Little is known about how the immune microenvironment of breast cancer evolves during disease progression.
We compared tumor infiltrating lymphocyte (TIL) count, programmed death-ligand 1 (PD-L1) ...protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes using Nanostring technology in primary and metastatic cancer samples.
TIL counts and PD-L1 positivity were significantly lower in metastases. Immune cell metagenes corresponding to CD8, T-helper, T-reg, Cytotoxic T, Dendritic and Mastoid cells, and expression of 13 of 29 immuno-oncology therapeutic targets in clinical development including PD1, PD-L1, and CTLA4 were significantly lower in metastases. There was also coordinated down regulation of chemoattractant ligand/receptor pairs (CCL19/CCR7, CXCL9/CXCR3, IL15/IL15R), interferon regulated genes (STAT1, IRF-1,-4,-7, IFI-27,-35), granzyme/granulysin, MHC class I and immune proteasome (PSMB-8,-9,-10) expression in metastases. Immunotherapy response predictive signatures were also lower. The expression of macrophage markers (CD163, CCL2/CCR2, CSF1/CSFR1, CXCR4/CXCL12), protumorigenic toll-like receptor pathway genes (CD14/TLR-1,-2,-4,-5,-6/MyD88), HLA-E, ecto-nuclease CD73/NT5E and inhibitory complement receptors (CD-59,-55,-46) remained high in metastases and represent potential therapeutic targets.
Metastatic breast cancers are immunologically more inert than the corresponding primary tumors but some immune-oncology targets and macrophage and angiogenesis signatures show preserved expression and suggest therapeutic combinations for clinical testing.
High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need ...of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy.
Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population.
The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab 44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab.
The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way.
•Atezolizumab with neoadjuvant carboplatin/nab-paclitaxel led to non-significantly higher pCR rate in PD-L1+ TNBC.•In other trials neoadjuvant ICIs and chemotherapy significantly improved pCR rate, but EFS was independent of pCR.•Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC.•Lack of pCR improvement may be misleading as to the impact of atezolizumab on long-term efficacy in high risk TNBC.
•The application of DIN 19539 allows the discrimination of three soil carbon pools.•Two organic (TOC400 and ROC) and one inorganic (TIC900) carbon pools.•TOC400 at 300−400 °C, ROC at 510−600 °C, ...TIC900 at 700−900 °C.•TOC400/ROC ratio vsδ13CTOC links SOM thermal and compositional features.•Temperature of carbonate breakdown vsδ13CTIC reflects mineralogical differences.
The quantification of soil carbon pools is a pressing topic both for the agriculture productivity and to evaluate the Greenhouse Gases (GHG) sequestration potential, therefore a rapid and precise analytical protocol for carbon speciation is needed. Temperature-dependent differentiation of soil carbon in compliance with the DIN (German Institute for Standardization) 19539 standard has been applied for the first time on 24 agricultural soil samples from the Po River Plain (Italy), with the aim of investigate their thermal behavior in the 50−900 °C interval. The results invariably show the existence of three soil carbon pools having different thermal stabilities, namely, thermally labile organic carbon (TOC400), residual oxidizable carbon (ROC) and total inorganic carbon (TIC900), in the intervals of 300−400 °C, 510−600 °C and 700−900 °C, respectively. Significant relationships have been observed between the above mentioned organic and inorganic carbon pools and the associated isotopic composition: 1) inverse correlation between TOC400/ROC and δ13C links thermal stability and soil organic matter (SOM) composition; 2) direct correlation between carbonate breakdown temperature and δ13C denotes the mineralogical association of the inorganic pool. The results give clues regarding the nature and evolution of soil carbon pools.
The thermal emission of cirrus clouds, spectrally resolved in the 100–1400 cm−1 range (100–7.1 μm), has been modeled and compared with measurements performed during two field campaigns from the ...ground‐based site of Testa Grigia on the Italian Alps at 3480 m of altitude. The analysis of cirrus microphysics, through spectral fitting, shows the importance of using also the far infrared portion of the emitted spectrum at wave numbers below the 667 cm−1 carbon dioxide absorption band, where only a few measurements exist because of the high opacity of the atmosphere caused by the strong water vapor absorption. The resulted distribution of the fitted cloud parameters is in good agreement with the typical statistical distribution of the midlatitude cirrus cloud parameters.
Key Points
Water vapor and temperature profiles, and cirrus cloud microphysics are better simultaneously retrieved using wide band infrared spectra
The far infrared spectral region increases the accuracy for the retrieval of the cirrus particle effective diameter
The retrieved cirrus parameters follow the statistical distribution reported by Heymsfield
•Petrography of Construction and Demolition Wastes (CDWs)•Characterization of CDWs through XRPD and XRF analysis methodologies.•Proposal general protocol to analyse the petrography of CDW worldwide.
...The density, colour and texture, plus mineral and chemical features of 18 ceramic-like CDW samples from the Abruzzo region (Central Italy) were characterised. The concretes, natural stones, tiles, roof-tiles, bricks and perforated bricks are either aphanitic to porphyric. Concretes and natural stones are grey to white and tend to be > 2.0 g/cm3; the masonries are brown to reddish and close to < 2.0 g/cm3. Concrete and natural stone are rich or even exclusively made up of calcite, with high amounts of CaO (>40 wt%) and LOI (volatiles, CO2 + H2O). The masonries are instead calcite-, CaO- (<25 wt%) and LOI-poor (<8 wt%) but enriched in SiO2 (45 to 70 wt%) stabilised as quartz and/or cristobalite, with significant amount of Al2O3 (12 to 20 wt%). S and Cl contents are similar among concrete, bricks and perforated bricks.
The petrography of CDW concretes is similar among geographical areas with abundance of limestones used as aggregates. However, in limestone-poor areas CDW are SiO2- and Al2O3-rich, reflecting the prevalent use of masonry and/or silicate-rich construction materials, implying that each geographical area is characterised by peculiar CDW composition. Therefore, the knowledge of mesoscopic, physical and petrographic aspects has to be known for planning adequate sorting methods, promoting upcycling reusing applications. Some of the studied CDW samples are susceptible to release relative high Cr and As content.
New geochemical data integrated in a petrogenetic model indicate that the ∼30 Ma Northern Ethiopian continental flood basalts (CFBs) preserve a record of magmas generated from the centre to the ...flanks of a plume head, currently corresponding to the ‘Afar hotspot’. Basaltic lavas appear zonally arranged with Low-Ti tholeiites (LT) in the west, High-Ti tholeiites (HT1) to the east and very High-Ti transitional basalts and picrites (HT2, TiO2 4–6 wt %) closer to the Afar triple junction. Modelling provides estimates of the P–T–X conditions of magma generation showing that the Ethiopian CFBs could be generated in the pressure range 1·3–3·0 GPa at an approximate depth of 40–100 km from mantle sources that were increasingly metasomatized and hotter (1200–1500°C) from west to east; that is, from the outer zones (LT) to the core of the plume head (HT2 ultra-titaniferous basalts and picrites). Metasomatizing agents can be envisaged as alkali–silicate melts that integrate various geochemical components (e.g. Ti and related high field strength elements, low field strength elements, light rare earth elements, H2O, noble gases, etc.) scavenged and pooled along the plume axis, and derived from heterogeneous mantle materials mixed during the plume rise. This has significant implications for the current debate about mantle plumes, as the modelled compositionally and thermally zoned plume head (T excess ≥ 300°C with respect to ambient mantle) is in accordance with seismic tomography and buoyancy flux, as well as geochemical characteristics, thus supporting a deep provenance of the Afar plume, which possibly originated in the transition zone or lower mantle.
Literature has demonstrated hypoglossal nerve stimulation to be a safe and effective treatment for patients with obstructive sleep apnea nonadherent to positive airway pressure therapy. However, the ...recommended criteria for patient selection are still unable to identify all the unresponsive patients, highlighting the need for improved understanding about hypoglossal nerve stimulation for obstructive sleep apnea.
A 48-year-old Caucasian male patient with obstructive sleep apnea had been successfully treated with electrical stimulation of the hypoglossal nerve trunk, documented by level 1 polysomnography data. However, due to snoring complaints, he underwent postoperation drug-induced sleep endoscopy for evaluation of electrode activation during upper airway collapse, aiming to improve electrostimulation parameters. Concurrent surface electromyography of the suprahyoid muscles and masseter was obtained. Activation of electrodes 2, 3, and 6 promoted upper airway opening most strongly at the velopharynx and tongue base during drug-induced sleep endoscopy. The same channels also significantly increased the electrical activity on suprahyoid muscles bilaterally, but predominantly on the stimulated side (right). The masseters also presented a considerable asymmetry in electrical potential on the right side (> 55%).
Beyond the genioglossus muscle, our findings demonstrate recruitment of other muscles during hypoglossal nerve stimulation, which may be attributed to the electrical stimulation of the nerve trunk. This data provides new insights on how stimulation of the hypoglossal nerve trunk may contribute to obstructive sleep apnea treatment.
To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or ...both (THP), or monoclonal antibodies alone (HP).
Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation.
TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only.
The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.
The 2‐methylhopanes (2‐MeHops) are molecular fossils of 2‐methylbacteriohopanepolyols (2‐MeBHPs) and among the oldest biomarkers on Earth. However, these biomarkers’ specific sources are currently ...unexplained, including whether they reflect an expansion of marine cyanobacteria. Here, we study the occurrence of 2‐MeBHPs and the genes involved in their synthesis in modern bacteria and explore the occurrence of 2‐MeHops in the geological record. We find that the gene responsible for 2‐MeBHP synthesis (hpnP) is widespread in cyano‐ and ⍺‐proteobacteria, but absent or very limited in other classes/phyla of bacteria. This result is consistent with the dominance of 2‐MeBHP in cyano‐ and ⍺‐proteobacterial cultures. The review of their geological occurrence indicates that 2‐MeHops are found from the Paleoproterozoic onwards, although some Precambrian samples might be biased by drilling contamination. During the Phanerozoic, high 2‐MeHops’ relative abundances (index >15%) are associated with climatic and biogeochemical perturbations such as the Permo/Triassic boundary and the Oceanic Anoxic Events. We analyzed the modern habitat of all hpnP‐containing bacteria and find that the only one species coming from an undisputed open marine habitat is an ⍺‐proteobacterium acting upon the marine nitrogen cycle. Although organisms can change their habitat in response to environmental stress and evolutionary pressure, we speculate that the high sedimentary 2‐MeHops’ occurrence observed during the Phanerozoic reflect ⍺‐proteobacteria expansion and marine N‐cycle perturbations in response to climatic and environmental change.
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