin injection. Myeloma progression was monitored every 7 days until the mice develop hind limb paralysis or the bioluminescence signal (ROI) is more than 2 × 10 10. Results: CAR-T cells were detected by flow cytometry using the RQR8-specific CD34 antibody. The BCMA-CD24 CAR was found to be expressed on roughly 13% of T-cells. To determine the selective lysis by the CAR-T cells, we performed co-culture killing assays in which MM cell lines over-expressing CD24 (ARP-1 CD24OE or OCI CD24OE cells) were incubated with CAR-T cells. When the CAR-T: MM ratio was 5:1, the lysis percentage of target cells was 99% (ARP-1 CD24OE) and 89% (OCI CD24OE). CAR-T cell activation was determined by increased CD69 expression and IL-2 production. As expected, exposure to CD24 + MM cells resulted in strong activation of CAR-T cells, and CAR-T cells did target and kill the TIC population. Bioluminescence imaging showed CAR-T mediated antitumor activity, yielding near-complete tumor clearance. Additionally, mice treated with CAR-T cells exhibited increased survival compared with mice in the control groups. Conclusion and Significance: This study developed a BCMA-CD24 CAR-T, a novel MM immunotherapy. We have demonstrated strong cytotoxic activity and selectivity for MM cells in vitro and in vivo. Future studies will be aimed at determining if BCMA-CD24 CAR-T can target TIC-mediated relapses. Disclosures No relevant conflicts of interest to declare.

Background: Recent treatment advances have greatly improved the survival in multiple myeloma (MM), the second most common hematologic malignancy in the US. However, large racial and ethnic disparities in MM survival still exist. Previous Surveillance, Epidemiology and End Results (SEER)-based analyses suggest Hispanics have lower utilization rate of effective antimyeloma therapies and worse overall survival than non-Hispanic whites (NHWs) with MM, but the factors associated with these disparities are not clear. To understand the nature of the disparity, we used a novel tapered matching approach to examine the sequential effects of demographics, clinical, and treatment-related factors on the disparities in survival time between Hispanic and NHW patients with MM. Methods: We identified 1,591 Hispanic and 20,831 NHW patients, 65 years or older, diagnosed with MM between 1999 and 2017 in the SEER-Medicare database (2020 release). MM diagnosis was defined by International Classification of Diseases for Oncology, Third Edition using topography codes (C42.1) and histologic codes (M9732/3). All patients have continuous enrollment in Medicare parts A and B from 12 months before MM diagnosis to at least 12 months after MM diagnosis or death, whichever occurs first. Patients were followed up until death from any cause, maximum claim date, or December 31, 2018. Four sets of 1,591 NHW patients were matched sequentially to the same set of 1,591 Hispanic patients, based on demographics (age, sex, year of diagnosis, SEER site, and marital status), socioeconomic status (SES, demographic variables plus SES), presentation (SES variables plus comorbidities) and treatment (presentation variables plus chemotherapy, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and autologous stem cell transplantation (ASCT)). All matching was performed using the OPTNET procedure in SAS 9.4 to identify the optimal 1:1 matched cohort that had the minimal total distance between Hispanic and NHW matched pairs. We used paired Cox proportional hazards models to examine survival over time and hazard ratios (HRs) and used the bootstrap method to obtain standard errors for the paired differences in survival. Results: Overall, compared to the unmatched NHWs, Hispanics were younger on average (75.8 vs. 77.1 years), more likely to be female (52.6% vs. 48.0%), to have low SES (52.6% vs. 23.1%), but less likely to be married at diagnosis (36.4% vs. 40.2%). Hispanics also had more comorbidities (Comorbidity Index = 0, 16.2% vs. 22.0%), but were less likely to receive ASCT (4.0% vs. 5.3%) than NHWs (all P < 0.05, Table 1). During follow-up evaluation, 1,217 of 1,591 Hispanics (76.5%) and 16,479 of 20,831 NHWs (79.1%) died. Compared with demographics matched NHWs, Hispanics had a significantly shorter median survival (30.0 vs. 37.0 months; P=0.004). After matching on SES, the difference in median survival was no longer significant (P=0.46), neither in the matching on presentation (P=0.38) nor treatment (P=0.19). The absolute difference in 5-year survival between Hispanics (29.6%) and NHWs (33.2%) was 3.6% (95%CI, 0.1%-6.9%, P = 0.002) in the demographics match. After we matched for SES, the difference in 5-year survival was reduced to 2.2% (95%CI, -1.2%-5.7%) and was not statistically significant (P = 0.32). No 5-year survival difference was observed in the presentation or treatment match (both P > 0.05) (Table 2 and Figure 1). We further conducted stratified analysis by SES and found that among those with low SES, NHWs still had a marginally significant longer median survival (30.0 vs 26.0 months, P=0.06) and better 5-year survival (28.4% vs. 25.5%, P =0.07) than Hispanics in the demographics match. Further matching on presentation and treatment eliminated the survival differences between NHWs and Hispanics who were both at low SES. However, if NHWs and Hispanics were both at high SES, they experienced similar survival across the demographics, presentation and treatment match (all P > 0.1). Conclusions: In the SEER-Medicare database, SES could account for the disparities in survival time between Hispanic and NHW patients with MM. While SES is an important prognostic factor of MM, additional social, clinical, and biological factors also need to be investigated to understand the mechanisms underlying survival disparity in patients with low SES, so proper intervention and policy development could be implemented. Figure 1 Figure 1. Disclosures Mohan: Medical College of Wisconsin: Current Employment. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Dhakal: Fate: Research Funding; Carsgen: Research Funding; Natera: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.

Introduction The development of new treatments for high-risk multiple myeloma (HRMM) are needed. The PD-1/PD-L1 axis is one of the chief inhibitory immune checkpoints in antitumor immunity. Despite the success of PD-1 (PDCD1) / PD-L1 (CD274) blockade in some neoplasms, use of it as a monotherapy has failed to improve outcome in RRMM. We have previously demonstrated that the cell-cycle-regulated serine-threonine kinase, NEK2 is elevated in HRMM and that inhibition of NEK2 can overcome drug-resistance and prolong survival of xenografted MM cells. Here, we aimed to investigate the possible role of NEK2 in regulating the immune checkpoint response in MM and development of possible anti-PD1/PDL1 combination therapies. Methods Gene expression profiles and pathway enrichment analyses were conducted on oligonucleotide microarray gene expression profiles from over 1000 primary MM samples to evaluate the correlation of NEK2 and immune checkpoint expression levels. To elucidate the underlying mechanism, we used Nek2 -/- mice crossed with EμMyc mice to generate B cell tumor mouse model with NEK2 deficiency. RNA-sequencing analyses of premalignant B cells was compared between EμMyc/Nek2 WT and EμMyc/Nek2 -/- mice. The hub molecular regulators in the NEK2 correlated pathways were further determined by western blot using NEK2 overexpressing and knockdown cell lines and then verified by co-immunoprecipitation with a NEK2 antibody. Lastly, to establish its clinic significance, the efficacy of INH1 (small compound NEK2 inhibitor), (D)-PPA 1 (peptide-based PD-1/PD-L1 interaction inhibitor) or a PD-L1 (monoclonal antibody) was tested in bone marrow BM mononuclear cells from primary MM patients in-vitro as well as in MM xenografts. Tumor burden and T cell immune responses were monitored by M-spike and mass cytometry. Results Gene expression profiles demonstrated that CD274 expression was significantly higher in the non-proliferative hyperdiploid (HY) subtype of MM, representing between 25-35% of all MM. NEK2 was negatively correlated with CD274 gene expression across all 7 MM subtypes. Gene set enrichment analysis showed that the IFN-γ signaling pathway, which can induce CD274 expression, was significantly enriched in the HY subtype as well as premalignant B cells from EμMyc/Nek2 -/- mice. Elevated expression of EZH2, a histone methyltransferase gene, is also highly correlated wirth NEK2 levels in primary MM. We found that NEK2 inhibition increases CD274 expression as well as reduced EZH2 expression and H3K27me3 levels in MM cell lines. In contrarst, myeloma cells overexpressing NEK2 showed increased expression and activity of EZH2 and H3K27me3 levels. Thus, NEK2 appears to regulate CD274/PD-L1 expression through EZH2-mediated histone methylation. Next we demonstrated that NEK2 and EZH2 directly interact and that overexpression of NEK2 leads to increased methylation of the CD274/PD-L1 gene. We treated BM mononuclear cells from primary MM with PD-1/PD-L1 inhibitor with and without a NEK2 inhibitor. The combination was most effective at eliminating CD138 + myeloma cells while having no effects on T, B and myeloid cell populations. Conclusion Our study showed that expression of CD274/PD-L1 is suppressed in primary HRMM and that CD274/PD-L1 expression is negatively regulated by NEK2 via EZH2-mediated methylation. Inhibition of NEK2 sensitizes myeloma cells to PD-1/PD-L1 blockade, showing either a synergistic or an additive effect in MM cell cytotoxicity. Disclosures No relevant conflicts of interest to declare.

// Wang Wang 1, 2, * , Yi Zhang 3, * , Ruini Chen 2, * , Zhidan Tian 4 , Yongpin Zhai 5 , Siegfried Janz 6 , Chunyan Gu 1, 2 and Ye Yang 1, 2 1 The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, 210023, China 2 School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China 3 Department of Burns and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, China 4 Department of Pathology, Nanjing First Hospital, Nanjing, 210006, China 5 Department of Hematology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China 6 Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, 52242, USA * These authors contributed equally to this work Correspondence to: Chunyan Gu, email: guchunyan@njucm.edu.cn Ye Yang, email: yangye876@sina.com Keywords: chromosomal instability, proliferation, drug resistance, multiple myeloma Received: March 09, 2017 Accepted: August 26, 2017 Published: September 11, 2017 ABSTRACT Chromosomal instability (CIN) is an important hallmark of human cancer. CIN not only contributes to all stages of tumor development (initiation, promotion and progression) but also drives, in large measure, the acquisition of drug resistance by cancer cells. Although CIN is a cornerstone of the complex mutational architecture that underlies neoplastic cell development and tumor heterogeneity and has been tightly associated with treatment responses and survival of cancer patients, it may be one of the least understood features of the malignant phenotype in terms of genetic pathways and molecular mechanisms. Here we review new insights into the type of CIN seen in multiple myeloma (MM), a blood cancer of terminally differentiated, immunoglobulin-producing B-lymphocytes called plasma cells that remains incurable in the great majority of cases. We will consider bona fide myeloma CIN genes, methods for measuring CIN in myeloma cells, and novel approaches to CIN-targeted treatments of patients with myeloma. The new findings generate optimism that enhanced understanding of CIN will lead to the design and testing of new therapeutic strategies to overcome drug resistance in MM in the not-so-distant future.

We design perfectly vertical grating couplers with minimum feature sizes above 100 nm, high coupling efficiencies up to 75%, and low back reflection of -20 dB over 100 nm bandwidth, using a machine learning method., Integrated Photonics Research, Silicon and Nanophotonics 2020 , July 13-16, 2020, Washington, DC

An InAs-on-InP quantum dash buried heterostructure laser and silicon chip optimized for mutual integration by direct facet-to-facet coupling have achieved -1.2 dB coupling efficiency, with coupled laser RIN of -150 dB/Hz and 152 kHz linewidth., 2020 22nd International Conference on Transparent Optical Networks (ICTON), July 19-23, 2020, Bari, Italy

We present the design of a 3.6-µm-long silicon antenna with vertical emission. Across the optical communication C band, diffraction efficiency is above of 0.9, back-reflection below -18 dB, and the emission angle shifts by only 4.3 ◦ .

An accurate model for the silicon refractive index including its temperature and wavelength dependence is critically important for many disciplines of science and technology. Currently, such a model for temperatures above 22°C in the optical communication bands is not available. The temperature dependence in the spectral response of integrated echelle grating filters made in silicon-on-insulator is solely determined by the optical properties of the slab waveguide, making it largely immune to dimensional uncertainties. This feature renders the echelle filters a reliable tool to evaluate the thermo-optic properties of silicon. Here we investigate the temperature dependence of silicon echelle filters for the wavelength range of both O and C bands, measured between 22°C to 80°C. We show that if a constant thermo-optic coefficient of silicon is assumed for each band, as is common in the literature, the predictions show an underestimate of up to 10% in the temperature-induced channel wavelength shift. We propose and assess a model of silicon refractive index that encompasses both the wavelength and temperature dependence of its thermo-optic coefficients. We start from literature data for bulk silicon and further refine the model using the echelle filter measurement results. This model is validated through accurate predictions of device channel wavelengths and their temperature dependence, including the quadratic term, over a wide wavelength and temperature range. This work also demonstrates a new high-precision method for characterizing the optical properties of a variety of materials.

Nanophotonics finds ever broadening applications requiring complex components with many parameters to be simultaneously designed. Recent methodologies employing optimization algorithms commonly focus on a single performance objective, provide isolated designs, and do not describe how the design parameters influence the device behaviour. Here we propose and demonstrate a machine-learning-based approach to map and characterize the multi-parameter design space of nanophotonic components. Pattern recognition is used to reveal the relationship between an initial sparse set of optimized designs through a significant reduction in the number of characterizing parameters. This defines a design sub-space of lower dimensionality that can be mapped faster by orders of magnitude than the original design space. The behavior for multiple performance criteria is visualized, revealing the interplay of the design parameters, highlighting performance and structural limitations, and inspiring new design ideas. This global perspective on high-dimensional design problems represents a major shift in modern nanophotonic design and provides a powerful tool to explore complexity in next-generation devices., Machine learning is increasingly used in nanophotonics for designing novel classes of complex devices but the general parameter behavior is often neglected. Here, the authors report a new methodology to discover and visualize optimal design spaces with respect to multiple performance objectives.

Metamaterial engineered waveguide structures are emerging as fundamental building blocks for integrated photonics. Here we present an overview of our recent advances in this field, including fiber-chip couplers, ultra-broadband beam splitters, nanophotonic waveguides with engineered anisotropy and integrated Bragg filters., 2019 IEEE Photonics Conference (IPC), September 29 - October 3, 2019, San Antonio, TX, USA

Astronomical instrumentation is traditionally costly, large, and alignment-sensitive owing to the use of bulk optics. The use of integrated photonic devices in astronomical instrumentation can mitigate such drawbacks in certain applications where high light throughput and spectral bandwidth are less crucial. In this work, we present an ultra-compact carbon dioxide detection scheme using a single silicon waveguide ring resonator. The comb-like absorption line spectrum of CO2 around 1580 nm wavelength can closely match the comb spectrum of an appropriately designed ring resonator. By actively correlating such a ring spectrum with the CO2 absorption lines, a specific detection signal can be generated. We design the free spectral range of a ring resonator to match the absorption line spacing of carbon dioxide lines in the range from 1575 to 1585 nm. Using thermo-optic modulation, the ring resonator drop or through port transmission spectrum can be shifted back and forth across the incoming CO2 light spectrum, resulting in a modulated signal with an amplitude proportional to the CO2 absorption line strength. Furthermore, high frequency modulation and lock-in detection can result in a significant improvement in the signal to noise ratio. We demonstrate that such a device can provide real-time carbon dioxide detection for applications in ground- and satellite-based astronomy, as well as remote atmospheric sensing, in a compact package. In future work, such a sensor can be adapted to a range of gases and used to determine radial velocities and compositional maps of astronomical objects.

Use of subwavelength metastructures opens new degrees of freedom to control and manipulate propagation of light in planar waveguide devices. This advantage comes with the cost of increased design complexity since more parameters must be simultaneously optimized. Here we show how machine learning dimensionality reduction can be used to obtain a compact representation of a multi-parameter design space revealing the relationship between different design parameters. This provides the designer with a global perspective on the design space and enables informed decisions based on the relative priorities of different performance metrics., 2019 International Conference on Numerical Simulation of Optoelectronic Devices (NUSOD), 8-12 July 2019, Ottawa, ON, Canada

We report on the design of an ultra-compact integrated wavelength demultiplexer in echelle configuration for the optical O-band realized on silicon-on-insulator technology. The device has four channels with channel spacing of 800 GHz and a small footprint of 260 &times, 83 &mu, m2. Channel crosstalk lower than &minus, 28 dB across the four channels is experimentally demonstrated along with insertion losses of &minus, 1.5 dB.

We present the design and experimental results for a silicon photonic thermometer module for secondary and working thermometry standards. The chip is mechanically robust and insensitive to contamination. Using surface coupling gratings the chip temperature can be monitored remotely using free space beams, thereby eliminating temperature hysteresis effects arising from conventional optical assembly methods and materials., 2019 Photonics North (PN), May 21-23, 2019, Quebec City, QC, Canada

We present a correlation spectrometer using a silicon waveguide ring resonator for the identification of molecules in stellar and planetary atmospheres. We tailor the free spectral range of a ring resonator to the vibronic overtones of carbon dioxide in the near infrared. The ring resonator spectrum is modulated via the thermo-optic effect and produces a detection signal unique to carbon dioxide. This spectrometer can be used for real-time remote gas detection and radial velocities of exoplanets in a narrow spectral band., 2019 Photonics North (PN), May 21-23, 2019, Quebec City, QC, Canada

Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival ( P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.

Temperature sensitivity is an issue that severely affects many integrated silicon photonic devices. Proper circuit functionality is normally ensured by active thermal control at the expense of energy consumption. In some cases, athermal behavior can be achieved exploiting cladding materials with a negative thermo-optic coefficient to counterbalance the positive coefficients of silicon and silica. On the other hand, in echelle grating filters this method is not effective because in the slab free-propagation region the modal overlap with the cladding is small, especially for TEpolarized light. Moreover the need to add non-standard materials to the established silicon-on-insulator (SOI) fabrication process could make these solutions impractical. Here we present the design of a temperature-insensitive echelle grating demultiplexer with four channels operating in the TE polarization that does not use any materials with negative thermooptic coefficient and relies exclusively on standard processes for SOI photonics. The design exploits a temperaturesynchronized Mach-Zehnder interferometer as input to the echelle to compensate the shift of the imaged field with temperature. The device achieves a significant reduction in the temperature dependence of the overall transmission with a residual channel wavelength fluctuation smaller than 45 pm over a temperature range of 20 K, compared to a 1.6-nm shift for the same grating with a conventional waveguide input. The excess loss due to the use of the Mach-Zehnder input is no more than 0.7 dB for all four channels. Furthermore, the proposed design shows a very good tolerance to fabrication uncertainty, with minimum degradation of the performance for waveguide width variations of 10 nm., Silicon Photonics XIV, February 2-7, 2019, San Francisco, United States, Series: Proceedings of SPIE

Integrated nanophotonic component design processes are often constrained by computational resources. Advances in simulation and optimization tools have allowed more efficient exploration of larger design spaces. These developments reduce the time-consuming and intuition-limited effort of encoding physical insights into the design structure. However, we argue that efficient optimization is only part of the solution to tackle larger multi-parameter design spaces. Finding patterns in such a space can be more valuable than identifying the individual optima alone. This is particularly true when transitioning from simulation to real device fabrication, where considerations such as tolerance to fabrication imperfections, bandwidth, etc. take an important role but are ignored at the optimization stage. The elucidation of patterns in a complex design space enables efficient identification of designs addressing these additional considerations. As an example, in this presentation we demonstrate how limited data collected from the optimization process of a multisegment vertical grating coupler can be used to identify such patterns through the application of machine learning techniques. The identified patterns, some more interpretable than others, can be used in multiple ways: from speeding up the remaining optimization process itself to gaining insight into the properties of an interesting subset of designs. Together those insights offer a significantly clearer picture of the design space and form the basis for making much more informed decisions on the final designs to be fabricated., Integrated Optics: Devices, Materials, and Technologies XXIII, February 2-7, 2019, San Francisco, USA, Series: Proceedings of SPIE; no. 10921

The autonomic nervous system (ANS), which consists of antagonistic sympathetic (adrenergic) and parasympathetic (cholinergic) arms, has emerged as an important regulator of neoplastic development, yet little is known about its role in multiple myeloma (MM). Clinical findings that anti-adrenergic β-blocker intake reduces risk of disease-specific death and overall mortality in patients with MM have indicated that adrenergic input may worsen myeloma outcome. However, preclinical studies using β-adrenergic receptor agonists or antagonists produced controversial results as to whether sympathetic pathways promote or inhibit myeloma. Retrospective outcome data demonstrating that high message levels of cholinergic receptor genes predict inferior survival in the Multiple Myeloma Research Foundation CoMMpass trial suggest that parasympathetic input may drive myeloma progression in a subset of patients. Here we review the ill-defined role of the ANS in MM, put myeloma in the context of other cancers, and discuss knowledge gaps that may afford exciting research opportunities going forward.

Optical antennas are key components in optical phased arrays for light detection and ranging technology requiring long sensing range and high scanning resolution. To achieve a narrow beam width in the far-field region, antenna lengths of several millimeters or more are required. To date, such long antennas have been impossible to achieve in silicon waveguides because currently demonstrated technologies do not allow accurate control of grating strength. Here, we report on a new type of surface-emitting silicon waveguide with a dramatically increased antenna length of L = 3.65 m m . This is achieved by using a subwavelength metamaterial waveguide core evanescently coupled with radiative segments laterally separated from the core. This results in a far-field diffracted beam width of 0.025°, which is a record small beam divergence for a silicon photonics surface-emitting device. We also demonstrate that by using a design with L -shaped surface-emitting segments, the radiation efficiency of the antenna can be substantially increased compared to a conventional design, with an efficiency of 72% at the wavelength of 1550 nm.

We present perfectly vertical grating couplers for the 220 nm silicon-on-insulator platform incorporating subwavelength metamaterials to increase the minimum feature sizes and achieve broadband low back-reflection. Our study reveals that devices with high coupling efficiencies are distributed over a wide region of the design space with varied back-reflections, while still maintaining minimum feature sizes larger than 100 nm and even 130 nm. Using 3D-finite-difference time-domain simulations, we demonstrate devices with broadband low back-reflection of less than − 20 d B over more than 100 nm bandwidth centered around the C-band. Coupling efficiencies of 72% and 67% are achieved for minimum feature sizes of 106 nm and 130 nm, respectively. These gratings are also more fabrication tolerant compared to similar designs not using metamaterials.