Modeling the CO2-effects of forest management and wood usage on a regional basis

BACKGROUND: At the 15(th) Conference of Parties of the UN Framework Convention on Climate Change, Copenhagen, 2009, harvested wood products were identified as an additional carbon pool. This modification eliminates inconsistencies in greenhouse gas reporting by recognizing the role of the forest and timber sector in the global carbon cycle. Any additional CO(2)-effects related to wood usage are not considered by this modification. This results in a downward bias when the contribution of the forest and timber sector to climate change mitigation is assessed. The following article analyses the overall contribution to climate protection made by the forest management and wood utilization through CO(2)-emissions reduction using an example from the German state of North Rhine-Westphalia. Based on long term study periods (2011 to 2050 and 2100, respectively). Various alternative scenarios for forest management and wood usage are presented. RESULTS: In the mid- to long-term (2050 and 2100, respectively) the net climate protection function of scenarios with varying levels of wood usage is higher than in scenarios without any wood usage. This is not observed for all scenarios on short and mid term evaluations. The advantages of wood usage are evident although the simulations resulted in high values for forest storage in the C pools. Even the carbon sink effect due to temporal accumulation of deadwood during the period from 2011 to 2100 is outbalanced by the potential of wood usage effects. CONCLUSIONS: A full assessment of the CO(2)-effects of the forest management requires an assessment of the forest supplemented with an assessment of the effects of wood usage. CO(2)-emission reductions through both fuel and material substitution as well as CO(2) sink in wood products need to be considered. An integrated assessment of the climate protection function based on the analysis of the study’s scenarios provides decision parameters for a strategic approach to climate protection with regard to forest management and wood use at regional and national levels. The short-term evaluation of subsystems can be misleading, rendering long-term evaluations (until 2100, or even longer) more effective. This is also consistent with the inherently long-term perspective of forest management decisions and measures

ATRT-02. Neuropsychological function in infant atypical teratoid/rhabdoid tumor versus low-grade glioma survivors reflects tumor malignancy and multimodal treatment [Abstract]

BACKGROUND: Therapy of infants with brain tumors predisposes these patients to increased risks for cognitive sequelae, especially following radiotherapy. Neuropsychological outcome gains importance for those 40-60% of patients with an atypical teratoid/rhabdoid tumor (ATRT) who survive beyond 2 years. Still, reports on cognitive late-effects in children with ATRT are scarce compared to other pediatric brain tumor groups. We analyzed neuropsychological outcome for long-term ATRT-survivors registered in EU-RHAB and infant low-grade glioma (LGG) survivors from the SIOP-LGG 2004-study and LGG-registry. PATIENTS+METHODS: Age at diagnosis of both cohorts was 0-36 months. ATRT-patients (n=13) treated with up to 54Gy radiotherapy (median age 22 months (±7.1)) were evaluated with the “ATRT-Neuropsychology” tool based on SIOPE-BTG QoS-Group recommendations at median 6.8 years (±2.8) after diagnosis. LGG-patients (n=15) treated without radiotherapy (4/15 with chemotherapy) were analyzed with the German “Neuropsychological-Basic-Diagnostic” tool 5.2 years (±0.6) post-diagnosis. RESULTS: The ATRT- vs. LGG-cohorts were comparable for median age at diagnosis, sex-ratio and tumor-localization, though they differed slightly in median age at assessment (9.5/7.2 years (±2.5/1.1)). Results of age-appropriate tests showed increased impairments for ATRT-patients in fluid intelligence (FI) (p=.006, d=1.214) and in visual-spatial processing (VSP) (p<.001, d=2.233) compared to LGG-patients. The median for neuropsychological test results of ATRT-patients spanned from considerably below the normal to the lower normal range (median=65-90), while results of LGG-patients were mostly in the lower normal range (median=83-103). Results for psychomotor speed abilities (PMS) were distinctly below the norm for both patient groups (p=.002-.007). CONCLUSION: Infant ATRT- and LGG-patients develop significant impairments in PMS abilities following multimodal treatment. Long-term survivors of ATRT suffer from additional FI and VSP deficits. Our data suggest that high malignancy requiring multimodal treatment determines the inferior cognitive outcome for the ATRT-cohort. Long-term neuropsychological monitoring (and treatment options) should be implemented as standard of care in ATRT- and LGG-trials

ETMR-05: Single-cell transcriptomics of ETMR reveals developmental cellular programs and tumor-pericyte communications in the microenvironment [Abstract]

BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are pediatric brain tumors bearing a grim prognosis, despite intensive multimodal therapeutic approaches. Insights into cellular heterogeneity and cellular communication of tumor cells with cells of the tumor microenvironment (TME), by applying single-cell (sc) techniques, potentially identify mechanisms of therapy resistance and target-directed treatment approaches. MATERIAL AND METHODS: To explore ETMR cell diversity, we used single-cell RNA sequencing (scRNA-seq) in human (n=2) and murine ETMR (transgenic mode; n=4) samples, spatial transcriptomics, 2D and 3D cultures (including co-cultures with TME cells), multiplex immunohistochemistry and drug screens. RESULTS: ETMR microenvironment is composed of tumor and non-tumor cell types. The ETMR malignant compartment harbour cells representing distinct transcriptional metaprograms, (NSC-like, NProg-like and Neuroblast-like), mirroring embryonic neurogenic cell states and fuelled by neurogenic pathways (WNT, SHH, Hippo). The ETMR TME is composed of oligodendrocyte and neuronal progenitor cells, neuroblasts, microglia, and pericytes. Tumor-specific ligand-receptor interaction analysis showed enrichment of intercellular communication between NProg-like ETMR cells and pericytes (PC). Functional network analyses reveal ETMR-PC interactions related to stem-cell signalling and extracellular matrix (ECM) organization, involving factors of the WNT, BMP, and CxCl12 networks. Results from ETMR-PC co-culture and spatial transcriptomics pointed to a pivotal role of pericytes in keeping ETMR in a germinal neurogenic state, enriched in stem-cell signalling. Drug screening considering cellular heterogeneity and cellular communication suggested novel therapeutic approaches. CONCLUSION: ETMR demonstrated diversity in the microenvironment, with enrichment of cell-cell communications with pericytes, supporting stem-cell signalling and interfering in the organization of the tumor extracellular matrix. Targeting ETMR-PC interactions might bring new opportunities for target-directed therapy

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease

Life-threatening hypersplenism due to idiopathic portal hypertension in early childhood: case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings.</p> <p>Case Presentation</p> <p>We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy.</p> <p>Conclusions</p> <p>Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH.</p

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

Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway

Dlk/ZIP kinase is a member of the Death Associated Protein (DAP) kinase family of pro-apoptotic serine/threonine kinases that have been implicated in regulation of apoptosis and tumour suppression. Expression of both Dlk/ZIP kinase and its interaction partner Par-4 is maintained in four medulloblastoma cell lines investigated, whereas three of seven neuroblastoma cell lines have lost expression of Par-4. Overexpression of a constitutively pro-apoptotic deletion mutant of Dlk/ZIP kinase induced significant apoptosis in D283 medulloblastoma cells. Cell death was characterized by apoptotic membrane blebbing, and a late stage during which the cells had ceased blebbing and were drastically shrunken or disrupted into apoptotic bodies. Over-expression of the anti-apoptotic Bcl-xL protein had no effect on Dlk/ZIP kinase-induced membrane blebbing, but potently inhibited Dlk/ZIP kinase-induced cytochrome c release and transition of cells to late stage apoptosis. Treatment with caspase inhibitors delayed, but did not prevent entry into late stage apoptosis. These results demonstrate that Dlk/ZIP kinase-triggered apoptosis involves the mitochondrial apoptosis pathway. However, cell death proceeded in the presence of caspase inhibitors, suggesting that Dlk/ZIP kinase is able to activate alternative cell death pathways. Alterations of signal transduction pathways leading to Dlk/ZIP kinase induced apoptosis or loss of expression of upstream activators could play important roles in tumour progression and metastasis of neural tumours. © 2001 Cancer Research Campaign http://www.bjcancer.co