Updates in Small Interfering RNA for the Treatment of Dyslipidemias.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. RECENT FINDINGS: The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance.

BACKGROUND: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. RESULTS: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. CONCLUSIONS: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

A new dawn for managing dyslipidemias: The era of rna-based therapies.

The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) [Lp(a)]. In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.

Dynamics of a broad-band quantum cascade laser: from chaos to coherent dynamics and mode-locking.

The dynamics of a multimode quantum cascade laser, are studied in a model based on effective semiconductor Maxwell-Bloch equations, encompassing key features for the radiation-medium interaction such as an asymmetric frequency dependent gain and refractive index as well as the phase-amplitude coupling provided by the linewidth enhancement factor. By considering its role and that of the free spectral range, we find the conditions in which the traveling wave emitted by the laser at the threshold can be destabilized by adjacent modes, thus leading the laser emission towards chaotic or regular multimode dynamics. In the latter case our simulations show that the field oscillations are associated to self-confined structures which travel along the laser cavity, bridging mode-locking and solitary wave propagation. In addition, we show how a RF modulation of the bias current leads to active mode-locking yielding high-contrast, picosecond pulses. Our results compare well with recent experiments on broad-band THz-QCLs and may help in the understanding of the conditions for the generation of ultrashort pulses and comb operation in mid-IR and THz spectral regions.

Near-field spectroscopy and tuning of sub-surface modes in plasmonic terahertz resonators.

Highly confined modes in THz plasmonic resonators comprising two metallic elements can enhance light-matter interaction for efficient THz optoelectronic devices. We demonstrate that sub-surface modes in such double-metal resonators can be revealed with an aperture-type near-field probe and THz time-domain spectroscopy despite strong mode confinement in the dielectric spacer. The sub-surface modes couple a fraction of their energy to the resonator surface via surface waves, which we detected with the near-field probe. We investigated two resonator geometries: a λ/2 double-metal patch antenna with a 2 µm thick dielectric spacer, and a three-dimensional meta-atom resonator. THz time-domain spectroscopy analysis of the fields at the resonator surface displays spectral signatures of sub-surface modes. Investigations of strong light-matter coupling in resonators with sub-surface modes therefore can be assisted by the aperture-type THz near-field probes. Furthermore, near-field interaction of the probe with the resonator enables tuning of the resonance frequency for the spacer mode in the antenna geometry from 1.6 to 1.9 THz (~15%).

Time resolved Fabry-Perot measurements of cavity temperature in pulsed QCLs.

Temperature rise during operation is a central concern of semiconductor lasers and especially difficult to measure during a pulsed operation. We present a technique for in situ time-resolved temperature measurement of quantum cascade lasers operating in a pulsed mode at ~9.25 µm emission wavelength. Using a step-scan approach with 5 ns resolution, we measure the temporal evolution of the spectral density, observing longitudinal Fabry-Perot modes that correspond to different transverse modes. Considering the multiple thin layers that make up the active layer and the associated Kapitza resistance, thermal properties of QCLs are significantly different than bulk-like laser diodes where this approach was successfully used. Compounded by the lattice expansion and refractive index changes due to time-dependent temperature rise, Fabry-Perot modes were observed and analyzed from the time-resolved emission spectra of quantum cascade lasers to deduce the cavity temperature. Temperature rise of a QCL in a pulsed mode operation between -160 °C to -80 °C was measured as a function of time. Using the temporal temperature variations, a thermal model was constructed that led to the extraction of cavity thermal conductivity in agreement with previous results. Critical in maximizing pulsed output power, the effect of the duty cycle on the evolution of laser heating was studied in situ, leading to a heat map to guide the operation of pulsed lasers.

Lipid-lowering therapy of everolimus-related severe hypertriglyceridaemia in a pancreatic neuroendocrine tumour (pNET).

WHAT IS KNOWN AND OBJECTIVE: Hypertriglyceridaemia (HTG) is a potentially serious side effect of everolimus therapy. We here report a case of severe HTG in an everolimus-treated patient and provide recommendations for its management. CASE SUMMARY: The patient was a 70-year-old woman, being treated with everolimus for a pancreatic neuroendocrine tumour (pNET). She developed severe HTG to a maximum of 969 mg/dL after 22 months of therapy. Treatment with fenofibrate rapidly normalized triglyceride (TG) levels. WHAT IS NEW AND CONCLUSION: Severe HTG may occur in everolimus-treated patients. Prescription of the appropriate therapy can allow patients to continue this medication.

Mode stabilization in quantum cascade lasers via an intra-cavity cascaded nonlinearity.

We present self-stabilization of the inter-mode separation of a quantum cascade laser (QCL) emitting at 9 µm via cascaded second order nonlinearity. This effect has been observed in lasers that have the optical cavity embedded into a microwave strip-line. The intermodal beat note spectra narrow with increasing laser output power, up to less than 100 kHz. A flat frequency response to direct modulation up to 14 GHz is reported for these microstrip QCLs. The laser inter-mode spacing can be locked to an external RF signal and tuned by more than 1 MHz from the free-running spacing. A parallel study on the same laser material in a non-microstrip line waveguide shows superior performances of the microstrip QCL in terms of the intermodal spectral locking and stability. Finally by analyzing our results with the theory of the injection locking of coupled oscillators, we deduce that the microwave power injected in the microstrip QCL is 2 orders of magnitude higher than in the reference laser.

Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort.

BACKGROUND AND AIMS: The efficacy and safety of lomitapide as adjunct treatment for adults with homozygous familial hypercholesterolaemia (HoFH) have been confirmed in a phase 3 trial. Given the small number of patients (N = 29), and variations in patient characteristics, examining individual cases provides additional details regarding patient management with lomitapide. Here, we examine the details of the Italian patient cohort in the phase 3 trial. METHODS AND RESULTS: The methodology of the multinational, single-arm, open-label, 78-week, dose-escalation, phase 3 trial has been previously reported. The current report details the Italian cohort of six patients (three males, three females) based on individual patient data, individual patient histories and narratives, and by mean data ± SD. Lomitapide was administered according to the dose-escalation protocol. At Week 78, concentrations of low-density lipoprotein-cholesterol were decreased by a mean of 42.6 ± 21.8% compared with baseline. Lomitapide was similarly well tolerated in the Italian cohort as in the entire study population. The most common adverse events were gastrointestinal symptoms. One patient showed an increase in liver transaminases >5× upper limit of normal that resolved after lomitapide treatment was reduced and maintained at a lower dose. CONCLUSION: The efficacy, safety and tolerability of lomitapide demonstrated in the Italian subgroup of patients are consistent with findings in the entire study population, and illustrate the broad applicability of lomitapide therapy across genotypes and clinical phenotypes. These data also provide an insight into the management of lomitapide use in a cohort of patients within a clinical trial protocol. Clinicaltrials.gov Identifier: NCT00730236.

Optical sideband generation up to room temperature with mid-infrared quantum cascade lasers.

Mid-infrared (MIR) sideband generation on a near infrared (NIR) optical carrier is demonstrated within a quantum cascade laser (QCL). By employing an externally injected NIR beam, E(NIR), that is resonant with the interband transitions of the quantum wells in the QCL, the nonlinear susceptibility is enhanced, leading to both frequency mixing and sideband generation. A GaAs-based MIR QCL (E(QCL) = 135 meV) with an aluminum-reinforced waveguide was utilized to overlap the NIR and MIR modes with the optical nonlinearity of the active region. The resulting difference sideband (E(NIR) - E(QCL)) shows a resonant behavior as a function of NIR pump wavelength and a maximum second order nonlinear susceptibility, χ((2)), of ~1 nm/V was obtained. Further, the sideband intensity showed little dependence with the operating temperature of the QCL, allowing sideband generation to be realized at room temperature.

Superradiant Emission from a Collective Excitation in a Semiconductor.

We report an anomalous wide broadening of the emission spectra of an electronic excitation confined in a two-dimensional potential. We attribute these results to an extremely fast radiative decay rate associated with superradiant emission from the ensemble of confined electrons. Lifetimes extracted from the spectra are below 100 fs and, thus, 6 orders of magnitude faster than for single particle transitions at similar wavelength. Moreover, the spontaneous emission rate increases with the electronic density, as expected for superradiant emission. The data, all taken at 300 K, are in excellent agreement with our theoretical model, which takes into account dipole-dipole Coulomb interaction between electronic excitations. Our experimental results demonstrate that the interaction with infrared light, which is usually considered a weak perturbation, can be a very efficient relaxation mechanism for collective electronic excitations in solids.

Electrical modulation of the complex refractive index in mid-infrared quantum cascade lasers.

We have demonstrated an integrated three terminal device for the modulation of the complex refractive index of a distributed feedback quantum cascade laser (QCL). The device comprises an active region to produce optical gain vertically stacked with a control region made of asymmetric coupled quantum wells (ACQW). The optical mode, centered on the gain region, has a small overlap also with the control region. Owing to the three terminals an electrical bias can be applied independently on both regions: on the laser for producing optical gain and on the ACQW for tuning the energy of the intersubband transition. This allows the control of the optical losses at the laser frequency as the absorption peak associated to the intersubband transition can be electrically brought in and out the laser transition. By using this function a laser modulation depth of about 400 mW can be achieved by injecting less than 1 mW in the control region. This is four orders of magnitude less than the electrical power needed using direct current modulation and set the basis for the realisation of electrical to optical transducers.

Measurement of the intrinsic linewidth of terahertz quantum cascade lasers using a near-infrared frequency comb.

We report the measurement of the frequency noise power spectral density of a quantum cascade laser emitting at 2.5THz. The technique is based on heterodyning the laser emission frequency with a harmonic of the repetition rate of a near-infrared laser comb. This generates a beatnote in the radio frequency range that is demodulated using a tracking oscillator allowing measurement of the frequency noise. We find that the latter is strongly affected by the level of optical feedback, and obtain an intrinsic linewidth of ~230Hz, for an output power of 2mW.

Charge-induced coherence between intersubband plasmons in a quantum structure.

In this Letter we investigate a low dimensional semiconductor system, in which the light-matter interaction is enhanced by the cooperative behavior of a large number of dipolar oscillators, at different frequencies, mutually phase locked by Coulomb interaction. We experimentally and theoretically demonstrate that, owing to this phenomenon, the optical response of a semiconductor quantum well with several occupied subbands is a single sharp resonance, associated with the excitation of a bright multisubband plasmon. This effect illustrates how the whole oscillator strength of a two-dimensional system can be concentrated into a single resonance independently from the shape of the confining potential. When this cooperative excitation is tuned in resonance with a cavity mode, their coupling strength can be increased monotonically with the electronic density, allowing the achievement of the ultrastrong coupling regime up to room temperature.

Phase-locking of a 2.5 THz quantum cascade laser to a frequency comb using a GaAs photomixer.

We report the heterodyne detection and phase locking of a 2.5 THz quantum cascade laser (QCL) using a terahertz frequency comb generated in a GaAs photomixer using a femtosecond fiber laser. With 10 mW emitted by the QCL, the phase-locked signal at the intermediate frequency yields 80 dB of signal-to-noise ratio in a bandwidth of 1 Hz.

Maternal exposure to air pollutants, PCSK9 levels, fetal growth and gestational age - An Italian cohort.

OBJECTIVE: Exposure to airborne pollutants during pregnancy appears to be associated with uterine growth restriction and adverse neonatal outcome. Proprotein convertase subtilisin/kexin type (PCSK9), the key modulator of low-density lipoprotein (LDL) metabolism, increases following particulate matter (PM10) exposure. Because maternal cholesterol is required for fetal growth, PCSK9 levels could be used to evaluate the potential impact of airborne pollutants on fetal growth. DESIGN: A cohort of 134 healthy women during early pregnancy (11-12 weeks of gestational age) was studied. RESULTS: A significant association between circulating PCSK9 levels and three tested air pollutants (PM10, PM2.5, nitric oxide (NO2)) was found. Of importance, gestational age at birth was reduced by approximately 1 week for each 100 ng/mL rise in circulating PCSK9 levels, an effect that became more significant at the highest quartile of PM2.5 (with a 1.8 week advance in delivery date for every 100 ng/mL rise in circulating PCSK9; p for interaction = 0.026). This finding was supported by an elevation of the odds ratio for urgent cesarean delivery for each 100 ng/mL rise in PCSK9 (2.99, 95% CI, 1.22-6.57), similar trends being obtained for PM10 and NO2. CONCLUSIONS: The association between exposure to air pollutants during pregnancy and elevation in PCSK9 advances our understanding of the unforeseen influences of environmental exposure in terms of pregnancy associated disorders.

Optical properties of metal-dielectric-metal microcavities in the THz frequency range.

We present an experimental and theoretical study of the optical properties of metal-dielectric-metal structures with patterned top metallic surfaces, in the THz frequency range. When the thickness of the dielectric slab is very small with respect to the wavelength, these structures are able to support strongly localized electromagnetic modes, concentrated in the subwavelength metal-metal regions. We provide a detailed analysis of the physical mechanisms which give rise to these photonic modes. Furthermore, our model quantitatively predicts the resonance positions and their coupling to free space photons. We demonstrate that these structures provide an efficient and controllable way to convert the energy of far field propagating waves into near field energy.

Semiconductor surface plasmon sources.

Surface-plasmon polaritons (SPPs) are propagating electromagnetic modes bound at a metal-dielectric interface. We report on electrical generation of SPPs by reproducing the analogue in the near field of the slit-doublet experiment, in a device which includes all the building blocks required for a fully integrated plasmonic active source: an electrical generator of SPPs, a coupler, and a passive metallic waveguide. SPPs are generated upon injection of electrical current, and they are then launched at the edges of a passive metallic strip. The interference fringes arising from the plasmonic standing wave on the surface of the metallic strip are unambiguously detected with apertureless near-field scanning optical microscopy.

Ultrastrong light-matter coupling regime with polariton dots.

The regime of ultrastrong light-matter interaction has been investigated theoretically and experimentally, using zero-dimensional electromagnetic resonators coupled with an electronic transition between two confined states of a semiconductor quantum well. We have measured a splitting between the coupled modes that amounts to 48% of the energy transition, the highest ratio ever observed in a light-matter coupled system. Our analysis, based on a microscopic quantum theory, shows that the nonlinear polariton splitting, a signature of this regime, is a dynamical effect arising from the self-interaction of the collective electronic polarization with its own emitted field.

A semiconductor laser device for the generation of surface-plasmons upon electrical injection.

Surface plasmons are electromagnetic waves originating from electrons and light oscillations at metallic surfaces. Since freely propagating light cannot be coupled directly into surface-plasmon modes, a compact, semiconductor electrical device capable of generating SPs on the device top metallic surface would represent an advantage: not only SP manipulation would become easier, but Au-metalized surfaces can be easily functionalized for applications. Here, we report a demonstration of such a device. The direct proof of surface-plasmon generation is obtained with apertureless near-field scanning optical microscopy, which detects the presence of an intense, evanescent electric field above the device metallic surface upon electrical injection.