According to the hitherto accepted view, neutrophils kill ingested microorganisms by subjecting them to high concentrations of highly toxic reactive oxygen species (ROS) and bringing about ...myeloperoxidase-catalysed halogenation. We show here that this simple scheme, which for many years has served as a satisfactory working hypothesis, is inadequate. We find that mice made deficient in neutrophil-granule proteases but normal in respect of superoxide production and iodinating capacity, are unable to resist staphylococcal and candidal infections. We also show that activation provokes the influx of an enormous concentration of ROS into the endocytic vacuole. The resulting accumulation of anionic charge is compensated for by a surge of K+ ions that cross the membrane in a pH-dependent manner. The consequent rise in ionic strength engenders the release of cationic granule proteins, including elastase and cathepsin G, from the anionic sulphated proteoglycan matrix. We show that it is the proteases, thus activated, that are primarily responsible for the destruction of the bacteria.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated the membrane localization of CD95 in type I and type II cells, which differ in their ability to recruit and activate caspase‐8. We found that CD95 was preferentially located inlipid ...rafts of type I cells, while it was present both in raft and non‐raft plasma membrane sub‐domains of type II cells. After stimulation, CD95 located in phospholipid‐rich plasma membrane was recruited to lipid rafts in both types of cells. Similarly, CD95 cross‐linking resulted in caspase‐independent translocation of FADD/MORT1 and caspase‐8 to the lipid rafts, which was prevented by a death domain‐defective receptor. CD95 internalization was then rapid in type I and delayed in type II cells and showed a substantial correlation with the kinetics of Fas‐associated death domain (FADD)and caspase‐8 recruitment to lipid rafts. Finally, electron microscopy analysis showed that after CD95 stimulation lipid rafts aggregated in large clusters that were internalized in endosomal vesicles, where caspase‐8 underwent massive processing. Taken together, our data demonstrate that CD95 death‐inducing signaling complex formation and internalization in type I and type II cells occur in lipidrafts, which are a major site of caspase‐8 activation.
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•Production of patinas that are representative of modern copper-based works of art.•Characterization of chloride and sulphate-induced degradation products.•Effective use of infrared ...spectroscopy to distinguish Cu2(OH)3Cl polymorphs.•Identification of copper hydroxysulphates by means of X-ray diffraction.
Naturally grown patinas are typically detected onto the surface of modern copper-based artefacts and strictly affect their surface reactivity and appearance. The production of representative patinas is a key issues in order to obtain model systems which can be used for the development and validation of appropriate conservation materials and methods. In this study, we have prepared different artificial representative patinas by using a quaternary Cu-Sn-Zn-Pb alloy with chemical composition and metallurgical features similar to those of valuable modern works of art. In order to produce degradation products usually observed onto their surface, chloride and sulphate species were used to induce corrosion processes. Different patinas were produced by changing the nature of corrosive species and the set-up for the accelerated degradation. The composition and structural properties of the patinas were investigated by attenuated total reflectance Fourier transform infrared spectroscopy, X-ray diffraction, optical microscopy and scanning electron microscopy combined with energy dispersive X-ray spectroscopy. The results allow to identify degradation products and to distinguish copper hydroxychloride polymorphs and copper hydroxysulphates with similar structure. Our findings show that patina composition can be tailored by modifying the degradation procedure and patinas representative of modern artefacts made of quaternary Cu-Sn-Zn-Pb alloy can be obtained.
•Long-term corrosion of bronzes in seawater studied by SEM-EDS, XRD, FTIR, OM and XPS.•Identification of Cl− as main harmful corrosive species.•Corrosion forms complex microstructures including ...anions and cations from environment.•Useful information to tailor reliable effective long-lasting conservation strategies.
The corrosion products naturally formed on archaeological Cu-based artefacts during their long-term exposure to seawater have been investigated in details by means of X-ray diffraction (XRD), scanning electron microscopy coupled with energy dispersive spectrometry (SEM + EDS), optical microscopy (OM), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), differential thermal analysis-thermogravimetry (DTA-TG), inductively coupled plasma mass spectrometry (ICP-MS) and X-ray photoelectron spectroscopy (XPS). The bronze artefacts include fragments of valuable statues and objects that were retrieved some decades ago from different seabeds along the Italian coast of the Mediterranean basin including the so called “Punta del Serrone” area (Apulia), the Sicilian channel (Sicily) and the Arburese coast (Sardinia). Our findings show that the alloy matrix is often heavily corroded also in the bulk and reveal the dangerous presence of chlorine from seawater as main dangerous corrosive agent. Chlorine is present as copper nantokite (CuCl) in the inner layers of the patina and is potentially inducing with oxygen and moisture the cyclic and often relentless copper degradation phenomenon commonly called “bronze disease”. The most common corrosion products are also lead carbonate (cerussite, PbCO3) and aragonite (CaCO3), likely related to the large abundance of CO2 in the seawater where is assimilated much more than in fresh water. Furthermore, the results reveal that other environmental elements contributing to the composition of the patina are sulphur, magnesium and phosphorous thus giving rise to a patina with a chemically and structurally complex structure. The results reveal also the contribution of bio-organism to the formation of the patina as supported by the presence of vanadium and copper sulphides. These information allow, as a whole, to propose a tentative correlation between the patina’s nature, the chemical composition and metallurgical features of the alloys and the marine environment where the objects lived for about two thousands years. From a conservation point of view, the findings reported in this work can provide some insights useful to tailor more efficient conservation strategies with the purpose to ensure a long-term chemical-physical stability to the bronze artefacts.
•Surface studies of ancient fire gilded artefacts to decipher production technologies.•Identification of Cl, S and P from surrounding environment as main corrosion agents.•Metal galvanic coupling ...enhances corrosion phenomena.•Corrosion forms a layered structure with noble metal remains, soil components and Cu-based compounds.•Useful information to select cleaning and long-lasting conservation strategies.
Gilded brooches dating back to 16th–17th centuries CE were investigated by means of integrated and complementary analytical techniques such as high spatial resolution field emission scanning electron microscopy coupled with energy dispersive X-ray spectrometry (FE-SEM+EDS), time of flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and optical microscopy (OM). The results reveal in detail the surface and subsurface morphology and the chemical features of the micrometric decorative Au layer that has been deposited by means of the so-called fire-gilding technique based on the use of an amalgam. Moreover, the results allow to recognise chlorine, sulphur and phosphorous species as the main degradation agents and to identify the corrosion products naturally formed during the long-term interaction with the burial soil constituents. The findings show also that the galvanic coupling between the two dissimilar metals, i.e. Cu and Au, lead to enhancement of corrosion phenomena causing the spalling of the gold thin film and the disfigurement of the object. From a conservation point of view, the results suggest a targeted use of low-toxic inhibitors to hinder the detrimental role of chlorine as possible responsible of future further severe degradation phenomena. In conclusions, the micro and nano-chemical, structural and morphological investigations in a depth range from a few nanometers to micrometers have revealed the complex nature of corroded surface of ancient gold coated artefacts, highlighting some specific aspects related to their peculiar degradation mechanisms thus extending the scientific relevance of the tailored use of complementary and integrated surface and subsurface analytical techniques for the investigation of ancient coated artefacts.
•Counterfeited silver Roman coins studied by XPS, SEM+EDS and OM.•Sophisticated plating methods and surface modification performed by using amalgam.•Micro-chemical results contributing to the ...interpretation of historic events.•Useful information to select effective conservation materials and methods.•Identification of Cl− from surrounding environment as main corrosion agent.
By means of the combined use of X-ray photoelectron spectroscopy (XPS), optical microscopy (OM) and scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectroscopy (EDS) the surface and subsurface chemical and metallurgical features of silver counterfeited Roman Republican coins are investigated to decipher some aspects of the manufacturing methods and to evaluate the technological ability of the Roman metallurgists to produce thin silver coatings. The results demonstrate that over 2000 ago important advances in the technology of thin layer deposition on metal substrates were attained by Romans. The ancient metallurgists produced counterfeited coins by combining sophisticated micro-plating methods and tailored surface chemical modification based on the mercury-silvering process. The results reveal that Romans were able systematically to chemically and metallurgically manipulate alloys at a micro scale to produce adherent precious metal layers with a uniform thickness up to few micrometers. The results converge to reveal that the production of forgeries was aimed firstly to save expensive metals as much as possible allowing profitable large-scale production at a lower cost. The driving forces could have been a lack of precious metals, an unexpected need to circulate coins for trade and/or a combinations of social, political and economic factors that requested a change in money supply. Finally, some information on corrosion products have been achieved useful to select materials and methods for the conservation of these important witnesses of technology and economy.
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•Corrosion of archaeological Ag-based alloys studied by SEM+EDS, FTIR, XRD, XPS and OM.•Identification of Cl− and more rarely of Br− as main corrosion agents from the surrounding ...environment.•Metal galvanic coupling enhancing selective corrosion phenomena.•Useful information to tailor effective conservation strategies.
Ancient silver-based alloys objects are of a great interest because they were world-wide used to produce high value works of art and precious items as jewels and ornaments with a relevant artistic, religious or historical value. Silver-based alloys were also largely used everyday as monetary currency and form of saving playing a relevant role for the development and growth of the economy. By means of the combined use of complementary surface analytical techniques such as scanning electron microscopy coupled with energy dispersive spectrometry (SEM+EDS), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and optical microscopy (OM) we have investigated the micro- and nano-chemical nature of the products of corrosion naturally formed on archaeological silver-based Roman objects characterised by different burial conditions. The results allow the identification of different corrosion products formed during the long interaction between the elements constituting the alloy, i.e. Ag and Cu, and degradation agents present in the surrounding environment. The results of the integrated analytical methodologies highlight the role of chlorine, that is always present in the patina as chloroargyrite (AgCl, also known as cerargyrite or horn silver) and also in some cases of bromine which forms bromargyrite (AgBr) or bromian-chloroargyrite Ag(Br,Cl) as dominant corrosion products. The unusual presence of Br in the silver patina reflects the peculiar environmental chemistry suffered by the buried object likely due to the presence of degrading organic matter under aerobic conditions. Furthermore, the results reveal that chlorine often preferentially corrodes the numerous local copper enrichments randomly dispersed in the silver host matrix inducing the formation of harmful copper-chlorine compounds including Cu2Cl(OH)3 (atacamite and its polymorphs) and likely CuCl (nantokite) generally related to the copper cyclic corrosion called by conservators “bronze disease”. Finally, different corrosion patterns have been observed with the outermost layers often enriched by soil elements as S, Ca, Al, Si and Fe thus confirming the strong interaction of the alloys elements with the burial soil components.
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Background: In patients with advanced non-small cell lung cancer (aNSCLC) with non-squamous histology, treatment guidelines recommend molecular testing for EGFR mutations and ...first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) in those with sensitizing EGFR mutations. We investigated real-world treatment regimens and outcomes in aNSCLC patients with EGFR-sensitizing mutations from US community oncology clinics. Methods: The Flatiron Health electronic health record-derived database contains deidentified data from > 55,000 aNSCLC patients. Our retrospective cohort included patients diagnosed from Jan-2014 to Mar-2018 who had a positive EGFR test prior to initiation of 1L therapy. Patients with EGFR T790M mutations were excluded. Demographics, clinical characteristics, treatment and survival outcomes were compared between patients receiving 1L EGFR TKIs vs other 1L anti-cancer therapies. Minimum follow-up after initiation of 1L therapy was 4 months. Results: 23,321 patients had non-squamous or NOS histology. Of those, 1107 had sensitizing EGFR mutations detected prior to 1L treatment (median age 70 years, 67% women, 58% Caucasian). 910 (82%) received EGFR TKIs and 197 (18%) received other 1L therapies (including chemotherapy, immunotherapy and anti-VEGF therapy). 2L treatment data were available for 519 patients: 317 (61%) received EGFR TKIs and 202 (39%) received other therapies. In the 1L setting, median treatment duration was longer for patients receiving EGFR TKIs than for those receiving other therapies (8 vs. 4 months, unadjusted HR 1.70; 95% CI 1.45–1.99; p < 0.0001). Median overall survival (OS) was not affected by the type of 1L treatment (21 months vs 20 months, p = 0.55). Conclusions: Real-world examination of treatment patterns and outcomes in US community oncology clinics showed that nearly 20% of aNSCLC patients with non-squamous or NOS histology and EGFR sensitizing mutations prior to initiation of 1L therapy did not receive 1L EGFR TKIs. In those who did, guideline-concordant use of EGFR TKIs was associated with longer 1L treatment duration but no improvement in OS, supporting the generalizability of results from randomized clinical trials.
The diagnostic industry faces environmental changes that will require more focus on the Medical Value (MV) component in the future. MV products deliver actionable and medically relevant information ...enabling support and guidance in decision-making and justifying the change of current disease management by addressing unmet medical needs. This article analyzes the perception of customers from Emerging (EM) and Developed Markets (DM) on the MV-component in an online-based survey. 231 physicians from 8 countries participated in a survey with 3 pivotal multiple choice questions on MV. Responses from countries have been allocated to income levels according to world-bank data. Answers have been statistically analyzed according to the market subgroups. Clinically validated treatment algorithms were rated as the most important factor qualifying for a MV-product. Physicians emphasized the need for algorithms, predominantly for existing markers. Lower priority has been given to technical excellence in DM comparing to EM. Cost control was more strongly emphasized in DM. Physicians rated result generalizability (global technical standardization and data comparability) as important features of MV. Both, EM and DM demand more clinical trials to establish algorithms for diagnostic tests. MV is a pivotal factor for sustainable business success of the diagnostic industry.
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Background: ECF/X (epirubicin (E) + cisplatin (C) + 5-fluoruracil (F) or capecitabine (X)) is a reference chemotherapy (CT) regimen in metastatic GC. Trastuzumab with CF/X prolonged ...survival (OS) of metastatic HER2+ gastric or esophagogastric junction cancer (GC) patients (pts). Lapatinib (LAP) inhibits both, EGFR1 and HER2, and showed activity in phase II GC trials. This double-blind Phase II study prospectively addressed efficacy and safety of LAP with ECF/X in GC pts with discordant FISH or IHC HER2 status or EGFR1+. Methods: Pts without prior palliative CT, screened centrally for HER2/EGFR1 (by FISH and IHC) were enrolled into 3 strata: 1) HER2 FISH+ and IHC 2/3+, 2) HER2 FISH- and IHC 2/3+, or 3) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts without HER2 + or EGFR1+, by FISH or IHC, were excluded. Pts were randomized to LAP 1250mg (arm 1) or placebo (arm 2), with ECF or ECX (investigator-selected) for 6 cycles. Primary endpoint was progression free survival (PFS). Secondary endpoints were toxicity, response rates, OS, HER2 concordance and correlation of HER2/EGFR. Results: The trial was prematurely closed to patient accrual given the LOGIC trial results at ASCO 2013. A total of 69 pts were tested in central lab of whom 9 (13%), 5 (7.2%) and 25 (36.2%) were in stratum 1, 2 and 3. Of these, 28 patients (6/4/18) were randomized (14 in arm 1, 14 in arm 2) and followed up. Due to the low number of pts accrued, no formal statistical tests were carried out. No safety concerns were found in arm 1. No complete responses were seen. 6 pts had partial responses in arm 1 vs. 3 pts in arm 2. Median PFS was 7.1 months in arm 1 vs. 5.9 months in arm 2 (HR=0.94, 95% CI: 0.41-2.14) for all pts, and 6.2 months in arm 1 vs. 6.3 months in arm 2 (HR=0.99, 95% CI: 0.36-2.75) for stratum 3 pts, respectively. Median overall survival was 13.8 months in arm 1 vs. 10.1 months in arm 2 (HR=0.90, 95% CI: 0.35-2.27) for all pts. Conclusions: Lapatinib with ECF/X did not show appealing activity in EGFR+ metastatic GC patients in this small phase 2 trial. The combination was well tolerated. Clinical trial information: NCT01123473.
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