Whole-genome characterization of myoepithelial carcinomas of the soft tissue

Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers

Elemental distributions within multiphase quaternary Pb chalcogenide thermoelectric materials determined through three-dimensional atom probe tomography

Nanostructured multiphase p-type lead chalcogenides have shown the highest efficiencies amongst thermoelectric materials. However, their electronic transport properties have been described assuming homogenous distribution of dopants between phases. Here, we have analyzed elemental distributions in precipitates and matrices of nanostructured multiphase quaternary Pb chalcogenides doped to levels below and above the solubility limit of the matrix, using three-dimensional atom probe tomography. We demonstrate that partitioning of sodium and selenium occur between the matrix and secondary phase in both lightly- and heavily-doped compounds and that the concentrations of sodium and selenium in precipitates are higher than those in the matrices. This can contribute to the transport properties of such multiphase compounds The sodium concentration reached ~3 at% in sulfur-rich (PbS) precipitates and no nano precipitates of Na-rich phases were observed within either phase, a result that is supported by high resolution TEM analysis, indicating that the solubility limit of sodium in PbS is much higher than previously thought. However, non-equilibrium segregation of sodium is identified at the precipitates/matrix interfaces. These findings can lead to further advances in designing and characterizing multiphase thermoelectric materials

Thermoelectric performance of tellurium-reduced quaternary p-type lead-chalcogenide composites

A long-standing technological challenge to the widespread application of thermoelectric generators is obtaining high-performance thermoelectric materials from abundant elements. Intensive study on PbTe alloys has resulted in a high figure of merit for the single-phase ternary PbTe–PbSe system through band structure engineering, and the low thermal conductivity achieved due to nanostructuring leads to high thermoelectric performance for ternary PbTe–PbS compounds. Recently, the single-phase p-type quaternary PbTe–PbSe–PbS alloys have been shown to provide thermoelectric performance superior to the binary and ternary lead chalcogenides. This occurs via tuning of the band structure and from an extraordinary low thermal conductivity resulting from high-contrast atomic mass solute atoms. Here, we present the thermoelectric efficiency of nanostructured p-type quaternary PbTe–PbSe–PbS composites and compare the results with corresponding single-phase quaternary lead chalcogenide alloys. We demonstrate that the very low lattice thermal conductivity achieved is attributed to phonon scattering at high-contrast atomic mass solute atoms rather than from the contribution of secondary phases. This results in a thermoelectric efficiency of ∼1.4 over a wide temperature range (650–850 K) in a p-type quaternary (PbTe)0.65(PbSe)0.1(PbS)0.25 composite that is lower than that of single-phase (PbTe)0.85(PbSe)0.1(PbS)0.05 alloy without secondary phases

Chemical composition tuning in quaternary p-type Pb-chalcogenides – a promising strategy for enhanced thermoelectric performance

Recently a significant improvement in the thermoelectric performance of p-type ternary PbTe–PbSe and PbTe–PbS systems has been realized through alternating the electronic band structure and introducing nano-scale precipitates to bulk materials respectively. However, the quaternary system of PbTe–PbSe–PbS has received less attention. In the current work, we have excluded phase complexity by fabricating single phase sodium doped PbTe, alloyed with PbS up to its solubility limit which is extended to larger concentrations than in the ternary system of PbTe–PbS due to the presence of PbSe. We have presented a thermoelectric efficiency of approximately 1.6 which is superior to ternary PbTe–PbSe and PbTe–PbS at similar carrier concentrations and the binary PbTe, PbSe and PbS alloys. The quaternary system shows a larger Seebeck coefficient than the ternary PbTe–PbSe alloy, indicative of a wider band gap, valence band energy offset and heavier carriers effective mass. In addition, the existence of PbS in the alloy further reduces the lattice thermal conductivity originated from phonon scattering on solute atoms with high contrast atomic mass. Single phase quaternary PbTe–PbSe–PbS alloys are promising thermoelectric materials that provide high performance through adjusting the electronic band structure by regulating chemical composition

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer