👤 Michaela Sander

The study aimed to assess the effectiveness of three clinical diagnostic criteria [Simon Broome (SB), MEDPED (MP), and guideline-derived (GL-EAS)] in identifying children with familial hypercholesterolaemia (FH) compared with genetic testing. The evaluation involved 1337 children with elevated LDL cholesterol (LDL-C) levels, focusing on the sensitivity and specificity of these clinical scores in detecting genetically confirmed FH cases. Clinical data were gathered by a self-reporting questionnaire. Clinical FH was defined in accordance with the tested FH score. Genetically confirmed heterozygous FH (HeFH) was defined by a (likely) pathogenic variant. Of the 1337 children undergoing genetic analysis, 211 showed a pathogenic FH mutation. Applying SB, MP, and GL-EAS criteria resulted in 210/1337, 125/1337, and 112/835 children being categorized to have FH clinically. The sensitivity of the clinical scores ranged from 0.44 to 0.54 with a positive predictive value (PPV) of 0.51-0.79. The specificity was 0.91-0.97 with a negative predictive value (NPV) of 0.89-0.91. Similar results were observed for the three clinical scores regarding sensitivity, specificity, PPV, and NPV in subgroup analyses defined by gender, age (<10 years vs. ≥10 years), or weight [≥90th BMI (body mass index) percentile vs. <90th BMI percentile]. Clinical FH scores offer a high degree of specificity for FH diagnosis in children, but at the expense of low sensitivity. Specifically, half of the mutation-positive children in this study would have been missed for early diagnosis and preventive treatment. Given the widespread availability of affordable genetic testing, such analysis should be performed at a lower threshold than that indicated by these clinical scores. Show less

Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC) with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, where EGFR-mediated RAS-MAPK pathway reactivation can be targeted toimprove response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear. Mechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models. We observed RTK-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models, but limited to those with epithelial differentiation. Conversely, adaptive RAS MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from TCGA, EGFR and ERBB3 expression was highly correlated with expression of epithelial markers, while expression of FGFR1 and mesenchymal markers were correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared to combinations of KRASi and EGFR blockade. In PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in PDAC patients. Show less

Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity. Show less

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment. Show less

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ( We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funded by Roche Sequencing Solutions, Inc. Show less