Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial

HLA-C and HIV-1: friends or foes?

The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins

Enhanced sensistivity at higher-order exceptional points

Non-Hermitian degeneracies, also known as exceptional points, have recently emerged as a new way to engineer the response of open physical systems, that is, those that interact with the environment. They correspond to points in parameter space at which the eigenvalues of the underlying system and the corresponding eigenvectors simultaneously coalesce1,2,3. In optics, the abrupt nature of the phase transitions that are encountered around exceptional points has been shown to lead to many intriguing phenomena, such as loss-induced transparency4, unidirectional invisibility5,6, band merging7,8, topological chirality9,10 and laser mode selectivity11,12. Recently, it has been shown that the bifurcation properties of second-order non-Hermitian degeneracies can provide a means of enhancing the sensitivity (frequency shifts) of resonant optical structures to external perturbations13. Of particular interest is the use of even higher-order exceptional points (greater than second order), which in principle could further amplify the effect of perturbations, leading to even greater sensitivity. Although a growing number of theoretical studies have been devoted to such higher-order degeneracies14,15,16, their experimental demonstration in the optical domain has so far remained elusive. Here we report the observation of higher-order exceptional points in a coupled cavity arrangement—specifically, a ternary, parity–time-symmetric photonic laser molecule—with a carefully tailored gain–loss distribution. We study the system in the spectral domain and find that the frequency response associated with this system follows a cube-root dependence on induced perturbations in the refractive index. Our work paves the way for utilizing non-Hermitian degeneracies in fields including photonics, optomechanics10, microwaves9 and atomic physics17,18