We examined the prognostic value of tumour‐infiltrating lymphocytes (TILs) in patients with squamous cell carcinoma of the head and neck (SCCHN) after surgery and postoperative cisplatin‐based ...chemoradiotherapy. FFPE‐tissue originating from the surgery of 161 patients treated in 8 DKTK partner sites was immunohistochemically stained for CD3 and CD8. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), local progression‐free survival (LPFS) and distant metastases free‐survival (DMFS), also in the context of the HPV16‐DNA/p16 status. After a median follow‐up of 48 months (range: 4100 months), OS at 4 years was 46.5% for the entire cohort. In multivariate analysis, high CD8 expression was confirmed as an independent prognostic parameter for OS (p = 0.002), LPFS (p = 0.004) and DMFS (p = 0.006), while CD3 expression lacked significance. In multivariate analysis HPV16 DNA positivity was associated with improved OS (p = 0.025) and LPFS (p = 0.013) and p16‐positive patients showed improved DMFS (p = 0.008). Interestingly, high CD8 expression was a prognostic parameter for the clinical outcome in both HPV16 DNA‐positive and HPV16 DNA‐negative patients. Similar findings were observed in the multivariate analysis for the combined HPV16 DNA/p16 status. Altogether, CD8+ TILs constitute an independent prognostic marker in SCCHN patients treated with adjuvant chemoradiotherapy. These data indicate that CD8‐positive TILs have antitumour activity and could be used for treatment stratification. Further validation of the prognostic value of CD8+ TILs as a biomarker and its role in the immune response in SCCHN patients after adjuvant chemoradiotherapy is warranted and will be performed in the prospective DKTK‐ROG study.
What's New?
Squamous cell carcinomas of the head and neck (SCCHN) are not a homogenous group of tumors. This means that biomarkers are urgently needed, so that prognosis and treatment can be individualised. In this study, the authors found that patients with higher levels of CD8+ tumor‐infiltrating lymphocytes (TILs) within their tumors had improved outcomes after treatment. These results suggest that CD8‐positive TILs may have antitumor activity, and that their expression may be a useful prognostic biomarker for treatment stratification.
Squamous cell carcinoma of the head and neck (SCCHN) represents about 6% of the total cancer incidence and approximately 500,000 new cases are diagnosed each year worldwide. Radical surgery including resection of the primary tumour and neck dissection of regional lymph nodes followed by postoperative chemoradiotherapy (CRT) is commonly performed in locally advanced SCCHN with a 5‐year survival rate of 40–60% .
•Trace element and Sm–Nd isotopic compositions of the ∼2.6Ga Krivoy Rog BIF.•Trace element systematics discriminate pure and impure BIFs.•Geochronology of the Krivoy Rog BIF constrains late Archean ...age.•REY patterns and Nd isotope compositions reveal REY sources in the BIF and seawater.•EuCN/Eu*CN (and ɛNd) of BIFs mirror magmatic history of the Early Earth.
Pure Superior-type Banded Iron Formation (BIF) samples from the Krivoy Rog Supergroup (Ukraine) are excellent archives of ambient Early Precambrian seawater. They show low concentrations of incompatible elements such as Zr, Hf, and Th, and shale-normalized Rare Earths and Yttrium (REYSN) patterns similar to those of modern seawater, i.e. heavy REYSN enriched patterns with positive LaSN, GdSN and YSN anomalies. Lack of CeSN and presence of positive EuSN anomalies indicate REY contributions to anoxic ferruginous seawater from high-temperature hydrothermal fluids.
The depositional age of the Krivoy Rog BIF is ill-defined, but a Late Archean to Paleoproterozoic age has been suggested based on U–Pb zircon ages for units stratigraphically above and below the BIF. We determined Sm–Nd isotopic compositions of pure and impure samples from the Krivoy Rog BIF, which yield an errorchron with an apparent age of 2406±350Ma (MSWD 15), that falls within this broad age range. All pure BIF samples show chondrite-normalized (subscript CN) REY patterns with strong positive EuCN anomalies that are typical for Archean but rather rare and much less pronounced in Proterozoic BIFs. Associated schists also show Archean – rather than post-Archean-style REY distributions. The REY geochemistry of both, chemical and epiclastic sediments, therefore, is more consistent with a Late Archean rather than a post-Archean depositional age of the Krivoy Rog Supergroup.
Initial ɛNd values of impure BIFs and of associated schist reveal variable contributions from TTGs less radiogenic in Nd and a more radiogenic component possibly comprised of basement amphibolites or mafic volcanics of the stratigraphically underlying New Krivoy Rog Group. The purest Krivoy Rog BIF, representing local Krivoy Rog seawater, displays an ɛNd2.60Ga value of −2.3. This value is less radiogenic than impure Krivoy Rog BIFs or other near-contemporaneous Neoarchean pure chemical sediments. To preserve this specific local isotopic fingerprint in anoxic Archean seawater, the Krivoy Rog BIF must have been deposited in an isolated sea basin with limited exchange with ferruginous deep-waters of the open ocean.
A compilation of REY data for high-purity Precambrian BIFs reveals that EuCN/Eu*CN ratios of Precambrian seawater follow a general global evolution curve, that shows specific peaks which reflect times of increased high-temperature hydrothermal REY input into seawater. Following declining EuCN/EuCN ratios from the Eoarchean to the Mesoarchean, the ratios suddenly rise at 2.7Ga and reach a maximum at 2.6Ga, indicating an increased flux of high-temperature hydrothermal REY to Neoarchean seawater, which supports the hypothesis that times of widespread BIF deposition coincided with periods of intense submarine hydrothermal activity, probably triggered by major mantle plume events. This association is supported by a strong increase of the ɛNd(t) values of pure seawater archives at 2.7–2.6Ga, which reflects an increased flux of mantle Nd into seawater. These results suggest that Eu-REY systematics (and potentially ɛNd systematics) are robust tools to indentify episodes of enhanced mantle plume activity.
The Real Options (RO) approach is a powerful tool for decision analysis in dynamic or non-stationary stochastic settings, as it considers the value of decision flexibility under uncertainty. In ...recent years, there has been a significant increase in the use of the RO approach in the transportation literature, where it has been applied to model and analyze various topics in different transportation sectors. To better understand the development of RO analysis in transportation research, we conduct a review of 51 papers from 19 internationally-renowned transportation journals published in the past 30 years. These publications are categorized into three main areas: maritime, aviation, and road/railway/transit. We examine the themes, sources of uncertainty, models, and solving methods used in each publication to identify possible future research directions. Overall, our review highlights the growing use of the RO approach in transportation research and its potential for improving decision-making in uncertain environments. The insights gained from this review can help researchers identify areas for future investigation and facilitate the development of more effective and efficient transportation systems.
Studying on the anode materials with high energy densities for next-generation lithium-ion batteries (LIBs) is the key for the wide application for electrochemical energy storage devices. Ti-based ...compounds as promising anode materials are known for their outstanding high-rate capacity and cycling stability as well as improved safety over graphite. However, Ti-based materials still suffer from the low capacity, thus largely limiting their commercialized application. Here, we present an overview of the recent development of Ti-based anode materials in LIBs, and special emphasis is placed on capacity enhancement by rational design of hybrid nanocomposites with conversion-/ alloying-type anodes. This review is expected to provide a guidance for designing novel Ti-based materials for energy storage and conversion.
•We present the first strontium isotope data from the Paratethys domain in Messinian Salinity Crisis times.•Paratethys paced the hydrological changes in the Mediterranean during the MSC.•The ...Mediterranean 87Sr/86Sr values during MSC Stage 3 appear dominated by Paratethys waters.•Evaporation of a low-salinity surface layer rich in calcium and sulfate saturates with respect to gypsum at a salinity of 40.•Paratethys outflow should be considered as additional driver for the cyclic gypsum beds of the Mediterranean MSC.
During the so-called Messinian Salinity Crisis (MSC: 5.97-5.33 Myr ago), reduced exchange with the Atlantic Ocean caused the Mediterranean to develop into a “saline giant” wherein ∼1 million km3 of evaporites (gypsum and halite) were deposited. Despite decades of research it is still poorly understood exactly how and where in the water column these evaporites formed. Gypsum formation commonly requires enhanced dry conditions (evaporation exceeding precipitation), but recent studies also suggested major freshwater inputs into the Mediterranean during MSC-gypsum formation. Here we use strontium isotope ratios of ostracods to show that low-saline water from the Paratethys Seas actually contributed to the precipitation of Mediterranean evaporites. This apparent paradox urges for an alternative mechanism underlying gypsum precipitation. We propose that Paratethys inflow would enhance stratification in the Mediterranean and result in a low-salinity surface-water layer with high Ca/Cl and SO4/Cl ratios. We show that evaporation of this surface water can become saturated in gypsum at a salinity of ∼40, in line with salinities reported from fluid inclusions in MSC evaporites.
Abstract Objective To investigate the impact of HPV status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received surgery and cisplatin-based postoperative ...radiochemotherapy. Materials and methods For 221 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity treated at the 8 partner sites of the German Cancer Consortium, the impact of HPV DNA, p16 overexpression and p53 expression on outcome were retrospectively analysed. The primary endpoint was loco-regional tumour control; secondary endpoints were distant metastases and overall survival. Results In the total patient population, univariate analyses revealed a significant impact of HPV16 DNA positivity, p16 overexpression, p53 positivity and tumour site on loco-regional tumour control. Multivariate analysis stratified for tumour site showed that positive HPV 16 DNA status correlated with loco-regional tumour control in patients with oropharyngeal carcinoma ( p = 0.02) but not in the oral cavity carcinoma group. Multivariate evaluation of the secondary endpoints in the total population revealed a significant association of HPV16 DNA positivity with overall survival ( p < 0.01) but not with distant metastases. Conclusions HPV16 DNA status appears to be a strong prognosticator of loco-regional tumour control after postoperative cisplatin-based radiochemotherapy of locally advanced oropharyngeal carcinoma and is now being explored in a prospective validation trial.
This paper contributes to the understanding of the genesis of epigenetic, hypogene BIF-hosted iron deposits situated in the eastern part of Ukrainian Shield. It presents new data from the Krivoy Rog ...iron mining district (Skelevatske–Magnetitove deposit, Frunze underground mine and Balka Severnaya Krasnaya outcrop) and focuses on the investigation of ore genesis through application of fluid inclusion petrography, microthermometry, Raman spectroscopy and baro-acoustic decrepitation of fluid inclusions. The study investigates inclusions preserved in quartz and magnetite associated with the low-grade iron ores (31–37% Fe) and iron-rich quartzites (38–45% Fe) of the Saksaganskaya Suite, as well as magnetite from the locally named high-grade iron ores (52–56% Fe). These high-grade ores resulted from alteration of iron quartzites in the Saksaganskiy thrust footwall (Saksaganskiy tectonic block) and were a precursor to supergene martite, high-grade ores (60–70% Fe). Based on the new data two stages of iron ore formation (metamorphic and metasomatic) are proposed.
The metamorphic stage, resulting in formation of quartz veins within the low-grade iron ore and iron-rich quartzites, involved fluids of four different compositions: CO2-rich, H2O, H2O–CO2(±N2–CH4)–NaCl(±NaHCO3) and H2O–CO2(±N2–CH4)–NaCl. The salinities of these fluids were relatively low (up to 7mass% NaCl equiv.) as these fluids were derived from dehydration and decarbonation of the BIF rocks, however the origin of the nahcolite (NaHCO3) remains unresolved. The minimum P–T conditions for the formation of these veins, inferred from microthermometry are Tmin=219–246°C and Pmin=130–158MPa. The baro-acoustic decrepitation analyses of magnetite bands indicated that the low-grade iron ore from the Skelevatske–Magnetitove deposit was metamorphosed at T=~530°C.
The metasomatic stage post-dated and partially overlapped the metamorphic stage and led to the upgrade of iron quartzites to the high-grade iron ores. The genesis of these ores, which are located in the Saksaganskiy tectonic block (Saksaganskiy ore field), and the factors controlling iron ore-forming processes are highly controversial. According to the study of quartz-hosted fluid inclusions from the thrust zone the metasomatic stage involved at least three different episodes of the fluid flow, simultaneous with thrusting and deformation. During the 1st episode three types of fluids were introduced: CO2–CH4–N2(±C), CO2(±N2–CH4) and low salinity H2O–N2–CH4–NaCl (6.38–7.1mass% NaCl equiv.). The 2nd episode included expulsion of the aqueous fluids H2O–N2–CH4–NaCl(±CO2, ±C) of moderate salinities (15.22–16.76mass% NaCl equiv.), whereas the 3rd event involved high salinity fluids H2O–NaCl(±C) (20–35mass% NaCl equiv.). The fluids most probably interacted with country rocks (e.g. schists) supplying them with CH4 and N2. The high salinity fluids were most likely either magmatic–hydrothermal fluids derived from the Saksaganskiy igneous body or heated basinal brines, and they may have caused pervasive leaching of Fe from metavolcanic and/or the BIF rocks. The baro-acoustic decrepitation analyses of magnetite comprising the high-grade iron ore showed formation T=~430–500°C. The fluid inclusion data suggest that the upgrade to high-grade Fe ores might be a result of the Krivoy Rog BIF alteration by multiple flows of structurally controlled, metamorphic and magmatic–hydrothermal fluids or heated basinal brines.
Background
: We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen ...targeted to DCIR2
+ dendritic cells (DCs)
in vivo inhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2
+ DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production.
Methods
: To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis.
Results
: Although NOD.Zbtb32
-/- male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly,
in vitro stimulation of lymphocytes from NOD.Zbtb32
-/- mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes.
Conclusions
: The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype.
A gigantic cascade of Atlantic waters, filling the deep desiccated Mediterranean basin at the beginning of the Pliocene, has commonly been envisaged to end the Messinian Salinity Crisis (MSC). The ...Mediterranean lowstand during its final “Lago-Mare” phase, however, has long been subject to major controversy and has recently been seriously questioned again. Here, we present high-resolution ostracod distribution patterns of the MSC successions in the Black Sea basin (Zheleznyi Rog section; Russia) and the Mediterranean (Cuevas del Almanzora section; Spain) to study the origin and migration history of the Lago-Mare ostracods. We conclude that two major phases of faunal migration have taken place in the Messinian. The first phase corresponds to the Maeotian–Pontian boundary interval (~6.1–6.0Ma) of the Paratethys, where mainly Pannonian species suddenly invaded the Black Sea region. The second migration event corresponds to the Lago-Mare phase of the Mediterranean when first (5.55–5.47Ma) some opportunistic taxa (species of Cyprideis and Loxoconcha genera) and then (5.40–5.33Ma) a more diverse assemblage of Paratethyan species occupied the entire Mediterranean region. The Spanish ostracod assemblages show a high percentage of Paratethyan (Pontian) ostracods, in agreement with previously studied Italian Lago-Mare sections. The similar palaeoenvironmental changes that developed roughly synchronously in the western and central Mediterranean marginal basins provide more evidence for intrabasinal exchange at high water level during the final stage of the Lago-Mare phase. This indicates that the Mediterranean in the latest Messinian was full of water (comparable to the present Caspian Sea) and that the Zanclean deluge, if happened, only surged some tens, up to few hundred metres, into the Mediterranean.
•We present the first detailed ostracod biostratigraphy for the Messinian Black Sea basin.•Two major phases of Paratetyan fauna migration have taken place during the Messinian: during the basal Pontian into the Black Sea and during the Lago-Mare into the Mediterranean.•At 5.4Ma, a diverse Paratethyan ostracod fauna occupied the entire Mediterranean.•The Mediterranean was full of water during the latest Messinian.•The alleged Zanclean waterfall at Gibraltar was not that gigantic as previously assumed.
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