Abstract Background Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has ...been reported as a potential cause. Methods Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry). Results We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii ) and 14 cases of ILD (53.8%) resulted as drug-induced ILD (DI–ILD). According to anti-rejection protocols, DI–ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVLTLC ) and cyclosporine (2nd-hour concentration: CyAC2 ) levels were higher than in patients in the same regimen but with ILD− (EVLTLC ng/mL 9.84 versus 6.85; CyAC2 ng/mL 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVLTLC + CyAC2 /100) resulted in a significant difference between groups of patients (12.88 ± 1.61 versus 9.83 ± 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 ( P = .0081) and 0.9082 ( P = .0028), respectively, when using EVLTLC or the combination formula with both drugs. Conclusions In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVLTLC is >9.03 ng/mL or >11.41 when a formula with summation of EVLTLC and CyAC2 is used.
The ongoing Coronavirus pandemic (COVID-19) showed similar characteristics with the severe acute respiratory syndrome (SARS). In the most compromised cases, COVID-19 infection leads to death due to ...severe respiratory complications. COVID-19-related acute respiratory distress syndrome (ARDS) is the primary cause of death in these patients. In the present study, we show an ultrastructural analysis on the lungs of a patient affected by COVID-19.
Lung specimens obtained at autopsy from a 63-years old patient affected by COVID-19 were fixed in 1% paraformaldehyde. Slices of 300 µm thickness were dehydrated and dried by Critical Point Drying in CO2. Slices were covered with a conductive gold film approximately 30 nm thick and observed at a Zeiss Sigma 300 SEM FEG in the secondary electron (SE) and backscattered electron (BSE) modes. As case control a lung biopsy from a 60-year-old man was considered.
At low power in all COVID-19 lung specimens severe changes in the pulmonary architecture were found, due to the collapse of air spaces. Moreover, alveolar cavities were covered by large membranes. At high power, alveolar membranes showed a fibrillar structure, suggestive of a loose network of fibrin. It has been also found that intra-alveolar red blood cells were frequently present in the alveolar spaces, surrounded by a reticular fibrin network, suggestive for fibrin-hemorrhagic alveolitis. Alveolar changes were constantly associated with pathological features related to the pulmonary vessels. Vascular changes were prominent, including endothelial damage and thrombosis of large pulmonary vessels. Fibrinous microthrombi were frequently detected in the inter-alveolar septal capillaries. In addition, it has been frequently detected capillary proliferation in the alveolar septa with finding suggestive for intussusceptive neo-angiogenesis.
In conclusion, our electron microscopy analysis showed that COVID-19-related lung disease is characterized by a substantial architectural distortion, with the interactions between alveolar and vascular changes. Intra-alveolar hyaline membranes are associated with macro- and micro-thrombotic angiopathy, ending with capillary proliferation. The new blood vessel formation originates from the septa and extends into the surrounding parenchyma. Our findings confirm previous reports on the specificity of the multiple and complex morphological pattern typical, and apparently specific, of COVID-19-related lung disease.
Cetuximab is a human/mouse chimeric IgG1 monoclonal antibody (mAb) to epidermal growth factor receptor, approved for colorectal carcinoma treatment in combination with chemotherapy. The ...immune‐mediated effects elicited by its human fraction of crystallization moiety might critically contribute to the overall anti‐tumor effectiveness of the antibody. We therefore investigated cetuximab ability to promote colon cancer cell opsonization and phagocytosis by human dendritic cells (DCs) that are subsequently engaged in antigen‐cross presentation to cytotoxic T‐lymphocyte (CTL) precursors. Human colon cancer cell lines were evaluated for susceptibility to DC‐mediated phagocytosis before and after treatment with chemotherapy ± cetuximab in vitro. Human DCs loaded with control or drug‐treated cetuximab‐coated colon cancer cells were used to in vitro generate cytotoxic T cell clones from peripheral blood mononuclear cells of human leucocyte antigen‐A(*)02.01+ donors. T‐cell cultures were characterized for immune‐phenotype and tumor‐antigen specific CTL activity. The results confirmed that treatment of tumor cells with irinotecan + L‐folinate + 5‐flurouracil (ILF) or with gemcitabine + ILF increased tumor antigen expression. Moreover, malignant cells exposed to chemotherapy and cetuximab were highly susceptible to phagocytosis by human DCs and were able to promote their activation. The consequent DC‐mediated cross‐priming of antigens derived from mAb‐covered/drug‐treated cancer cells elicited a robust CTL anti‐tumor response. On the basis of our data, we suggest a possible involvement of CTL‐dependent immunity in cetuximab anti‐cancer effects.
As part of an experimental project on the treatment of bleach plant effluents the results of biodegradability and toxicity assessment of effluents from a bench-scale horizontal anaerobic immobilized ...bioreactor (HAIB) are discussed in this paper. The biodegradability of the bleach plant effluents from a Kraft pulp mill treated in the HAIB was evaluated using the modified Zahn-Wellens test. The inoculum came from a pulp mill wastewater treatment plant and the dissolved organic carbon (DOC) was used as the indicator of organic matter removal. The acute and chronic toxicity removal during the anaerobic treatment was estimated using Daphnia similis and Ceriodaphnia silvestrii respectively. Moreover, the evaluation of chromosome aberrations (CA), micronucleus frequencies (MN) and mitotic index (IM) in Allium cepa cells were used as genotoxicity indicators. The results indicate that the effluents from the anaerobic reactor are amenable to aerobic polishing. Acute and chronic toxicity were reduced by 90 and 81%, respectively. The largest CA and MN incidence in the meristematic cells of A. cepa were observed after exposure to the raw bleach plant effluent. The HAIB was able to reduce the acute and chronic toxicity as well as chromosome aberrations and the occurrence of micronucleus.
Even though the crucial role played by inflammation in cancer development and progression was first hypothesized by Rudolf Virchow at the beginning of the nineteenth century, only recently ...inflammation has been recognized as a hallmark of cancer. At present, the biology underlying the humoral and cellular immune-suppressive cancer-associated inflammatory microenvironment is an active area of preclinical and clinical investigation.1,2 Indeed, the possibility to modulate the inflammatory/immune microenvironment, by either antagonizing the tumor-associated immune-suppression or by enhancing the pre-existing anti-cancer immune response in tumor tissues, is a promising therapeutic option for cancer patients. In this context, the presence of infiltrating lymphocytes with specific immune-phenotypes within the tumor or in the surrounding stroma has predicted long-lasting responses and improved patients survival. Indeed, in a series of homogenously treated metastatic colorectal cancer (mCC) patients, we observed longest survival when high CCR7+ or FoxP3+ (Treg) lymphocytes infiltration occurred within tumor tissues. This latter finding provided a 'paradigm shift', since for the first time associated the density of an immune-suppressive population with a better outcome in mCC patients. This finding may be now explained by the recently disclosed 'regulatory' rather than 'suppressive' nature of Tregs. In this vision, in fact,
Opals are photonic structures with applications varying from coatings and pigments to photonics and optical devices. Colloidal self-assembly of polymer-based nanoparticles is a cheap and green method ...to create opals over large areas: recently, procedures combining co-deposition of crosslinker precursors and other additives with nanoparticle self-assembly have emerged as routes to large-area efficient deposition. We investigate how the presence of some common organic dyes and pigments affects the properties and self assembling behavior of core shell polystyrene particles with a poly(methacrylic acid) shell during horizontal deposition (casting) from water, studying both the variation of particles properties in solution and the structure and properties of the resulting films. The study further includes the effects of a precursor of silica crosslinking (Tetraethoxysilane), and its combination with the same dyes, and we are able to show how interactions starting in the nanoparticles dispersion affect the structure and properties of the crystals.
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•We studied the effect of some dyes and pigments on the self-assembly of polymer nanoparticles into photonic crystals.•Variations in particle properties (DLS diameter and Zeta potential) were observable already in suspension.•The ideality of the opal was modulated by the organic dyes while the pigments had a smaller effect.•Optical properties and surface order were compared to study the effect of the dyes on the quality of the film.•Opals crosslinked with TEOS in the presence of the same dyes were also studied.
The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth ...factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improved
and
cytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients.
A new type of polymer compound that allows the formation of highly ordered microstructured films by casting from a volatile solvent in the presence of humidity, and its characterization by ToF‐SIMS ...(time‐of‐flight secondary‐ion mass spectrometry) are presented. A honeycomb structure is obtained by activation of 2,2,6,6‐tetramethyl‐1‐piperidinyloxyl (TEMPO)‐terminated polystyrene (PS) with p‐toluenesulfonic acid (PTSA). The mechanism of this activation reaction, leading to a more polar PS termination, is deduced from simple experiments and supported by ToF‐SIMS characterization. Positive and negative ToF‐SIMS imaging allows different chemical regions correlating to the film morphology to be distinguished. This new, straightforward activation process, together with ToF‐SIMS chemical imaging, provides a better understanding of the phenomena underlying the formation of these films by directly linking the role of polar terminations to the microscale self‐organization. This new method, transposable to other organic acids, suggests interesting new perspectives in the field of self‐organized chemical and topographical patterning.
Breath‐figure imprinted films of p‐toluenesulfonate‐2,2,6,6‐tetramethyl‐1‐piperidinium‐oxyl polystyrene display a chemical patterning in addition to the regular ordering of cavities (see figure and cover). Time‐of‐flight secondary‐ion mass spectrometry (ToF‐SIMS) indicates that the polymer end groups are located on the cavities' surfaces.
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