Multiple and spectrally robust photonic magic angles in reconfigurable α-MoO3 trilayers.

The emergence of a topological transition of the polaritonic dispersion in twisted bilayers of anisotropic van der Waals materials at a given twist angle-the photonic magic angle-results in the diffractionless propagation of polaritons with deep-subwavelength resolution. This type of propagation, generally referred to as canalization, holds promise for the control of light at the nanoscale. However, the existence of a single photonic magic angle hinders such control since the canalization direction in twisted bilayers is unique and fixed for each incident frequency. Here we overcome this limitation by demonstrating multiple spectrally robust photonic magic angles in reconfigurable twisted α-phase molybdenum trioxide (α-MoO3) trilayers. We show that canalization of polaritons can be programmed at will along any desired in-plane direction in a single device with broad spectral ranges. These findings open the door for nanophotonics applications where on-demand control is crucial, such as thermal management, nanoimaging or entanglement of quantum emitters.

Twist-tunable polaritonic nanoresonators in a van der Waals crystal.

Optical nanoresonators are key building blocks in various nanotechnological applications (e.g., spectroscopy) due to their ability to effectively confine light at the nanoscale. Recently, nanoresonators based on phonon polaritons (PhPs)-light coupled to lattice vibrations-in polar crystals (e.g., SiC, or h-BN) have attracted much attention due to their strong field confinement, high quality factors, and their potential to enhance the photonic density of states at mid-infrared (mid-IR) frequencies, where numerous molecular vibrations reside. Here, we introduce a new class of mid-IR nanoresonators that not only exhibit the extraordinary properties previously reported, but also incorporate a new degree of freedom: twist tuning, i.e., the possibility of controlling their spectral response by simply rotating the constituent material. To achieve this result, we place a pristine slab of the van der Waals (vdW) α-MoO3 crystal, which supports in-plane hyperbolic PhPs, on an array of metallic ribbons. This sample design based on electromagnetic engineering, not only allows the definition of α-MoO3 nanoresonators with low losses (quality factors, Q, up to 200), but also enables a broad spectral tuning of the polaritonic resonances (up to 32 cm-1, i.e., up to ~6 times their full width at half maximum, FWHM ~5 cm-1) by a simple in-plane rotation of the same slab (from 0 to 45°). These results open the door to the development of tunable and low-loss IR nanotechnologies, fundamental requirements for their implementation in molecular sensing, emission or photodetection applications.

Hyperspectral Nanoimaging of van der Waals Polaritonic Crystals.

Phonon polaritons (PhPs) in van der Waals (vdW) crystal slabs enable nanoscale infrared light manipulation. Specifically, periodically structured vdW slabs behave as polaritonic crystals (vdW-PCs), where the polaritons form Bloch modes. Because the polariton wavelengths are smaller than that of light, conventional far-field spectroscopy does not allow for a complete characterization of vdW-PCs or for revealing their band structure. Here, we perform hyperspectral infrared nanoimaging and analysis of PhPs in a vdW-PC slab made of h-BN. We demonstrate that infrared spectra recorded at individual spatial positions within the unit cell of the vdW-PC can be associated with its band structure and local density of photonic states (LDOS). We thus introduce hyperspectral infrared nanoimaging as a tool for the comprehensive analysis of polaritonic crystals, which could find applications in the reconstruction of complex polaritonic dispersion surfaces in momentum-frequency space or for exploring exotic electromagnetic modes in topological photonic structures.

Planar refraction and lensing of highly confined polaritons in anisotropic media.

Refraction between isotropic media is characterized by light bending towards the normal to the boundary when passing from a low- to a high-refractive-index medium. However, refraction between anisotropic media is a more exotic phenomenon which remains barely investigated, particularly at the nanoscale. Here, we visualize and comprehensively study the general case of refraction of electromagnetic waves between two strongly anisotropic (hyperbolic) media, and we do it with the use of nanoscale-confined polaritons in a natural medium: α-MoO3. The refracted polaritons exhibit non-intuitive directions of propagation as they traverse planar nanoprisms, enabling to unveil an exotic optical effect: bending-free refraction. Furthermore, we develop an in-plane refractive hyperlens, yielding foci as small as λp/6, being λp the polariton wavelength (λ0/50 compared to the wavelength of free-space light). Our results set the grounds for planar nano-optics in strongly anisotropic media, with potential for effective control of the flow of energy at the nanoscale.

Enabling propagation of anisotropic polaritons along forbidden directions via a topological transition.

Polaritons with directional in-plane propagation and ultralow losses in van der Waals (vdW) crystals promise unprecedented manipulation of light at the nanoscale. However, these polaritons present a crucial limitation: their directional propagation is intrinsically determined by the crystal structure of the host material, imposing forbidden directions of propagation. Here, we demonstrate that directional polaritons (in-plane hyperbolic phonon polaritons) in a vdW crystal (α-phase molybdenum trioxide) can be directed along forbidden directions by inducing an optical topological transition, which emerges when the slab is placed on a substrate with a given negative permittivity (4H-silicon carbide). By visualizing the transition in real space, we observe exotic polaritonic states between mutually orthogonal hyperbolic regimes, which unveil the topological origin of the transition: a gap opening in the dispersion. This work provides insights into optical topological transitions in vdW crystals, which introduce a route to direct light at the nanoscale.

Giant optical anisotropy in transition metal dichalcogenides for next-generation photonics.

Large optical anisotropy observed in a broad spectral range is of paramount importance for efficient light manipulation in countless devices. Although a giant anisotropy has been recently observed in the mid-infrared wavelength range, for visible and near-infrared spectral intervals, the problem remains acute with the highest reported birefringence values of 0.8 in BaTiS3 and h-BN crystals. This issue inspired an intensive search for giant optical anisotropy among natural and artificial materials. Here, we demonstrate that layered transition metal dichalcogenides (TMDCs) provide an answer to this quest owing to their fundamental differences between intralayer strong covalent bonding and weak interlayer van der Waals interaction. To do this, we made correlative far- and near-field characterizations validated by first-principle calculations that reveal a huge birefringence of 1.5 in the infrared and 3 in the visible light for MoS2. Our findings demonstrate that this remarkable anisotropy allows for tackling the diffraction limit enabling an avenue for on-chip next-generation photonics.

Launching of hyperbolic phonon-polaritons in h-BN slabs by resonant metal plasmonic antennas.

Launching and manipulation of polaritons in van der Waals materials offers novel opportunities for field-enhanced molecular spectroscopy and photodetection, among other applications. Particularly, the highly confined hyperbolic phonon polaritons (HPhPs) in h-BN slabs attract growing interest for their capability of guiding light at the nanoscale. An efficient coupling between free space photons and HPhPs is, however, hampered by their large momentum mismatch. Here, we show -by far-field infrared spectroscopy, infrared nanoimaging and numerical simulations- that resonant metallic antennas can efficiently launch HPhPs in thin h-BN slabs. Despite the strong hybridization of HPhPs in the h-BN slab and Fabry-Pérot plasmonic resonances in the metal antenna, the efficiency of launching propagating HPhPs in h-BN by resonant antennas exceeds significantly that of the non-resonant ones. Our results provide fundamental insights into the launching of HPhPs in thin polar slabs by resonant plasmonic antennas, which will be crucial for phonon-polariton based nanophotonic devices.

Deeply subwavelength phonon-polaritonic crystal made of a van der Waals material.

Photonic crystals (PCs) are periodically patterned dielectrics providing opportunities to shape and slow down the light for processing of optical signals, lasing and spontaneous emission control. Unit cells of conventional PCs are comparable to the wavelength of light and are not suitable for subwavelength scale applications. We engineer a nanoscale hole array in a van der Waals material (h-BN) supporting ultra-confined phonon polaritons (PhPs)-atomic lattice vibrations coupled to electromagnetic fields. Such a hole array represents a polaritonic crystal for mid-infrared frequencies having a unit cell volume of [Formula: see text] (with λ0 being the free-space wavelength), where PhPs form ultra-confined Bloch modes with a remarkably flat dispersion band. The latter leads to both angle- and polarization-independent sharp Bragg resonances, as verified by far-field spectroscopy and near-field optical microscopy. Our findings could lead to novel miniaturized angle- and polarization-independent infrared narrow-band couplers, absorbers and thermal emitters based on van der Waals materials and other thin polar materials.

Nanoimaging of resonating hyperbolic polaritons in linear boron nitride antennas.

Polaritons in layered materials-including van der Waals materials-exhibit hyperbolic dispersion and strong field confinement, which makes them highly attractive for applications including optical nanofocusing, sensing and control of spontaneous emission. Here we report a near-field study of polaritonic Fabry-Perot resonances in linear antennas made of a hyperbolic material. Specifically, we study hyperbolic phonon-polaritons in rectangular waveguide antennas made of hexagonal boron nitride (h-BN, a prototypical van der Waals crystal). Infrared nanospectroscopy and nanoimaging experiments reveal sharp resonances with large quality factors around 100, exhibiting atypical modal near-field patterns that have no analogue in conventional linear antennas. By performing a detailed mode analysis, we can assign the antenna resonances to a single waveguide mode originating from the hybridization of hyperbolic surface phonon-polaritons (Dyakonov polaritons) that propagate along the edges of the h-BN waveguide. Our work establishes the basis for the understanding and design of linear waveguides, resonators, sensors and metasurface elements based on hyperbolic materials and metamaterials.

Controlling graphene plasmons with resonant metal antennas and spatial conductivity patterns.

Graphene plasmons promise unique possibilities for controlling light in nanoscale devices and for merging optics with electronics. We developed a versatile platform technology based on resonant optical antennas and conductivity patterns for launching and control of propagating graphene plasmons, an essential step for the development of graphene plasmonic circuits. We launched and focused infrared graphene plasmons with geometrically tailored antennas and observed how they refracted when passing through a two-dimensional conductivity pattern, here a prism-shaped bilayer. To that end, we directly mapped the graphene plasmon wavefronts by means of an imaging method that will be useful in testing future design concepts for nanoscale graphene plasmonic circuits and devices.

Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency.

Genetically defined mouse models offer an important tool to identify critical secondary genetic alterations with relevance to human cancer pathogenesis. We used newly generated MMTV-Cre105Ayn mice to inactivate p53 and/or Rb strictly in the mammary epithelium, and to determine recurrent genomic changes associated with deficiencies of these genes. p53 inactivation led to formation of estrogen receptor-positive raloxifene-responsive mammary carcinomas with features of luminal subtype B. Rb deficiency was insufficient to initiate carcinogenesis but promoted genomic instability and growth rate of neoplasms associated with p53 inactivation. Genome-wide analysis of mammary carcinomas identified a recurrent amplification at chromosome band 9A1, a locus orthologous to human 11q22, which contains protooncogenes cIAP1 (Birc2), cIAP2 (Birc3) and Yap1. It is interesting that this amplicon was preferentially detected in carcinomas carrying wild-type Rb. However, all three genes were overexpressed in carcinomas with p53 and Rb inactivation, likely due to E2F-mediated transactivation, and cooperated in carcinogenesis according to gene knockdown experiments. These findings establish a model of luminal subtype B mammary carcinoma, identify critical role of cIAP1, cIAP2 and Yap1 co-expression in mammary carcinogenesis and provide an explanation for the lack of recurrent amplifications of cIAP1, cIAP2 and Yap1 in some tumors with frequent Rb deficiency, such as mammary carcinoma.

Prostate stem cells and cancer.

Properties shared by neoplastic and stem cells indicate a possibility that somatic stem cells or transit-amplifying cells that have reacquired stem cell properties, particularly the ability for self-renewal, represent favorable targets for malignant transformation. In this review we discuss significance of the stem cell model for understanding prostate cancer pathogenesis and describe relevant studies in animals. It is proposed that dissemination of rare cancer stem cells may lead to metastatic disease and that resistance of such cells to multiple drugs and androgen ablation make them responsible for failure of current treatments. Thus further understanding of the cancer stem cell biology is needed for development of efficient rationally designed therapy permitting better targeting and better treatment outcomes for patients with prostate neoplasms.

Targeted disruption of the mouse ing1 locus results in reduced body size, hypersensitivity to radiation and elevated incidence of lymphomas.

Ing1 belongs to the family of evolutionary conserved genes encoding nuclear PHD finger-containing proteins implicated in a variety of processes, including tumorigenesis, replicative senescence, excision repair and response to genotoxic stress. We have generated mice deficient in all the isoforms of Ing1 by targeted disruption of the exon that is common for all ing1 transcripts. Embryonic fibroblasts from ing1-knockout mice were similar to the wild-type cells in their growth characteristics, replicative lifespan in culture, p53 induction and sensitivity to various cytotoxic treatments with minor alterations in cell cycle distribution in response to genotoxic stress. ing1-deficient animals are characterized by reduced size with no obvious morphological, physiological or behavioral abnormalities, indicating that ing1 function is dispensable for the viability of mice under normal physiological conditions. Loss of ing1 was associated with earlier onset and higher incidence of lymphomas. Consistent with the possible involvement of Ing1 in DNA repair, ing1-deficient mice were more sensitive to total body gamma radiation. Our observations are well in line with the suggested role of ing1 as a candidate tumor suppressor gene involved in control of DNA damage response.

Translational research in ovarian cancer: a must.

Ovarian cancer discovered at late clinical stage continues to be a fatal disease. It seems self-evident that if we are to make an impact on the survival of advanced ovarian cancer patients, we must begin to understand the disease more completely. This should improve the diagnosis of the disease at an early stage when it is curable by surgery or develop better/targeted drug treatments. Modern molecular techniques have provided insights into many of the molecular changes that occur when ovarian cancer develops, but one must understand that changes seen in this way can only be said to correlate with disease. It would be helpful to have a way to test candidate changes for causality. In many cancer types, genetically engineered animals are beginning to be used for this purpose and as a means to study the disease process in greater detail. To date, there has been no way to study ovarian cancer by this means. Efforts to model human ovarian cancer have been delayed by a general lack of understanding both of the disease process in humans and of the cells widely believed to be the precursors of epithelial ovarian cancer, the ovarian surface epithelial (OSE) cells. Here, we present recent progress in modeling ovarian cancer using genetically modified mice.

Temporal, spatial, and cell type-specific control of Cre-mediated DNA recombination in transgenic mice.

We have developed a universal system for temporal, spatial, and cell type-specific control of gene expression in mice that (1) integrates the advantages of tetracycline-controlled gene expression and Cre-recombinase-loxP site-mediated gene inactivation, and (2) simplifies schemes of animal crosses by combination of two control elements in a single transgene. Two transgenic strains were generated in which the cell type-specific control was provided by either the retinoblastoma gene promoter or the whey acidic protein promoter. Both promoters drive the expression of the reverse tetracycline-controlled transactivator (rtTA). Placed in cis configuration to the rtTA transcription unit, the rtTA-inducible promoter directs expression of Cre recombinase. In both strains crossed with cActXstopXLacZ reporter mice, which have a loxP-stop of transcription/translation-loxP-LacZ cassette driven by chicken beta-actin promoter, Cre-loxP-mediated DNA recombination leading to LacZ expression was accurately regulated in a temporal, spatial, and cell type-specific manner. This approach can be applied to establishment of analogous mouse strains with virtually any promoter as systems to control gene regulation in a variety of cell types.

RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice.

Alterations in pathways mediated by retinoblastoma susceptibility gene (RB) product are among the most common in human cancer. Mice with a single copy of the Rb gene are shown to develop a syndrome of multiple neuroendocrine neoplasia. The earliest Rb-deficient atypical cells were identified in the intermediate and anterior lobes of the pituitary, the thyroid and parathyroid glands, and the adrenal medulla within the first 3 months of postnatal development. These cells form gross tumors with various degrees of malignancy by postnatal day 350. By age of 380 days, 84% of Rb+/- mice exhibited lung metastases from C-cell thyroid carcinomas. Expression of a human RB transgene in the Rb+/- mice suppressed carcinogenesis in all tissues studied. Of particular clinical relevance, the frequency of lung metastases also was reduced to 12% in Rb+/- mice by repeated i.v. administration of lipid-entrapped, polycation-condensed RB complementary DNA. Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells. Restoration of RB function in humans may prove an effective general approach to the treatment of RB-deficient disseminated tumors.

A paradigm for cancer treatment using the retinoblastoma gene in a mouse model.

Discovery of tumor suppressor genes has provided a rational approach to cancer prevention and treatment. Loss of retinoblastoma susceptibility gene (Rb) function is a rate-limiting event in the development of human and mouse cancers. Establishment of animal models of cancer associated with Rb deficiency allowed us to develop and test long-awaited approaches to genetic correction for treating tumors in vivo. Recent studies demonstrated that (1) prevention of carcinogenesis is achieved by correction of gene copy number in Rb+/- mice, and (2) reconstitution of Rb gene functions is sufficient for suppression of neoplasia in immunocompetent mice. These results fulfill a promise of cancer treatment by reconstitution of tumor suppressor function.

Earlier onset of melanotroph carcinogenesis in mice with inherited mutant paternal allele of the retinoblastoma gene.

The role of genomic imprinting in the development of tumors with defective retinoblastoma protein function remains debatable. Disruption of either parental allele of the murine retinoblastoma (Rb) gene is sufficient for spontaneous melanotroph carcinogenesis to occur in almost all Rb+/- mice. Nevertheless, mice with a disrupted paternal Rb allele succumb to tumors faster. In these animals, the first foci of proliferating atypical Rb-negative cells appear and progress to overtly malignant tumors earlier. In addition, more foci of early atypical proliferation are observed. In Rb+/- mice, however, parental origin influences neither Rb expression nor proliferation of melanotrophs. Accordingly, Rb-/- mice rescued by the human RB transgene transmitted either paternally or maternally have similar survival rates. Taken together, the data point to the existence of an imprinted gene in an Rb-linked locus. The function of this gene affects the onset of melanotroph carcinogenesis, likely by controlling preferential survival of the cells with secondary loss of the Rb maternal allele. Rb+/- mice may serve as useful models to identify and characterize genomic imprinting mechanisms influencing carcinogenesis associated with Rb loss of function.

Adenovirus-mediated retinoblastoma gene therapy suppresses spontaneous pituitary melanotroph tumors in Rb+/- mice.

The retinoblastoma gene (RB) is the prototypic tumor suppressor. Studies to date have demonstrated cancer suppression with tumor cells reconstituted with RB ex vivo and implanted into immunodeficient mice, as well as with germline transmission of a human RB transgene into tumor-prone Rb +/- mice. To mimic the therapy of cancer more closely, spontaneous pituitary melanotroph tumors arising in immunocompetent Rb +/- mice were treated with a recombinant adenovirus carrying RB cDNA. Intratumoral RB gene transfer decreased tumor cell proliferation, reestablished innervation by growth-regulatory dopaminergic neurons, inhibited the growth of tumors, and prolonged the life spans of treated animals.