Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes ...immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
•Coexisting alterations in KEAP1, PBRM1, SMARCA4 and STK11 define a subset of lung adenocarcinoma unresponsive to immunotherapy.•Tumors harboring co-mutations had inferior survival outcomes compared with both single-mutant and wild-type tumors.•Tumors with co-occurring alterations are misclassified as immunoresponsive by tumor mutational burden.•An immunologically cold phenotype characterizes lung adenocarcinoma with coexisting mutations.
Abstract
Materials with strongly correlated electrons often exhibit interesting physical properties. An example of these materials is the layered oxide perovskite Sr
2
RuO
4
, which has been ...intensively investigated due to its unusual properties. Whilst the debate on the symmetry of the superconducting state in Sr
2
RuO
4
is still ongoing, a deeper understanding of the Sr
2
RuO
4
normal state appears crucial as this is the background in which electron pairing occurs. Here, by using low-energy muon spin spectroscopy we discover the existence of surface magnetism in Sr
2
RuO
4
in its normal state. We detect static weak dipolar fields yet manifesting at an onset temperature higher than 50 K. We ascribe this unconventional magnetism to orbital loop currents forming at the reconstructed Sr
2
RuO
4
surface. Our observations set a reference for the discovery of the same magnetic phase in other materials and unveil an electronic ordering mechanism that can influence electron pairing with broken time reversal symmetry.
We report optical measurements demonstrating that the low-energy relaxation rate (1/τ) of the conduction electrons in Sr(2)RuO(4) obeys scaling relations for its frequency (ω) and temperature (T) ...dependence in accordance with Fermi-liquid theory. In the thermal relaxation regime, 1/τ ∝ (ħω)(2)+(pπk(B)T)(2) with p = 2, and ω/T scaling applies. Many-body electronic structure calculations using dynamical mean-field theory confirm the low-energy Fermi-liquid scaling and provide quantitative understanding of the deviations from Fermi-liquid behavior at higher energy and temperature. The excess optical spectral weight in this regime provides evidence for strongly dispersing "resilient" quasiparticle excitations above the Fermi energy.
Abstract
A paradigmatic case of multi-band Mott physics including spin-orbit and Hund’s coupling is realized in Ca
2
RuO
4
. Progress in understanding the nature of this Mott insulating phase has ...been impeded by the lack of knowledge about the low-energy electronic structure. Here we provide—using angle-resolved photoemission electron spectroscopy—the band structure of the paramagnetic insulating phase of Ca
2
RuO
4
and show how it features several distinct energy scales. Comparison to a simple analysis of atomic multiplets provides a quantitative estimate of the Hund’s coupling
J
=0.4 eV. Furthermore, the experimental spectra are in good agreement with electronic structure calculations performed with Dynamical Mean-Field Theory. The crystal field stabilization of the
d
xy
orbital due to
c
-axis contraction is shown to be essential to explain the insulating phase. These results underscore the importance of multi-band physics, Coulomb interaction and Hund’s coupling that together generate the Mott insulating state of Ca
2
RuO
4
.
A paradigmatic case of multi-band Mott physics including spin-orbit and Hund's coupling is realized in Ca
RuO
. Progress in understanding the nature of this Mott insulating phase has been impeded by ...the lack of knowledge about the low-energy electronic structure. Here we provide-using angle-resolved photoemission electron spectroscopy-the band structure of the paramagnetic insulating phase of Ca
RuO
and show how it features several distinct energy scales. Comparison to a simple analysis of atomic multiplets provides a quantitative estimate of the Hund's coupling J=0.4 eV. Furthermore, the experimental spectra are in good agreement with electronic structure calculations performed with Dynamical Mean-Field Theory. The crystal field stabilization of the d
orbital due to c-axis contraction is shown to be essential to explain the insulating phase. These results underscore the importance of multi-band physics, Coulomb interaction and Hund's coupling that together generate the Mott insulating state of Ca
RuO
.
Thyroid carcinomas comprise a broad spectrum of tumors with different clinical behaviors. On the one side, there are occult papillary carcinomas (PTC), slow growing and clinically silent, and on the ...other side, rapidly growing anaplastic carcinomas (ATC), which are among the most lethal human neoplasms. We have analysed the microRNA (miR) profile of ATC in comparison to the normal thyroid using a microarray (miRNACHIP microarray). By this approach, we found an aberrant miR expression profile that clearly differentiates ATC from normal thyroid tissues and from PTC analysed in previous studies. In particular, a significant decrease in miR-30d, miR-125b, miR-26a and miR-30a-5p was detected in ATC in comparison to normal thyroid tissue. These results were further confirmed by northern blots, quantitative reverse transcription-PCR analyses and in situ hybridization. The overexpression of these four miRs in two human ATC-derived cell lines suggests a critical role of miR-125b and miR-26a downregulation in thyroid carcinogenesis, since a cell growth inhibition was achieved. Conversely, no effect on cell growth was observed after the overexpression of miR-30d and miR-30a-5p in the same cells. In conclusion, these data indicate a miR signature associated with ATC and suggest the miR deregulation as an important event in thyroid cell transformation.
•The variation of the craters generated by fs laser irradiation with repetition rate is investigated.•The influence of the laser pulse repetition rate on removal rate and surface texture on silicon ...is addressed.•Possible effects of plume shielding on crater features and laser surface structuring at high repetition rate is discussed.
The influence of the pulse repetition rate on laser irradiation of silicon, in air, with femtosecond laser pulses is experimentally investigated in the range 10 Hz – 200 kHz. The features of the produced crater and the laser-induced periodic surface structures generated on its surface are characterized by exploiting surface profilometry and scanning electron microscopy. The experimental characterization evidences an interesting influence of the pulse repetition rate on the crater size qualitatively addressing a progressive reduction of the material removal efficiency at higher repetition rates. Moreover, also the surface structures produced by an irradiation sequence with a fixed number of laser pulses (namely N = 100) shows a clear dependence on the repetition rate. The observed effects are rationalized by considering the possible influence of plume shielding and heat accumulation effects typically observed during laser processing with high repetition rate laser systems.
Abstract
The single-layered ruthenate Sr
2
RuO
4
is one of the most enigmatic unconventional superconductors. While for many years it was thought to be the best candidate for a chiral
p
-wave ...superconducting ground state, desirable for topological quantum computations, recent experiments suggest a singlet state, ruling out the original
p
-wave scenario. The superconductivity as well as the properties of the multi-layered compounds of the ruthenate perovskites are strongly influenced by a van Hove singularity in proximity of the Fermi energy. Tiny structural distortions move the van Hove singularity across the Fermi energy with dramatic consequences for the physical properties. Here, we determine the electronic structure of the van Hove singularity in the surface layer of Sr
2
RuO
4
by quasi-particle interference imaging. We trace its dispersion and demonstrate from a model calculation accounting for the full vacuum overlap of the wave functions that its detection is facilitated through the octahedral rotations in the surface layer.
Understanding and controlling the transition between antiferromagnetic states having different symmetry content with respect to time-inversion and space-group operations are fundamental challenges ...for the design of magnetic phases with topologically nontrivial character. Here, we consider a paradigmatic antiferromagnetic oxide insulator, Ca2RuO4, with symmetrically distinct magnetic ground states and unveil a novel path to guide the transition between them. The magnetic changeover results from structural and orbital reconstruction at the transition metal site that in turn arise as a consequence of substitutional doping. By means of resonant X-ray diffraction we track the evolution of the structural, magnetic, and orbital degrees of freedom for Mn doped Ca2RuO4 to demonstrate the mechanisms which drive the antiferromagnetic transition. While our analysis focuses on a specific case of substitution, we show that any perturbation that can impact in a similar way on the crystal structure, by reconstructing the induced spin–orbital exchange, is able to drive the antiferromagnetic reorganization.
PDF
