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BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells
(2021)
By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.
Purpose: Auditory functional MRI (fMRI) often uses silent inter-volume delays for stimulus presentation. However, maintaining the steady-state of the magnetization usually requires constant delays. Here, a novel acquisition scheme dubbed “pre-Saturated EPI using Multiple delays in Steady-state” (SEPIMS) is proposed, using spin saturation at a fixed delay before each volume to maintain steady-state conditions, independent of previous spin history. This concept allows for variable inter-volume delays and thus for flexible stimulus design in auditory fMRI. The purpose was to compare the signal stability of SEPIMS and conventional sparse EPI (CS-EPI). Methods: The saturation module comprises two non-selective adiabatic saturation pulses. The efficiency of the saturation and its effect on the SEPIMS signal stability is tested in vitro and in vivo. Results: Data show that SEPIMS yields the same signal stability as CS-EPI, even for extreme variations between inter-volume delay durations. However, dual saturation pulses are required to achieve sufficiently high saturation efficiency in compartments with long T1 values. Importantly, spoiler gradient pulses after the EPI readout have to be optimized to avoid eddy-current-induced image distortions. Conclusion: The proposed SEPIMS sequence maintains high signal stability in the presence of variable inter-volume durations, thus allowing for flexible stimulus design.
The C40A/C82A double mutant of barstar has been shown to undergo cold denaturation above the water freezing point. By rapidly applying radio-frequency power to lossy aqueous samples, refolding of barstar from its cold-denatured state can be followed by real-time NMR spectroscopy. Since temperature-induced unfolding and refolding is reversible for this double mutant, multiple cycling can be utilized to obtain 2D real-time NMR data. Barstar contains two proline residues that adopt a mix of cis and trans conformations in the low-temperature-unfolded state, which can potentially induce multiple folding pathways. The high time resolution real-time 2D-NMR measurements reported here show evidence for multiple folding pathways related to proline isomerization, and stable intermediates are populated. By application of advanced heating cycles and state-correlated spectroscopy, an alternative folding pathway circumventing the rate-limiting cis-trans isomerization could be observed. The kinetic data revealed intermediates on both, the slow and the fast folding pathway.
Background and Objective: Long-term tooth retention is the ultimate goal of periodontal therapy. Aim of this study was to evaluate tooth loss (TL) during 10 years of supportive periodontal therapy (SPT) in periodontal compromised patients and to identify factors influencing TL on patient level. Material and Methods: Patients were re-examined 120 ± 12 months after active periodontal therapy. TL and risk factors [smoking, initial diagnosis, SPT adherence, interleukin-1 polymorphism, cardiovascular diseases, age at baseline, bleeding on probing (BOP), change of practitioner, insurance status, number of SPT, marital and educational status] influencing TL on patient level were assessed. Results: One-hundred patients (52 female, mean age 65.6 ± 11 years) lost 121 of 2428 teeth (1.21 teeth/patient; 0.12 teeth/patient/y) during 10 years of SPT. Forty-two of these were lost for periodontal reasons (0.42 teeth/patient; 0.04 teeth/patient/y). Significantly more teeth were lost due to other reasons (P < .001). Smoking, baseline severity of periodontitis, non-adherent SPT, positive interleukin-1 polymorphism, marital and educational status, private insurance, older age at baseline and BOP, small number of SPT were identified as patient-related risk factors for TL (P < .05). Conclusion: During 120 ± 12 months of SPT, only a small number of teeth was lost in periodontally compromised patients showing the positive effect of a well-established periodontal treatment concept. The remaining risk for TL should be considered using risk-adopted SPT allocation.
The RHO gene encodes the G-protein-coupled receptor (GPCR) rhodopsin. Numerous mutations associated with impaired visual cycle have been reported; the G90D mutation leads to a constitutively active mutant form of rhodopsin that causes CSNB disease. We report on the structural investigation of the retinal configuration and conformation in the binding pocket in the dark and light-activated state by solution and MAS-NMR spectroscopy. We found two long-lived dark states for the G90D mutant with the 11-cis retinal bound as Schiff base in both populations. The second minor population in the dark state is attributed to a slight shift in conformation of the covalently bound 11-cis retinal caused by the mutation-induced distortion on the salt bridge formation in the binding pocket. Time-resolved UV/Vis spectroscopy was used to monitor the functional dynamics of the G90D mutant rhodopsin for all relevant time scales of the photocycle. The G90D mutant retains its conformational heterogeneity during the photocycle.
CD4+ T cell lymphopenia predicts mortality from Pneumocystis pneumonia in kidney transplant patients
(2020)
Background: Pneumocystis jirovecii pneumonia (PcP) remains a life-threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association between risk of developing PcP and low CD4+ T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post-renal transplant PcP increases the risk of mortality. Methods: We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4+ T cell counts, we used the Wilcoxon rank sum test for in-hospital mortality and a Cox proportional-hazards regression model for 60-day mortality. Results: In univariate analyses, high CRP, high neutrophils, CD4+ T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in-hospital mortality following presentation with PcP. In a receiver-operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4+ T cells/µL predicted in-hospital mortality, CD4+ T cell lymphopenia remained a risk factor in a Cox regression model. Conclusions: Low CD4+ T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in-hospital mortality following presentation with PcP.
Background: Cerebral O2 saturation (ScO2) reflects cerebral perfusion and can be measured noninvasively by near-infrared spectroscopy (NIRS). Objectives: In this pilot study, we describe the dynamics of ScO2 during TAVI in nonventilated patients and its impact on procedural outcome. Methods and Results: We measured ScO2 of both frontal lobes continuously by NIRS in 50 consecutive analgo-sedated patients undergoing transfemoral TAVI (female 58%, mean age 80.8 years). Compared to baseline ScO2 dropped significantly during RVP (59.3% vs. 53.9%, p < .01). Five minutes after RVP ScO2 values normalized (post RVP 62.6% vs. 53.9% during RVP, p < .01; pre 61.6% vs. post RVP 62.6%, p = .53). Patients with an intraprocedural pathological ScO2 decline of >20% (n = 13) had higher EuroSCORE II (3.42% vs. 5.7%, p = .020) and experienced more often delirium (24% vs. 62%, p = .015) and stroke (0% vs. 23%, p < .01) after TAVI. Multivariable logistic regression revealed higher age and large ScO2 drops as independent risk factors for delirium. Conclusions: During RVP ScO2 significantly declined compared to baseline. A ScO2 decline of >20% is associated with a higher incidence of delirium and stroke and a valid cut-off value to screen for these complications. NIRS measurement during TAVI procedure may be an easy to implement diagnostic tool to detect patients at high risks for cerebrovascular complications and delirium.
Cortical changes in epilepsy patients with focal cortical dysplasia: new insights with T2 mapping
(2020)
Background: In epilepsy patients with focal cortical dysplasia (FCD) as the epileptogenic focus, global cortical signal changes are generally not visible on conventional MRI. However, epileptic seizures or antiepileptic medication might affect normal-appearing cerebral cortex and lead to subtle damage. Purpose: To investigate cortical properties outside FCD regions with T2-relaxometry. Study Type: Prospective study. Subjects: Sixteen patients with epilepsy and FCD and 16 age-/sex-matched healthy controls. Field Strength/Sequence: 3T, fast spin-echo T2-mapping, fluid-attenuated inversion recovery (FLAIR), and synthetic T1-weighted magnetization-prepared rapid acquisition of gradient-echoes (MP-RAGE) datasets derived from T1-maps. Assessment: Reconstruction of the white matter and cortical surfaces based on MP-RAGE structural images was performed to extract cortical T2 values, excluding lesion areas. Three independent raters confirmed that morphological cortical/juxtacortical changes in the conventional FLAIR datasets outside the FCD areas were definitely absent for all patients. Averaged global cortical T2 values were compared between groups. Furthermore, group comparisons of regional cortical T2 values were performed using a surface-based approach. Tests for correlations with clinical parameters were carried out. Statistical Tests: General linear model analysis, permutation simulations, paired and unpaired t-tests, and Pearson correlations. Results: Cortical T2 values were increased outside FCD regions in patients (83.4 ± 2.1 msec, control group 81.4 ± 2.1 msec, P = 0.01). T2 increases were widespread, affecting mainly frontal, but also parietal and temporal regions of both hemispheres. Significant correlations were not observed (P ≥ 0.55) between cortical T2 values in the patient group and the number of seizures in the last 3 months or the number of anticonvulsive drugs in the medical history. Data Conclusion: Widespread increases in cortical T2 in FCD-associated epilepsy patients were found, suggesting that structural epilepsy in patients with FCD is not only a symptom of a focal cerebral lesion, but also leads to global cortical damage not visible on conventional MRI. Evidence Level: 21. Technical efficacy Stage: 3 J. MAGN. RESON. IMAGING 2020;52:1783–1789.