Beyond Climate Focus and Disciplinary Myopia. The Roles and Responsibilities of Hospitals and Healthcare Professionals

This paper calls for the need to address climate change within the concept of sustainable development, in recognition of the interrelationships between environmental, economic and social systems. So far, health- providing organizations such as hospitals have paid surprisingly little attention to the relationships between environmental change (e.g. climate change) and human health, or between hospitals (as professional organizations) and their impact on sustainable development. Although it is usually such industries as the chemical, extractive and metal industries, etc., that are associated with environmentally harmful activities, there is also an urgent need to emphasize the roles and responsibilities of hospitals and their embeddedness in a wider ecological, economic and social context. The key objective here is to discuss the relevance of sustainability and environmental management issues in a sector that until now has conveniently ignored its roles and responsibilities in relation to sustainability issues. The paper concludes that arguments based on systems theory, environment, medicine, economics and innovation strongly urge hospitals to reconsider their present roles and environmental responsibilities

ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02424-5

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency

The established causal genes in Alzheimer’s disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD

Association between copy number alterations estimated using low-pass whole genome sequencing of formalin-fixed paraffin-embedded prostate tumor tissue and cancer-specific clinical parameters

Abstract Copy number alterations (CNAs) are frequently observed in early-stage prostate cancer and are associated with disease recurrence and tumor aggressiveness. Cost-effective assessment of CNAs could enhance clinical utility of CNAs. Here, we combined the cost-effectiveness of low-pass (low coverage) whole genome sequencing (LPWGS) and the routine availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for assessing CNAs in a cohort of 187 men with early-stage localised prostate cancer. We detected well known CNAs in 8p, 8q, 13q and 16q and recurrent gains of the oncogene MYC and losses of the tumor suppressor genes NKX3-1, PTEN and RB1, indicating assay reliability. The estimated burden of CNAs was significantly associated with Gleason score, pathological T stage, surgical margin status and biochemical recurrence. Further, genomic losses or gains in specific chromosomal arms were significantly associated with worse BCR-free survival. Copy number signatures extracted from the LPWGS data showed potential for risk stratifying patients, where signatures S1 and S2 showed significant association to worse BCR-free survival compared to S3. Our study provides clinical validation of the associations between CNAs and tumor aggressiveness in an independent and representative RP cohort, while demonstrating the feasibility of performing LPWGS of FFPE tumor tissue for cost-effective assessment of CNAs

Impact of new molecular criteria on diagnosis and survival of adult glioma patients

The fifth edition WHO classification of Tumors of the Central nervous system (WHO-CNS5) integrated new molecular parameters to refine CNS tumor classification. This study aimed to reclassify a retrospective cohort of adult glioma patients according to WHO-CNS5, and assess if overall survival (OS) correlated with the revised diagnosis. Further, the diagnostic impact of methylation profiling (MP) was evaluated. Adult gliomas diagnosed according to 2016 WHO-CNS (n = 226) were evaluated according to WHO-CNS5 criteria. All patients had diagnostic NGS performed. 29 patients had 850k MP performed due to challenging tumor cases. OS was analyzed using Kaplan-Meier plots and log-rank test. 19 patients were reclassified. Specifically, diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma (DAG-G) were reclassified as glioblastoma (n = 15). Shifts to glioblastoma were because of TERT promoter (TERTp) mutation (n = 9), EGFR amplification (n = 2), EGFR amplification and TERTp mutation (n = 1), and TERTp mutation with gain of chromosome 7, but uncertain chromosome 10 status due to lack of NGS coverage (n = 3). Lower grade IDH-mutant astrocytomas were reclassified as astrocytoma IDH-mutant, WHO grade 4 due to CDKN2A/B homozygous deletion (n = 4). No significant difference in OS was found for reclassified DAG-G in whole group (p = 0.59) and for TERTp mutation only (p = 0.44), compared to glioblastoma. MP resulted in revised diagnosis (n = 2), confirmed diagnosis (n = 15) and no match (n = 12). Our study showed similar overall survival for glioblastoma and DAG patients, supporting that isolated TERTp mutation may have a prognostic role in IDH-wildtype gliomas. Further, our study suggests MP is useful for confirming the diagnoses in challenging tumors