Proteogenomic markers of chemotherapy resistance and response in triple-negative breast cancer

UNLABELLED: Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2-M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathologic complete response, higher chromosomal instability index (CIN), and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC preclinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications. SIGNIFICANCE: Proteogenomic analysis of triple-negative breast tumors revealed a complex landscape of chemotherapy response associations, including a 19q13.31-33 somatic deletion encoding genes serving lagging-strand DNA synthesis (LIG1, POLD1, and XRCC1), that correlate with lack of pathologic response, carboplatin-selective resistance, and, in pan-cancer studies, poor prognosis and CIN. This article is highlighted in the In This Issue feature, p. 2483

Simulation of semiconductor detectors in 3D with SolidStateDetectors.jl

The open-source software package SolidStateDetectors.jl to calculate the fields and simulate the drifts of charge carriers in solid state detectors, together with the corresponding pulses, is introduced. The package can perform all calculations in full 3D while it can also make use of detector symmetries. The effect of the surroundings of a detector can also be studied. The package is programmed in the user friendly and performance oriented language Julia, such that 3D field calculations and drift simulations can be executed efficiently and in parallel. While all kinds of semiconductor devices can be simulated, special emphasis is put on germanium detectors. The verification of the package is shown for an n-type segmented point-contact germanium detector. Additional features of SolidStateDetectors.jl planned for the near future are listed.Comment: 21 pages, 9 figure

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data

Assessment of spatio-temporal landscape changes from VHR images in three different permafrost areas in the western Russian Arctic

Our study highlights the usefulness of very high resolution (VHR) images to detect various types of disturbances over permafrost areas using three example regions in different permafrost zones. The study focuses on detecting subtle changes in land cover classes, thermokarst water bodies, river dynamics, retrogressive thaw slumps (RTS) and infrastructure in the Yamal Peninsula, Urengoy and Pechora regions. Very high-resolution optical imagery (sub-meter) derived from WorldView, QuickBird and GeoEye in conjunction with declassified Corona images were involved in the analyses. The comparison of very high-resolution images acquired in 2003/2004 and 2016/2017 indicates a pronounced increase in the extent of tundra and a slight increase of land covered by water. The number of water bodies increased in all three regions, especially in discontinuous permafrost, where 14.86 of new lakes and ponds were initiated between 2003 and 2017. The analysis of the evolution of two river channels in Yamal and Urengoy indicates the dominance of erosion during the last two decades. An increase of both rivers’ lengths and a significant widening of the river channels were also observed. The number and total surface of RTS in the Yamal Peninsula strongly increased between 2004 and 2016. A mean annual headwall retreat rate of 1.86 m/year was calculated. Extensive networks of infrastructure occurred in the Yamal Peninsula in the last two decades, stimulating the initiation of new thermokarst features. The significant warming and seasonal variations of the hydrologic cycle, in particular, increased snow water equivalent acted in favor of deepening of the active layer; thus, an increasing number of thermokarst lake formations. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Characterisation of a Coriolis flow meter for fuel consumption measurements in realistic drive cycle tests

When testing light-duty and heavy-duty vehicles on chassis dynamometers, as in the WLTP, or engines on engine test benches, as in the WHDC, it is required to measure the fuel consumption. In the preferable case, the measurement of the fuel consumption is carried out with suitable flow meters. These require high measurement accuracy in a wide flow range, independent of the fuel type, as the flow rate range is often very large and depends on the power range of the vehicle engines. Moreover, the fuel flow rate in the test cycles is very dynamically related to the loads. In the scope of the ongoing EMPIR Joint Research Project 20IND13 SAFEST the dynamic flow behaviour as well as the measurement accuracy of flow meters for different types of fuels are investigated. This paper presents first results from the realisation of dynamic flow profiles, and flow measurements with a Coriolis Flow Meter with different representative fuels in a wide density and viscosity range and a wide flow rate range at different fuel temperatures

Field induced transitions in a kagome antiferromagnet

The thermal order by disorder effect in magnetic field is studied for a classical Heisenberg antiferromagnet on the kagome lattice. Using analytical arguments we predict a unique H-T phase diagram for this strongly frustrated magnet: states with a coplanar and a uniaxial triatic order parameters respectively at low and high magnetic fields and an incompressible collinear spin-liquid state at a one-third of the saturation field. We also present the Monte Carlo data which confirm existence of these phases.Comment: 4 pages, 2 figures, accepted versio

Macrophage Subset Sensitivity to Endotoxin Tolerisation by Porphyromonas gingivalis

Macrophages (MΦs) determine oral mucosal responses; mediating tolerance to commensal microbes and food whilst maintaining the capacity to activate immune defences to pathogens. MΦ responses are determined by both differentiation and activation stimuli, giving rise to two distinct subsets; pro-inflammatory M1- and anti-inflammatory/regulatory M2- MΦs. M2-like subsets predominate tolerance induction whereas M1 MΦs predominate in inflammatory pathologies, mediating destructive inflammatory mechanisms, such as those in chronic P.gingivalis (PG) periodontal infection. MΦ responses can be suppressed to benefit either the host or the pathogen. Chronic stimulation by bacterial pathogen associated molecular patterns (PAMPs), such as LPS, is well established to induce tolerance. The aim of this study was to investigate the susceptibility of MΦ subsets to suppression by P. gingivalis. CD14hi and CD14lo M1- and M2-like MΦs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and vitamin D3, respectively. MΦ subsets were pre-treated with heat-killed PG (HKPG) and PG-LPS prior to stimulation by bacterial PAMPs. Modulation of inflammation was measured by TNFα, IL-1β, IL-6, IL-10 ELISA and NFκB activation by reporter gene assay. HKPG and PG-LPS differentially suppress PAMP-induced TNFα, IL-6 and IL-10 but fail to suppress IL-1β expression in M1 and M2 MΦs. In addition, P.gingivalis suppressed NFκB activation in CD14lo and CD14hi M2 regulatory MΦs and CD14lo M1 MΦs whereas CD14hi M1 pro-inflammatory MΦs were refractory to suppression. In conclusion, P.gingivalis selectively tolerises regulatory M2 MΦs with little effect on pro-inflammatory CD14hi M1 MΦs; differential suppression facilitating immunopathology at the expense of immunity

A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013

Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute)