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PET/CT-guided management of immune checkpoint blockade and post-treatment multi-modal profiling in long-term responders with metastatic lung cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM)
No full textCharacterization of anthracycline-induced cardiotoxicity by diffusion tensor magnetic resonance imaging
Get PDFAnthracyclines are highly potent anti-cancer drugs, but their clinical use is limited by severe cardiotoxic side effects. The impact of anthracycline-induced cardiotoxicity (AIC) on left ventricular (LV) microarchitecture and diffusion properties remains unknown. This study sought to characterize AIC by cardiovascular magnetic resonance diffusion tensor imaging (DTI). Mice were treated with Doxorubicin (DOX; n = 16) for induction of AIC or saline as corresponding control (n = 15). Cardiac function was assessed via echocardiography at the end of the study period. Whole hearts (n = 8 per group) were scanned ex vivo by high-resolution DTI at 7 T. Results were correlated with histopathology and mass spectrometry imaging. Mice with AIC demonstrated systolic dysfunction (LVEF 52 ± 3% vs. 43 ± 6%, P < 0.001), impaired global longitudinal strain (-19.6 ± 2.0% vs. -16.6 ± 3.0%, P < 0.01), and cardiac atrophy (LV mass index [mg/mm], 4.3 ± 0.1 vs. 3.6 ± 0.2, P < 0.01). Regional sheetlet angles were significantly lower in AIC, whereas helix angle and relative helicity remained unchanged. In AIC, fractional anisotropy was increased (0.12 ± 0.01 vs. 0.14 ± 0.02, P < 0.05). DOX-treated mice displayed higher planar and less spherical anisotropy (C(Planar) 0.07 ± 0.01 vs. 0.09 ± 0.01, P < 0.01; C(Spherical) 0.89 ± 0.01 vs. 0.87 ± 0.02, P < 0.05). C(Planar) and C(Spherical) yielded good discriminatory power to distinguish between mice with and without AIC (c-index 0.91 and 0.84, respectively, P for both < 0.05). AIC is associated with regional changes in sheetlet angle but no major abnormalities of global LV microarchitecture. The geometric shape of the diffusion tensor is altered in AIC. DTI may provide a new tool for myocardial characterization in patients with AIC, which warrants future clinical studies to evaluate its diagnostic utility
Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming [ES_ChIP_seq_H3K9me3_LA]
No full textSpatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here, we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naïve mouse pluripotent stem cells leads to upregulation of the cysteine generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naïve to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature aging, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Importantly, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity, and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases
Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming [ES_H3K9ac_ChIP-seq]
No full textSpatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here, we show that nuclear lamina dynamics regulate cysteine catabolic flux, crucial for proper stem cell fate and longevity. Lamin A/C loss in naïve pluripotent stem cells upregulates CTH and CBS enzyme expression, promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naïve to primed pluripotency and abnormal cell fate. Conversely, gain-of-function mutation of lamin A/C, associated with premature aging, reduces CTH and CBS levels. This reroutes the cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Importantly, modulation of cysteine metabolism rescues the abnormal cell fate, DNA damage repair defects, and the senescent phenotype upon lamin A/C mutation, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases
Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial
Get PDFBACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR. We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison with clinical indication biopsy. METHODS: In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate ≥20 mL/min/1.73 m(2), but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-month period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9 and 12 months. In the intervention group, dd-cfDNA >50 copies/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR. RESULTS: Thirty-nine of 40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group [median 2.8 months, interquartile range (IQR) 1.7–5.3 vs median 14.5 months, IQR 13.3–16.7, P = .003]. Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR. CONCLUSIONS: Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation
Informationsschatz aus Umweltproben [Treasure trove of information from environmental samples]
Get PDFOur environment is a treasure trove of genetic information. High-throughput sequencing enables a spectrum of investigations, from observing human pathogens to assessing the constitution of an ecosystem. Here, we summarize our work on longitudinal total RNA/DNA sequencing from wastewater samples combined with in-depth data analysis. We explore the wealth of data from known virus detection to discovery of novel biotechnological enzyme sequences, showcasing the potential of such systematic approaches
Reproducibility of electromagnetic field simulations of local radiofrequency transmit elements tailored for 7 T MRI
Get PDFThe literature reports on radiofrequency (RF) transmit (Tx) elements tailored for ultrahigh-field (UHF) magnetic resonance imaging (MRI) showed confounded reproducibility due to variations in simulation tools, modeling assumptions, and meshing techniques. This study proposes a standardized methodology to improve reproducibility and consistency across research sites (testers) and simulation tools (testing conditions). The methodology includes detailed simulation workflow and performance metrics for RF Tx elements. The impact of the used mesh setting is assessed. Following the methodology, a reproducibility study was conducted using CST Microwave Studio Suite, HFSS, and Sim4Life. The methodology and simulations were ultimately validated through 7 T MRI phantom experiments. The reproducibility study showed consistent performance with less than 6% standard deviation for B(1)(+) fields and 12% for peak SAR averaged over 10 g tissue (pSAR10g). The SAR efficiency metric (|B(1)(+)|/√pSAR(10g)) was particularly robust (<5%). The simulated and experimental |B(1)(+)| maps showed good qualitative agreement. This study demonstrates the feasibility of a standardized methodology for achieving reproducible RF Tx element electromagnetic field simulations. By following the FAIR principles including making the framework publicly available, we promote transparency and collaboration within the MRI community, supporting the advancement of technological innovation and improving patient safety in UHF-MRI
Expression and function of Connexin 43 and Connexin 37 in the murine zona glomerulosa
Get PDFThe zona glomerulosa (ZG) synthesizes the mineralocorticoid aldosterone. The primary role of aldosterone is the maintenance of volume and electrolyte homeostasis. Aldosterone synthesis is primarily regulated via tightly controlled oscillations in intracellular calcium levels in response to stimulation. It has previously been shown that calcium oscillations are synchronized through mechanical linkage between adjacent ZG cells. In many other cell types, similar synchronization is rather dependent on gap junctions (GJ). The recent discovery of mutations in CADM1 was linked to impaired GJ function in the ZG. Based on published transcriptomics data, we re-examined the presence and functional impact of GJ in the ZG. We found evidence for the expression of murine connexin 43 and 37 using microarray data, in-situ hybridization and immunohistology. Connexin 43 was also present in human samples. Calcium oscillations in ZG rosettes showed some degree of synchronization as reported previously. Unspecific GJ inhibition only had a small impact on this synchronicity. However, no signs of connections between cytosols could be observed as indicated by the lack of fluorescence recovery after photobleaching. We conclude that, while connexin proteins are expressed in the ZG, functional GJ in the physiological ZG are rare and of little consequence for calcium signaling
Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like subtype
Get PDFNeoadjuvant chemoradiation therapy (RCT) is a frequently used treatment regimen for esophageal adenocarcinoma (EAC); however, the response varies dramatically, and resistance is a clinical challenge. We aimed to identify the molecular mechanisms underlying RCT resistance. We established a mouse xenograft RCT model with human EAC cell lines representing different response groups, and tested enhanced genomic instability as a potential evolutionary modulator by reducing BRCA2 function. Xenografts that relapsed after RCT displayed upregulation of stress response keratins, including KRT6 and KRT16 connected with a basal-like transcriptomic/ proteomic phenotype. We screened our cohort of 728 patients with EAC and found significantly shorter overall survival for patients with KRT6-high tumors, driven by patients receiving neoadjuvant treatment. Overall, we identified a basal-like cell state in EAC that reflects RCT relapse. The basal-like subtype is a marker of treatment failure, providing a new avenue for translational research to overcome RCT resistance
Advancing optical coherence tomography diagnostic capabilities: machine learning approaches to detect autoimmune inflammatory diseases
No full textBACKGROUND: In many parts of the world including India, the prevalence of autoimmune inflammatory diseases such as neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and multiple sclerosis (MS) is rising. A diagnosis is often delayed due to insufficient diagnostic tools. Machine learning (ML) models have accurately differentiated eyes of patients with MS from those of healthy controls (HCs) using optical coherence tomography (OCT)-based retinal images. Examining OCT characteristics may allow for early differentiation of these conditions. The objective of this study was to determine feasibility of ML analyses to distinguish between patients with different autoimmune inflammatory diseases, other ocular diseases, and HCs based on OCT measurements of the peripapillary retinal nerve fiber layer (pRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layers (INLs). METHODS: Eyes of people with MS (n = 99 patients), NMOSD (n = 40), MOGAD (n = 74), other ocular diseases (OTHER, n = 16), and HCs (n = 54) from the Mangalore Demyelinating Disease Registry were included. Support vector machine (SVM) classification models incorporating age, pRNFL, GCIPL, and INL were performed. Data were split into training (70%) and testing (30%) data and accounted for within-patient correlations. Cross-validation was used in training to choose the best parameters for the SVM model. Accuracy and area under receiver operating characteristic curves (AUROCs) were used to assess model performance. RESULTS: The SVM models distinguished between eyes of patients with each condition (i.e., MOGAD vs NMOSD, NMOSD vs HC, MS vs OTHER, etc) with strong discriminatory power demonstrated from the AUROCs for these comparisons ranging from 0.81 to 1.00. These models also performed with moderate to high accuracy, ranging from 0.66 to 0.81, with the exception of the MS vs NMOSD comparison, which had an accuracy of 0.53. CONCLUSIONS: ML models are useful for distinguishing between autoimmune inflammatory diseases and for distinguishing these from HCs and other ocular diseases based on OCT measures. This study lays the groundwork for future deep learning studies that use analyses of raw OCT images for identifying eyes of patients with such disorders and other etiologies of optic neuropathy