An Antibody-Drug Conjugate Targeting GPR56 Demonstrates Efficacy in Preclinical Models of Colorectal Cancer

BACKGROUND: Long-term prognosis remains poor for colorectal cancer (CRC) patients with advanced disease due to treatment resistance. The identification of novel targets is essential for the development of new therapeutic approaches. GPR56, an adhesion GPCR, is highly expressed in CRC tumours and correlates with poor survival. Here, we describe the generation and preclinical evaluation of a novel ADC consisting of an anti-GPR56 antibody (10C7) conjugated with the DNA-damaging payload duocarmycin. METHODS: RNA-seq dataset analysis was performed to determine GPR56 expression in CRC subtypes. The specificity of binding, epitope mapping, and internalisation of 10C7 was examined. 10C7 was conjugated to payload and ADC cytotoxicity was assessed against a panel of CRC cell lines and tumour organoids. Antitumour efficacy was evaluated in xenograft models of CRC cell lines and patient-derived tumours. RESULTS: High GPR56 was shown to be associated with the microsatellite stable (MSS) subtype that accounts for 80-85% of CRC. GPR56 ADC selectively induced cytotoxicity in CRC cells and tumour organoids at low nanomolar potency in a GPR56-dependent manner and showed significant antitumour efficacy against GPR56-expressing xenograft models. CONCLUSIONS: This study provides the rationale for the future development of a GPR56-targeted ADC approach to potentially treat a large fraction of MSS CRC patients

Rotating optical soliton clusters

We introduce the concept of soliton clusters -- multi-soliton bound states in a homogeneous bulk optical medium, and reveal a key physical mechanism for their stabilization associated with a staircase-like phase distribution that induces a net angular momentum and leads to cluster rotation. The ringlike soliton clusters provide a nontrivial generalization of the concepts of two-soliton spiraling, optical vortex solitons, and necklace-type optical beams.Comment: 4 pages, 5 figure

Reconfigurable chaos in electro-optomechanical system with negative Duffing resonators

Generating various laser sources is important in the communication systems. We propose an approach that uses a mechanical resonator coupled with the optical fibre system to produce periodic and chaotic optical signals. The resonator is structured in such a way that the nonlinear oscillation occurs conveniently. The mechanical apparatus in the configuration is the well known resonating system featured by the negative stiffness. The mechanical resonance is converted to reflected optical signal with the same dynamic properties as the mechanical oscillation, subsequently interacting with the optical signal within the optical fibre. The optical radiative force on the mechanical structure is also considered in the analysis. The coupled electro-optomechanical system has been analysed, and results show that the mechanical resonator has the capability to control the dynamics of the optical signal precisely. The system will have potential applications in tunable laser sources

Self-locked optical parametric oscillation in a CMOS compatible microring resonator: a route to robust optical frequency comb generation on a chip

We report a novel geometry for OPOs based on nonlinear microcavity resonators. This approach relies on a self-locked scheme that enables OPO emission without the need for thermal locking of the pump laser to the microcavity resonance. By exploiting a CMOS-compatible microring resonator, we achieve oscillation featured by a complete absence of “shutting down”, i.e. the self-terminating behavior that is a very common and detrimental occurrence in externally pumped OPOs. Further, our scheme consistently produces very wide bandwidth (>300nm, limited by our experimental set-up) combs that oscillate at a spacing equal to the FSR of the micro cavity resonance

Integrated frequency comb source of heralded single photons

We report an integrated photon pair source based on a CMOS-compatible microring resonator that generates multiple, simultaneous, and independent photon pairs at different wavelengths in a frequency comb compatible with fiber communication wavelength division multiplexing channels (200 GHz channel separation) and with a linewidth that is compatible with quantum memories (110 MHz). It operates in a self-locked pump configuration, avoiding the need for active stabilization, making it extremely robust even at very low power levels

Stable vortex and dipole vector solitons in a saturable nonlinear medium

We study both analytically and numerically the existence, uniqueness, and stability of vortex and dipole vector solitons in a saturable nonlinear medium in (2+1) dimensions. We construct perturbation series expansions for the vortex and dipole vector solitons near the bifurcation point where the vortex and dipole components are small. We show that both solutions uniquely bifurcate from the same bifurcation point. We also prove that both vortex and dipole vector solitons are linearly stable in the neighborhood of the bifurcation point. Far from the bifurcation point, the family of vortex solitons becomes linearly unstable via oscillatory instabilities, while the family of dipole solitons remains stable in the entire domain of existence. In addition, we show that an unstable vortex soliton breaks up either into a rotating dipole soliton or into two rotating fundamental solitons.Comment: To appear in Phys. Rev.

Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated-skeletal muscle insulin resistance

Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation

All-optical switching and strong coupling using tunable whispering-gallery-mode microresonators

We review our recent work on tunable, ultrahigh quality factor whispering-gallery-mode bottle microresonators and highlight their applications in nonlinear optics and in quantum optics experiments. Our resonators combine ultra-high quality factors of up to Q = 3.6 \times 10^8, a small mode volume, and near-lossless fiber coupling, with a simple and customizable mode structure enabling full tunability. We study, theoretically and experimentally, nonlinear all-optical switching via the Kerr effect when the resonator is operated in an add-drop configuration. This allows us to optically route a single-wavelength cw optical signal between two fiber ports with high efficiency. Finally, we report on progress towards strong coupling of single rubidium atoms to an ultra-high Q mode of an actively stabilized bottle microresonator.Comment: 20 pages, 24 figures. Accepted for publication in Applied Physics B. Changes according to referee suggestions: minor corrections to some figures and captions, clarification of some points in the text, added references, added new paragraph with results on atom-resonator interactio

Spectral Line-by-Line Pulse Shaping of an On-Chip Microresonator Frequency Comb

We report, for the first time to the best of our knowledge, spectral phase characterization and line-by-line pulse shaping of an optical frequency comb generated by nonlinear wave mixing in a microring resonator. Through programmable pulse shaping the comb is compressed into a train of near-transform-limited pulses of \approx 300 fs duration (intensity full width half maximum) at 595 GHz repetition rate. An additional, simple example of optical arbitrary waveform generation is presented. The ability to characterize and then stably compress the frequency comb provides new data on the stability of the spectral phase and suggests that random relative frequency shifts due to uncorrelated variations of frequency dependent phase are at or below the 100 microHertz level.Comment: 18 pages, 4 figure

Inhibition of Wnt/β-Catenin Signaling by a Soluble Collagen-Derived Frizzled Domain Interacting with Wnt3a and the Receptors Frizzled 1 and 8

The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs), which have a cysteine-rich domain (CRD) structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18) inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth