Next-Generation Liquid Biopsies: Embracing Data Science in Oncology.

Deeper and broader sequencing of circulating tumor DNA (ctDNA) has identified a wealth of cancer markers in the circulation, resulting in a paradigm shift towards data science-driven liquid biopsies in oncology. Although panel sequencing for actionable mutations in plasma is moving towards the clinic, the next generation of liquid biopsies is increasingly shifting from analyzing digital mutation signals towards analog signals, requiring a greater role for machine learning. Concomitantly, there is an increasing acceptance that these cancer signals do not have to arise from the tumor itself. In this Opinion, we discuss the opportunities and challenges arising from increasingly complex cancer liquid biopsy data.

Particle-Hole Symmetry and the Fractional Quantum Hall Effect in the Lowest Landau Level.

We report on detailed experimental studies of a high-quality heterojunction insulated-gate field-effect transistor (HIGFET) to probe the particle-hole symmetry of the fractional quantum Hall effect (FQHE) states about half-filling in the lowest Landau level. The HIGFET is specially designed to vary the density of a two-dimensional electronic system under constant magnetic fields. We find in our constant magnetic field, variable density measurements that the sequence of FQHE states at filling factors ν=1/3,2/5,3/7… and its particle-hole conjugate states at filling factors 1-ν=2/3,3/5,4/7… have a very similar energy gap. Moreover, a reflection symmetry can be established in the magnetoconductivities between the ν and 1-ν states about half-filling. Our results demonstrate that the FQHE states in the lowest Landau level are manifestly particle-hole symmetric.

Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer.

Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response.

The translational potential of circulating tumour DNA in oncology.

The recent understanding of tumour heterogeneity and cancer evolution in response to therapy has raised questions about the value of historical or single site biopsies for guiding treatment decisions. The ability of ctDNA analysis to reveal de novo mutations (i.e., without prior knowledge), allows monitoring of clonal heterogeneity without the need for multiple tumour biopsies. Additionally, ctDNA monitoring of such heterogeneity and novel mutation detection will allow clinicians to detect resistant mechanisms early and tailor treatment therapies accordingly. If ctDNA can be used to detect low volume cancerous states, it will have important applications in treatment stratification post-surgery/radical radiotherapy and may have a role in patient screening. Mutant cfDNA can also be detected in other bodily fluids that are easily accessible and may aid detection of rare mutant alleles in certain cancer types. This article outlines recent advances in these areas.

Enhancement of the ν = 5/2 fractional quantum Hall state in a small in-plane magnetic field.

Using a 50-nm-width ultraclean GaAs/AlGaAs quantum well, we have studied the Landau level filling factor ν=5/2 fractional quantum Hall effect in a perpendicular magnetic field B∼1.7 T and determined its dependence on tilted magnetic fields. Contrary to all previous results, the 5/2 resistance minimum and the Hall plateau are found to strengthen continuously under an increasing tilt angle 0<θ<25° (corresponding to an in-plane magnetic field 060°, and the composite fermion series [2+p/(2p±1), p=1,2] can be identified. Based on our results, we discuss the relevance of a Skyrmion spin texture at ν=5/2 associated with small Zeeman energy in wide quantum wells, as proposed by Wójs et al. [Phys. Rev. Lett. 104, 086801 (2010)].

Spin transition in the ν=8/3 fractional quantum Hall effect.

We present here the results from a density dependent study of the activation energy gaps of the fractional quantum Hall effect states at Landau level fillings ν=8/3 and 7/3 in a series of high quality quantum wells. In the density range from 0.5×10(11) to 3×10(11) cm(-2), the 7/3 energy gap increases monotonically with increasing density, supporting its ground state being spin polarized. For the 8/3 state, however, its energy gap first decreases with increasing density, almost vanishes at n~0.8×10(11) cm(-2), and then turns around and increases with increasing density, clearly demonstrating a spin transition.

Termination of two-dimensional metallic conduction near the metal-insulator transition in a Si/SiGe quantum well.

We report in this Letter our recent low-temperature transport results in a Si/SiGe quantum well with moderate peak mobility. An apparent metal-insulating transition is observed. Within a small range of densities near the transition, the conductivity σ displays a nonmonotonic temperature dependence. After an initial decrease at high temperatures, σ first increases with decreasing temperature T, showing a metallic behavior. As T continues decreasing, a downturn in σ is observed. This downturn shifts to a lower T at higher densities. More interestingly, the downturn temperature shows a power-law dependence on the mobility at the downturn position, suggesting that a similar downturn is also expected to occur deep in the apparent metallic regime at albeit experimentally inaccessible temperatures. This thus hints that the observed metallic phase in 2D systems might be a finite temperature effect.

Impact of disorder on the 5/2 fractional quantum Hall state.

We compare the energy gap of the ν = 5/2 fractional quantum Hall effect state obtained in conventional high mobility modulation-doped quantum-well samples with those obtained in high quality GaAs transistors (heterojunction insulated gate field-effect transistors). We are able to identify the different roles that long-range and short-range disorders play in the 5/2 state and observe that the long-range potential fluctuations are more detrimental to the strength of the 5/2 state than short-range potential disorder.

Pinning-mode resonance of a Skyrme crystal near Landau-level filling factor ν=1.

Microwave pinning-mode resonances found around integer quantum Hall effects, are a signature of crystallized quasiparticles or holes. Application of in-plane magnetic field to these crystals, increasing the Zeeman energy, has negligible effect on the resonances just below Landau-level filling ν=2, but increases the pinning frequencies near ν=1, particularly for smaller quasiparticle or hole densities. The charge dynamics near ν=1, characteristic of a crystal order, are affected by spin, in a manner consistent with a Skyrme crystal.

Observation of a pinning mode in a Wigner solid with ν=1/3 fractional quantum Hall excitations.

We report the observation of a resonance in the microwave spectra of the real diagonal conductivities of a two-dimensional electron system within a range of ∼ ± 0.015 from filling factor ν = 1/3. The resonance is remarkably similar to resonances previously observed near integer ν, and is interpreted as the collective pinning mode of a disorder-pinned Wigner solid phase of e/3-charged carriers.

Observation of reentrant phases induced by short-range disorder in the lowest Landau level of Al{x}Ga{1-x}As/Al{0.32}Ga{0.68}as heterostructures.

We report the observation of a reentrant quantum Hall effect in the lowest Landau level between filling factors of 2/3 and 3/5 in a Al{x}Ga{1-x}As/Al{0.32}Ga{0.68}As heterostructure sample with x=0.85%. A reentrant insulating phase is also observed between filling factors of 2/5 and 1/3, demonstrating particle-hole symmetry between these phases. A sample with x=0.21% shows much weaker reentrant features, indicating that increased short-range scattering, due to the Al alloy in the conduction channel, aids in the formation of these phases.

Scaling in plateau-to-plateau transition: a direct connection of quantum hall systems with the Anderson localization model.

The quantum Hall-plateau transition was studied at temperatures down to 1 mK in a random alloy disordered high mobility two-dimensional electron gas. A perfect power-law scaling with kappa=0.42 was observed from 1.2 K down to 12 mK. This perfect scaling terminates sharply at a saturation temperature of Ts approximately 10 mK. The saturation is identified as a finite-size effect when the quantum phase coherence length (Lphi proportional, T(-p/2)) reaches the sample size (W) of millimeter scale. From a size dependent study, Ts proportional, W(-1) was observed and p=2 was obtained. The exponent of the localization length, determined directly from the measured kappa and p, is nu=2.38, and the dynamic critical exponent z=1.

Pinning mode resonances of 2D electron stripe phases: effect of an in-plane magnetic field.

We study the anisotropic pinning-mode resonances in the rf conductivity spectra of the stripe phase of 2D electron systems around a Landau level filling of 9/2, in the presence of an in-plane magnetic field B(ip). The polarization along which the resonance is observed switches as B(ip) is applied, consistent with the reorientation of the stripes. The resonance frequency, a measure of the pinning interaction between the 2D electron systems and disorder, increases with B(ip). The magnitude of this increase indicates that disorder interaction is playing an important role in determining the stripe orientation.

Observation of pinning mode of stripe phases of 2D systems in high Landau levels.

We study the radio-frequency diagonal conductivities of the anisotropic stripe phases of higher Landau levels near half-integer fillings. In the hard direction, in which larger dc resistivity occurs, the spectrum exhibits a striking resonance, while in the orthogonal, easy direction, no resonance is discernible. The resonance is interpreted as a pinning mode of the stripe phase.

Anisotropic modification of the effective hole g factor by electrostatic confinement.

We investigate effects of lateral confinement on spin splitting of energy levels in 2D hole gases grown on [311] GaAs. We found that lateral confinement enhances anisotropy of spin splitting relative to the 2D gas for both confining directions. Unexpectedly, the effective g factor does not depend on the 1D energy level number N for B parallel[01[over ]1] while it has strong N dependence for B parallel[2[over ]33]. Apart from quantitative difference in the spin splitting of energy levels for the two orthogonal confinement directions, we also report qualitative differences in the appearance of spin-split plateaus, with nonquantized plateaus observed only for the confinement in the [01[over ]1] direction. In our samples we can clearly associate the difference with anisotropy of spin-orbit interactions.

Observation of a fractional quantum hall state at nu = 1/4 in a wide GaAs quantum well.

We report the observation of an even-denominator fractional quantum Hall state at nu = 1/4 in a high quality, wide GaAs quantum well. The sample has a quantum well width of 50 nm and an electron density of n(e) = 2.55 x 10(11) cm(-2). We have performed transport measurements at T - 35 mK in magnetic fields up to 45 T. When the sample is perpendicular to the applied magnetic field, the diagonal resistance displays a kink at nu = 1/4. Upon tilting the sample to an angle of theta = 20.3 degrees a clear fractional quantum Hall state emerges at nu = 1/4 with a plateau in the Hall resistance and a strong minimum in the diagonal resistance.

Comparison of T-Spot.TB and tuberculin skin test among silicotic patients.

In the present study, T-Spot.TB and the tuberculin skin test (TST) were compared in the screening of latent tuberculosis infection among silicotic patients. A conditional probability model was used to compare the potential clinical utilities of T-Spot.TB and TST performed on 134 silicotic subjects from December 1, 2004 to January 31, 2007. Data from a historical cohort were also reanalysed for further comparison. Agreement with T-Spot.TB was best using a TST cut-off of 10 mm. Age >or=65 yrs independently predicted a tuberculin reaction <10 mm (odds ratio = 3), but not a negative T-Spot.TB response. Lower measures of agreement were observed among current smokers and those aged >or=65 yrs. Tuberculin reaction size was well correlated with both early secretary antigenic target 6 and culture filtrate protein 10 spot counts, except among current smokers. Within the current estimates of sensitivity (88-95%) and specificity (86-99%) for T-Spot.TB, the positive likelihood ratio for T-Spot.TB test would be substantially higher (6.29-95.0 versus 1.65-1.94) and negative likelihood ratio substantially lower (0.05-0.14 versus 0.32-0.41) than the corresponding ratios for the tuberculin test. A low tuberculosis risk differential was similarly observed between tuberculin-negative and untreated tuberculin-positive subjects in the historical cohort. T-Spot.TB is likely to perform better than tuberculin test in the screening of latent tuberculosis infection among silicotic subjects.

Pinning modes and interlayer correlation in high-magnetic-field bilayer Wigner solids.

We report studies of pinning mode resonances in the low total Landau filling (nu) Wigner solid of a series of bilayer hole samples with negligible interlayer tunneling and with varying interlayer separation d. Comparison of states with equal layer densities (p,p) to single layer states (p,0) produced in situ by biasing, indicates that there is interlayer quantum correlation in the solid at small d. Also, the resonance frequency at small d is decreased just near nu = 1/2 and 2/3, indicating the importance in the solid of correlations related to those in the fractional quantum Hall effects.

Disappearance of metal-like behavior in GaAs two-dimensional holes below 30 mK.

The zero-field temperature dependence of the resistivity of two-dimensional holes is observed to exhibit two qualitatively different characteristics for a fixed carrier density for which only the metallic behavior of the so-called metal-insulator transition is anticipated. As T is lowered from 150 to 0.5 mK, the sign of the derivative of the resistivity with respect to T changes from being positive to negative when the temperature is lowered below approximately 30 mK and the resistivity continuously rises with cooling down to 0.5 mK, suggesting a crossover from being metal-like to insulatorlike.