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The Mediterranean Sea is one of the most critically polluted areas due to its semi-enclosed structure and its highly anthropized shoreline. Rivers are significant vectors for pollutant transfers from the continental to the marine environment. In this context, a 3D Lagrangian simulation of the dispersion of riverine microplastics (MPs) was performed, which included the application of a recently developed model that reassessed the MP fluxes discharged by rivers. MP physical properties from river samples were further investigated to approximate vertical displacement in modeled ocean currents. The use of a high-resolution circulation model, integrating Stokes drift, turbulent diffusion, and MP sinking and rising velocities, enabled us to establish stock balances. Our simulation suggested that 65% of river inputs may be made of floating MPs drifting in the surface layer and 35% of dense MPs sinking to deeper layers. The Eastern Mediterranean tends to accumulate floating MPs, primarily originating from the Western Mediterranean Basin, where major river sources are concentrated. After 2 years of simulation, modeled stranding sequestered 90% of the MP inputs, indicating relatively short average residence times from a few days to months at most for particles at sea. Although spatial distribution patterns stabilized after this period and a steady state may have been approached, the surface concentrations we modeled generally remained below field observations. This suggested either an underestimation of sources (rivers and unaccounted sources), by a factor of 6 at most, or an overestimation of MP withdrawal through stranding, to be reduced from 90 to around 60% or less if unaccounted sinks were considered. Graphical abstract

IntroductionChimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since “on-target/off-tumor” cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no “on-target/off-tumor” cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts.MethodsUsing the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity.ResultsSpecific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific.DiscussionGenetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding “on-target/off-tumor” cytotoxicity.

As the largest individual contributor of freshwater inflow to the basin, the Rhone River is likely to be one of the main sources of microplastics (MPs) to the Mediterranean Sea. In order to predict the fate of MPs discharged by the Rhone River, an innovative 3D Lagrangian dispersion of its particles associated with vertical velocities was modeled in Mediterranean ocean currents. Through winter and summer scenarios, the seasonal variability of transfers and the corresponding accumulation areas were depicted in the Northwestern Basin according to hydrodynamic conditions on the continental shelf of the Gulf of Lion and to the frontal dynamics from the Pyrenees to the North Balearic fronts. Our results indicated that MP transfers were driven by mesoscale and sub-mesoscale structures, resulting in steep concentration gradients across fronts during summer, while winter energetic mixing favored a more efficient and homogeneous spreading. After a year of drift, high MP retention (up to 50%) occurred in the coastal zone of the Gulf of Lion near the river mouth, with a large contribution of sinking MPs and an increase in stranding during the highest freshwater inflows of the winter season. Conversely, up to 60% of the floating MPs were exported to the Algerian Basin and then to the Eastern Mediterranean. This west-to-east transfer led to significant stranding on the islands, prevailing on the northern coasts of the Balearic Islands in winter (6% of floating inputs) and on the western coasts of Corsica and Sardinia in summer (13%). The southern Mediterranean coasts, from Algeria to Tunisia, represented also a major sink for floating debris with stranding ranging from 9 to 35% of MPs discharged in winter and in summer, respectively. We estimated that 3.5 to 5 t of the Rhone MPs remained in the surface layer at the end of the year, with high concentrations in the Ionian Sea. Graphical abstract Seasonal distribution of floating and sinking MPs discharged by the Rhone River into the surface and bottom layers of the Mediterranean Sea.

Monocytes, the circulating macrophage precursors, contribute to diseases like atherosclerosis and asthma. Long non-coding RNAs (lncRNAs) have been shown to modulate the phenotype and inflammatory capacity of monocytes. We previously discovered the lncRNA SMANTIS , which contributes to cellular phenotype expression by controlling BRG1 in mesenchymal cells. Here, we report that SMANTIS is particularly highly expressed in monocytes and lost during differentiation into macrophages. Moreover, different types of myeloid leukemia presented specific SMANTIS expression patterns. Interaction studies revealed that SMANTIS binds RUNX1, a transcription factor frequently mutated in AML, primarily through its Alu-element on the RUNT domain. RNA-seq after CRISPR/Cas9-mediated deletion of SMANTIS or RUNX1 revealed an association with cell adhesion and both limited the monocyte adhesion to endothelial cells. Mechanistically, SMANTIS KO reduced RUNX1 genomic binding and altered the interaction of RUNX1 with EP300 and CBFB. Collectively, SMANTIS interacts with RUNX1 and attenuates monocyte adhesion, which might limit monocyte vascular egress. The long non-coding RNA SMANTIS interacts with the transcription factor RUNX1 in an Alu-RUNT-dependent manner in monocytes and limits monocyte adhesion to endothelial cells.

Background To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults. Methods This retrospective cohort study combined data from two large US- based hospital electronic medical record databases. Severe hepatotoxicity was a Grade ≥ 3 liver function test (LFT) post-echinocandin initiation. Adjusted incidence rate ratios (IRRs) were estimated for anidulafungin versus caspofungin and micafungin, overall and in patients with normal baseline LFT (Grade 0). Results Treatments included anidulafungin ( n  = 1700), caspofungin ( n  = 4431), or micafungin ( n  = 6547). The proportions with LFT Grade ≥ 3 pre-echinocandin initiation were: anidulafungin 40.4% versus caspofungin 25.9% ( p  <  0.001) and micafungin 25.6% ( p  <  0.001). Rates of severe underlying diseases or comorbidities were: critical care admissions: 75.3% versus 52.6 and 48.6%; and organ failures: 69.4% versus 46.7 and 51.5%. Adjusted IRRs of severe hepatotoxicity for anidulafungin versus caspofungin and micafungin were 1.43 ( p  = 0.002) and 1.19 ( p  = 0.183) overall, and 0.88 ( P  = 0.773) and 0.97 ( P  = 0.945) for normal baseline LFT, respectively. Conclusions Accounting for confounders, severe hepatotoxicity risk was not significantly different across echinocandins in this real-world head-to-head study. Anidulafungin was used more frequently in patients with more comorbidities. Those with normal baseline LFT (least susceptible to confounding by indication), showed no elevated hepatotoxicity risk for anidulafungin.

The effects of prenatal exposure to pollutants from the World Trade Center (WTC) disaster on fetal growth and subsequent health and development of exposed children remain a source of concern. We assessed the impact of gestational timing of the disaster and distance from the WTC in the 4 weeks after 11 September on the birth outcomes of 300 nonsmoking women who were pregnant at the time of the event. They were recruited at delivery between December 2001 and June 2002 from three hospitals close to the WTC site. Residential and work addresses of all participants for each of the 4 weeks after 11 September 2001 were geocoded for classification by place and timing of exposure. Average daily hours spent at each location were based on the women's reports for each week. Biomedical pregnancy and delivery data extracted from the medical records of each mother and newborn included medical complications, type of delivery, length of gestation, birth weight, birth length, and head circumference. Term infants born to women who were pregnant on 11 September 2001 and who were living within a 2-mile radius of the WTC during the month after the event showed significant decrements in term birth weight (-149 g) and birth length (-0.82 cm), compared with infants born to the other pregnant women studied, after controlling for sociodemographic and biomedical risk factors. The decrements remained significant with adjustment for gestational duration (-122 g and -0.74 cm, respectively). Women in the first trimester of pregnancy at the time of the WTC event delivered infants with significantly shorter gestation (-3.6 days) and a smaller head circumference (-0.48 cm), compared with women at later stages of pregnancy, regardless of the distance of their residence or work sites from the WTC. The observed adverse effects suggest an impact of pollutants and/or stress related to the WTC disaster and have implications for the health and development of exposed children.

BackgroundOne of the most drastic changes in cancer is the altered glycosylation of proteins and lipids, giving rise to truncated or highly fucosylated and highly sialylated glycans which are almost absent on normal cells. Thus, developing antibodies against protein/carbohydrate combined epitopes (GlycoTargets) comprising these tumor-specific glycans enables highly potent therapies with reduced off-tumor toxicity and allows targeting of otherwise ’undruggable’ normal-tissue expressed proteins.Multiple EGF-like-domains 9 (MEGF9) is a transmembrane protein mainly expressed by immune cells and cells of the nervous system and has been associated with carcinogenic features in breast cancer and soft tissue tumors. Podocalyxin (PODXL) is a cell surface sialomucin normally expressed in several tissues including kidney and vascular endothelium, but it is also overexpressed in many cancers especially of epithelial origin. Both of these proteins contain mucin-like domains with a high density of potential GlycoTarget epitopes. Using our proprietary platform technology, we have developed antibodies against these two glycoproteins, which only bind to the respective tumor-associated glycoform of their target, thereby reducing recognition of the protein expressed on healthy cells.MethodsRecombinantly expressed target glycoforms were characterized by mass spectrometry and used to analyze the specificity of our antibodies for the respective O-glycosylated target in an ELISA format. Antibody specificity was further confirmed using our proprietary cell lines with distinct glycosylation patterns as well as tumor cell lines and human immune cells expressing varying levels of MEGF9 or PODXL. Furthermore, binding to healthy and tumor tissues was analyzed by immunohistochemistry.ResultsWe have successfully generated two different antibodies, which recognize PODXL and MEGF9, respectively, only if a specific tumor-associated glycan is present. Both clones do not cross-react with their non-glycosylated target or the carbohydrate structure on other carrier-proteins as confirmed by ELISA and flow cytometry. Our antibodies recognize various tumor cell lines as well as tumor tissues in a target-specific manner, but show drastically reduced binding to healthy cells compared to conventional protein-binding control antibodies.ConclusionsOur platform technology is suitable to target protein/carbohydrate combined epitopes with specific antibodies. We successfully generated two antibodies which target distinct, tumor-specific epitopes on two mucin-like proteins, respectively, comprising a tumor-associated glycan in combination with the specific target protein. Due to this glycan dependency, our antibodies show markedly decreased off-tumor binding which may improve safety for highly potent therapeutic approaches like ADCs, CARs or radiopharmaceutics.

Polycyclic aromatic hydrocarbons (PAHs) are toxic pollutants released by the World Trade Center (WTC) fires and various urban combustion sources. Benzo[a]pyrene (BaP) is a representative member of the class of PAHs. PHA-DNA adducts, or BaP-DNA adducts as their proxy, provide a measure of chemical-specific genetic damage that has been associated with increased risk of adverse birth outcomes and cancer. To learn whether PAHs from the WTC disaster increased levels of genetic damage in pregnant women and their newborns, we analyzed BaP-DNA adducts in maternal (n = 170) and umbilical cord blood (n = 203) obtained at delivery from nonsmoking women who were pregnant on 11 September 2001 and were enrolled at delivery at three downtown Manhattan hospitals. The mean adduct levels in cord and maternal blood were highest among newborns and mothers who resided within 1 mi of the WTC site during the month after 11 September, intermediate among those who worked but did not live within this area, and lowest in those who neither worked nor lived within 1 mi (reference group). Among newborns of mothers living within 1 mi of the WTC site during this period, levels of cord blood adducts were inversely correlated with linear distance from the WTC site (p = 0.02). To learn whether PAHs from the WTC disaster may have affected birth outcomes, we analyzed the relationship between these outcomes and DNA adducts in umbilical cord blood, excluding preterm births to reduce variability. There were no independent fetal growth effects of either PAH-DNA adducts or environmental tobacco smoke (ETS), but adducts in combination with in utero exposure to ETS were associated with decreased fetal growth. Specifically, a doubling of adducts among ETS-exposed subjects corresponded to an estimated average 276-g (8%) reduction in birth weight (p = 0.03) and a 1.3-cm (3%) reduction in head circumference (p = 0.04). The findings suggest that exposure to elevated levels of PAHs, indicated by PAH-DNA adducts in cord blood, may have contributed to reduced fetal growth in women exposed to the WTC event.

Background Information exists as unstructured medical text in healthcare databases. Such information is not routinely considered in safety surveillance but typically relies solely on structured (coded) data. Natural language processing (NLP) may allow the capture of concepts from unstructured data and thus enhance safety surveillance capability. Objectives We sought to assess the added contribution of unstructured data extracted from medical text by NLP for detecting acute liver dysfunction (ALD) in patients with inflammatory bowel disease (IBD). Methods Using a previously developed rule, we evaluated structured and unstructured NLP-extracted terms from a commercially available electronic medical record (EMR) system. The rule was intended to identify ALD diagnosis and timing of onset and was the result of three iterations of rule development using 150 ALD candidate cases. We evaluated the performance of the rule with or without NLP among all candidate cases and among 50 new cases with clinical adjudication. Results NLP terms were necessary for the diagnosis of 9% of cases and for ruling out 3% of false-positive cases. Inclusion of NLP terms led to an identification of an additional  9% of ALD-onset dates, with consequent earlier recognition in 5%. Conclusions NLP-derived terms in one large commercially available EMR system modestly improved the sensitivity and specificity in the identification of ALD and identified earlier onset.