Naturally-phasematched second harmonic generation in a whispering gallery mode resonator

We demonstrate for the first time natural phase matching for optical frequency doubling in a high-Q whispering gallery mode resonator made of Lithium Niobate. A conversion efficiency of 9% is achieved at 30 micro Watt in-coupled continuous wave pump power. The observed saturation pump power of 3.2 mW is almost two orders of magnitude lower than the state-of-the-art. This suggests an application of our frequency doubler as a source of non-classical light requiring only a low-power pump, which easily can be quantum noise limited. Our theoretical analysis of the three-wave mixing in a whispering gallery mode resonator provides the relative conversion efficiencies for frequency doubling in various modes

Coherent Transport through an interacting double quantum dot: Beyond sequential tunneling

Various causes for negative differential conductance in transport through an interacting double quantum dot are investigated. Particular focus is given to the interplay between the renormalization of the energy levels due to the coupling to the leads and the decoherence of the states. The calculations are performed within a basis of many-particle eigenstates and we consider the dynamics given by the von Neumann-equation taking into account also processes beyond sequential tunneling. A systematic comparison between the levels of approximation and also with different formalisms is performed. It is found that the current is qualitatively well described by sequential processes as long as the temperature is larger than the level broadening induced by the contacts.Comment: 11 pages, 5 figures included in tex

Quantum-Enhanced continuous-wave stimulated Raman spectroscopy

Stimulated Raman spectroscopy has become a powerful tool to study the spatiodynamics of molecular bonds with high sensitivity, resolution and speed. However, sensitivity and speed of state-of-the-art stimulated Raman spectroscopy are currently limited by the shot-noise of the light beam probing the Raman process. Here, we demonstrate an enhancement of the sensitivity of continuous-wave stimulated Raman spectroscopy by reducing the quantum noise of the probing light below the shot-noise limit by means of amplitude squeezed states of light. Probing polymer samples with Raman shifts around 2950 $cm^{-1}$ with squeezed states, we demonstrate a quantum-enhancement of the stimulated Raman signal-to-noise ratio (SNR) of 3.60 dB relative to the shot-noise limited SNR. Our proof-of-concept demonstration of quantum-enhanced Raman spectroscopy paves the way for a new generation of Raman microscopes, where weak Raman transitions can be imaged without the use of markers or an increase in the total optical power.Comment: 6 pages, 6 figure

Assessing the Polarization of a Quantum Field from Stokes Fluctuation

We propose an operational degree of polarization in terms of the variance of the projected Stokes vector minimized over all the directions of the Poincar\'e sphere. We examine the properties of this degree and show that some problems associated with the standard definition are avoided. The new degree of polarization is experimentally determined using two examples: a bright squeezed state and a quadrature squeezed vacuum.Comment: 4 pages, 2 figures. Comments welcome

Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression

Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification. © 1999 Cancer Research Campaig

Atomic spectroscopy studies of short-lived isotopes and nuclear isomer separation with the ISOLDE RILIS

The Resonance Ionization Laser Ion Source (RILIS) at the ISOLDE on-line isotope separator is based on the selective excitation of atomic transitions by tunable laser radiation. Ion beams of isotopes of 20 elements have been produced using the RILIS setup. Together with the mass separator and a particle detection system it represents a tool for high-sensitive laser spectroscopy of short-lived isotopes. By applying narrow-bandwidth lasers for the RILIS one can study isotope shifts (IS) and hyperfine structure (HFS) of atomic optical transitions. Such measurements are capable of providing data on nuclear charge radii, spins and magnetic moments of exotic nuclides far from stability. Although the Doppler broadening of the optical absorption lines limits the resolution of the technique, the accuracy of the HFS measurements examined in experiments with stable Tl isotopes approaches a value of 100 MHz. Due to the hyperfine splitting of atomic lines the RILIS gives an opportunity to separate nuclear isomers. Isomer selectivity of the RILIS has been used in studies of short-lived Ag, Cu and Pb isotopes

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered

Breakdown of the Isobaric Multiplet Mass Equation for the A = 20 and 21 Multiplets

Using the Penning trap mass spectrometer TITAN, we performed the first direct mass measurements of 20,21Mg, isotopes that are the most proton-rich members of the A = 20 and A = 21 isospin multiplets. These measurements were possible through the use of a unique ion-guide laser ion source, a development that suppressed isobaric contamination by six orders of magnitude. Compared to the latest atomic mass evaluation, we find that the mass of 21Mg is in good agreement but that the mass of 20Mg deviates by 3{\sigma}. These measurements reduce the uncertainties in the masses of 20,21Mg by 15 and 22 times, respectively, resulting in a significant departure from the expected behavior of the isobaric multiplet mass equation in both the A = 20 and A = 21 multiplets. This presents a challenge to shell model calculations using either the isospin non-conserving USDA/B Hamiltonians or isospin non-conserving interactions based on chiral two- and three-nucleon forces.Comment: 5 pages, 2 figure

Precision mass measurements of magnesium isotopes and implications on the validity of the Isobaric Mass Multiplet Equation

If the mass excess of neutron-deficient nuclei and their neutron-rich mirror partners are both known, it can be shown that deviations of the Isobaric Mass Multiplet Equation (IMME) in the form of a cubic term can be probed. Such a cubic term was probed by using the atomic mass of neutron-rich magnesium isotopes measured using the TITAN Penning trap and the recently measured proton-separation energies of $^{29}$Cl and $^{30}$Ar. The atomic mass of $^{27}$Mg was found to be within 1.6$\sigma$ of the value stated in the Atomic Mass Evaluation. The atomic masses of $^{28,29}$Mg were measured to be both within 1$\sigma$, while being 8 and 34 times more precise, respectively. Using the $^{29}$Mg mass excess and previous measurements of $^{29}$Cl we uncovered a cubic coefficient of $d$ = 28(7) keV, which is the largest known cubic coefficient of the IMME. This departure, however, could also be caused by experimental data with unknown systematic errors. Hence there is a need to confirm the mass excess of $^{28}$S and the one-neutron separation energy of $^{29}$Cl, which have both come from a single measurement. Finally, our results were compared to ab initio calculations from the valence-space in-medium similarity renormalization group, resulting in a good agreement.Comment: 7 pages, 3 figure

Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors

Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cellfree DNA (cfDNA) as a marker of treatment response to BRAF inhibitor (BRAFi) combination therapies in non-melanoma solid tumors included in the Copenhagen Prospective Personalized Oncology (CoPPO) program. Experimental design: Patients with BRAF V600E-mutated tumors were treated with combination therapies including BRAFi. Quantification of mutant cfDNA from plasma was determined and correlated to clinical outcomes. Exome sequencing was performed to identify possible resistance mutations. Results: Twenty-three patients had BRAF-mutated tumors out of 455 patients included in CoPPO and 17 started BRAFi combination (EGFRi/MEKi) therapy. Tumor responses were achieved in 8 out of 16 evaluable patients and the median overalland progression-free survival (OS and PFS) was 15 and 4.8 months, respectively. Longitudinal measurements of BRAF V600E-mutant cfDNA indicated disease progression prior to radiological evaluation and a reduction in the mutant fraction of more than 50% after 4 and 12 weeks of therapy was associated with a significantly longer PFS (p=0.003 and p=0.029) and OS (p=0.029 and p=0.017). Furthermore, the baseline mutant fraction and total level of cfDNA positively correlated with tumor burden (p=0.026 and p=0.024). Finally, analysis of cfDNA at progression revealed novel mutations potentially affecting the MAPK pathway. Conclusion: BRAFi combination therapies showed a response rate of 50% in BRAF V600E-mutated non-melanoma tumors. The fraction of BRAF-mutant cfDNA represent a sensitive indicator for clinical outcomes with plasma collected at week 4 and 12 as crucial time points for monitoring response and disease progression.This study was supported by the Danish Cancer Society, The Harboe Foundation, and the Oncological Research Fund, Department of Oncology, Copenhagen University Hospital, Denmark