Regarding the Influence of Additives and Additional Plasma-Induced Chemical Ionization on Adduct Formation in ESI/IMS/MS

Ion mobility spectrometers (IMS) separate ions based on their ion mobility, which depends mainly on collision cross-section, mass, and charge of the ions. However, the performance is often hampered in electrospray ionization (ESI) by the appearance of multiple ion mobility peaks in the spectrum for the same analyte due to clustering and additional sodium adducts. In this work, we investigate the influence of solvents and buffer additives on the detected ion mobility peaks using ESI. Additionally, we investigate the effects of an additional chemical ionization (CI) induced by plasma ionization on the ions formed by electrospray. For this purpose, we coupled our high-resolution IMS with a resolving power of Rp = 100 to a time-of-flight mass spectrometer. Depending on the analyte and the chosen additives, the ionization process can be influenced during the electrospray process. For the herbicide isoproturon, the addition of 5 mM sodium acetate results in the formation of the sodium adduct [M + Na]+, which is reflected in the ion mobility K0 of 1.22 cm2/(V·s). In contrast, the addition of 5 mM ammonium acetate yields the protonated species [M + H]+ and a correspondingly higher K0 of 1.29 cm2/(V·s). In some cases, as with the herbicide pyrimethanil, the addition of sodium acetate can completely suppress ionizations. By carefully choosing the solvent additive for ESI-IMS or additional CI, the formation of different ion mobility peaks can be observed. This can facilitate the assignment of ions to ion mobility peaks using IMS as a compact, stand-alone instrument, e.g., for on-site analysis

Early and Late Postnatal Myocardial and Vascular Changes in a Protein Restriction Rat Model of Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) is a risk factor for cardiovascular disease in later life. Early structural and functional changes in the cardiovascular system after IUGR may contribute to its pathogenesis. We tested the hypothesis that IUGR leads to primary myocardial and vascular alterations before the onset of hypertension. A rat IUGR model of maternal protein restriction during gestation was used. Dams were fed low protein (LP; casein 8.4%) or isocaloric normal protein diet (NP; casein 17.2%). The offspring was reduced to six males per litter. Immunohistochemical and real-time PCR analyses were performed in myocardial and vascular tissue of neonates and animals at day 70 of life. In the aortas of newborn IUGR rats expression of connective tissue growth factor (CTGF) was induced 3.2-fold. At day 70 of life, the expression of collagen I was increased 5.6-fold in aortas of IUGR rats. In the hearts of neonate IUGR rats, cell proliferation was more prominent compared to controls. At day 70 the expression of osteopontin was induced 7.2-fold. A 3- to 7-fold increase in the expression of the profibrotic cytokines TGF-β and CTGF as well as of microfibrillar matrix molecules was observed. The myocardial expression and deposition of collagens was more prominent in IUGR animals compared to controls at day 70. In the low-protein diet model, IUGR leads to changes in the expression patterns of profibrotic genes and discrete structural abnormalities of vessels and hearts in adolescence, but, with the exception of CTGF, not as early as at the time of birth. Invasive and non-invasive blood pressure measurements confirmed that IUGR rats were normotensive at the time point investigated and that the changes observed occurred independently of an increased blood pressure. Hence, altered matrix composition of the vascular wall and the myocardium may predispose IUGR animals to cardiovascular disease later in life

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted. (C) 2022 by American Society of Clinical Oncolog

Location-based monitoring in production environments: does transparency help to increase the acceptance of monitoring?

ABSTRACTIn the context of smart manufacturing, the technical development of monitoring systems has made it possible to track employees with the same systems that are used to track assets. This study contributes to our understanding of the acceptance of location-based monitoring of employees and investigates how the perceived privacy risk regarding monitoring can be tackled by examining the role of transparency and the perceived value of monitoring. We designed an experimental setting in which students assembled a 3D printer and manipulated transparency with two conditions: a detailed explanation of monitoring during the task vs. monitoring without any explanation. The results show that the higher the privacy concerns and perceived risks were, the lower was the acceptance for monitoring. However, the negative effect of perceived risk diminishes when both, transparency and the value of monitoring are high, but becomes even stronger when only transparency is high and perceived value is low

Glomerular and renal vascular structural changes in alpha8 integrin-deficient mice

Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the alpha8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. alpha8-deficient (alpha8-/-) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of alpha8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of alpha8-/- mice would be completely normal. Therefore, the renal phenotype of adult alpha8-/- mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. alpha8-/- mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and alpha8-/- mice. Quantitative morphologic analyses revealed that the glomeruli of alpha8-/- mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the alpha8 ligand fibronectin) was expanded in alpha8-/- mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of alpha8-/- mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor alpha2 integrin in alpha8-/- mice. The glomerular capillary length density was significantly greater in alpha8-/- mice than in wild-type mice. Cortical arterial vessel walls were not altered in alpha8-/- mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of alpha8, glomerular and renal vascular alterations in alpha8-/- mice were relatively mild. Only aged alpha8-/- mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of alpha8 can be largely compensated for, at least in younger alpha8-/- mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor alpha2 contribute to maintaining the glomerular structure in alpha8-/- mice. The compensatory mechanisms involved will be the subject of future research

Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

Background: Latent transforming growth factor-β-binding protein 1 (LTBP-1) and fibrillin-1 were shown to colocalize and interact in the extracellular matrix of the skin and vasculature. This interaction may regulate transforming growth factor-β (TGF-β ) activity. TGF-β is an important progression factor for glomerular diseases. We hypothesized that LTBP-1 and fi brillin-1 are coexpressed in the glomerulus and upregulated during glomerulonephritis. Methods: Acute anti-Thy1.1 glomerulonephritis was induced with a single intravenous injection (1 mg/kg body weight) of a monoclonal anti-Thy1.1 antibody in rats. Real-time RT-PCR and immunohistochemical analyses for LTBP-1 and fi brillin-1 were performed. Results: Induction of glomerular LTBP-1 mRNA was detected on day 2 of disease, while mRNA for fi brillin-1 was already upregulated 1 day after induction of disease. Both LTBP- 1 and fi brillin-1 showed a mesangial distribution. An expansion of the LTBP-1 and fi brillin-1-positive mesangial area was seen on day 6 of disease, when transient matrix accumulation was most prominent. On day 12 of disease, glomerular LTBP-1 and fi brillin-1 immunoreactivities had returned to control levels. In serial sections, some colocalization of LTBP-1 and fi brillin-1 was detected in control as well as in nephritic glomeruli. Conclusion: Mesangial expression of LTBP-1 and fi brillin-1 is induced early in experimental nephritis and LTBP-1 and fi brillin-1 are partially colocalized in the nephritic glomerulus. An interaction of these molecules could stabilize latent TGF-β complexes and thus attenuate the activation of TGF- β during this self-limited glomerular disease

Effects of Adrenomedullin on the Glomerular Adrenomedullin System in a Rat Model of Anti-Thy1 Glomerulonephritis

Background: Adrenomedullin (ADM) has antiproliferative effects on glomerular mesangial cells. The study was performed to determine changes in glomerular gene expression of the ADM system by ADM treatment in anti-Thy1 glomerulonephritis (GN). Methods: GN in rats was induced by injecting anti-Thy-1 antibody. To show the effect of ADM treatment, rats received ADM from day 3 to day 6 of GN. Supplemental rats were sacrificed on day 3, 7 and 14 of GN to show the expression pattern of adrenomedullin and its receptors. Glomeruli were prepared by sieving or laser-assisted microdissection. Expression of ADM, calcitonin receptor-like receptor (CLR), receptor activity-modifying proteins (RAMP) 1–3, CD34, Thy1 and nephrin was analyzed using real-time PCR. Results: During GN a reduction of CLR and RAMP 2 + 3 expressions was detected on days 3, 7 and 14, while RAMP 1 rose. ADM mRNA decreased on days 3 and 7. Thy1 expression as a surrogate of mesangial cell number was downregulated during GN. A significant reduction of CD34 expression, as a surrogate for endothelial cell number, was detected on day 7. A tendency towards reduction of nephrin gene expression, as a surrogate for number of podocytes, was seen. The administration of ADM during GN did not change the expression on Thy1, CD34 or nephrin. The results were similar for microdissected and sieved glomeruli. In ADM-treated GN animals ADM gene expression rose compared to untreated GN animals on day 6. These effects were detected both in sieved and microdissected glomeruli. ADM administration did not change the expression of the receptors. Conclusion: The downregulation of adrenomedullin during GN at the gene level can be improved by ADM application