Biology subjects

Malmberg, M.

Publications and source records attributed to Malmberg, M..

6 recordsLinked to original sources

bioRxiv2025

Coevolution of neoplastic and non-neoplastic reactive astrocyte states converges on mesenchymal-like and injury-response programs during murine glioblastoma progression and post-radiotherapy recurrence

Glioblastomas initially respond to radiotherapy but invariably recur, often within high-dose radiation treatment fields. Although stromal radiation responses are incompletely understood, evidence suggests that the tumor microenvironment becomes tumor-supportive after therapy. Using a genetically engineered glioblastoma mouse model, we profiled healthy brain, primary tumors, and post-radiotherapy recurrences with single-cell and spatial transcriptomics and immunohistochemistry. Across 13 non-neoplastic cell types and 10 tumor cell states, we mapped transcriptional adaptations accompanying progression from healthy brain to primary and recurrent glioblastoma. We identified distinct astrocyte states linked to disease stage, including reactive non-neoplastic astrocytes and tumor cells adopting reactive astrocyte-like phenotypes. Reactive astrocyte-like tumor cells with mesenchymal and injury-response signatures were enriched after radiotherapy and persisted in recurrent tumors. Receptor-ligand interactions between reactive astrocytes and tumor cells included known and putative drivers of aggressiveness. These findings highlight convergent reactive astrocyte programs in astrocytes and tumor cells as potential mediators of glioblastoma radioresistance.

cancer biology↗

bioRxiv2025

Phenotypic Screening Identifies Flunarizine as an Inhibitor of Radiotherapy-Induced Astrocyte Reactivity with Therapeutic Potential in Glioblastoma

Radiotherapy is part of the standard-of-care for glioblastoma, yet tumors invariably recur as incurable lesions post-treatment. Recent studies suggest that radiation-induced astrocyte reactivity fosters a tumor-supportive environment, however effective strategies targeting reactive astrocyte phenotypes are lacking. Using a novel image-based assay, we screened over 1,700 small molecule compounds, identifying 29 that inhibit radiation-induced astrocyte reactivity in human astrocytes. Among these, Flunarizine, a calcium-entry blocker approved for migraine treatment, significantly reduced astrocyte reactivity in vitro and in vivo. In a genetically engineered glioblastoma mouse model, combining Flunarizine with radiotherapy markedly improved survival without affecting unirradiated controls, indicating specificity for a radiation-induced phenotype. Mechanistically, Flunarizine inhibited radiation-induced fibrosis in vivo and directly suppressed astrocytic TGF-beta activation in vitro. Notably, Flunarizine treatment had no direct effect on primary glioblastoma cells, emphasizing its microenvironmental specificity. In conclusion, we identified Flunarizine as a promising repurposed compound capable of effectively mitigating radiation-induced astrocyte reactivity and delaying glioblastoma recurrence. This approach offers a viable therapeutic strategy to enhance current glioblastoma treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/664538v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@d4d0d6org.highwire.dtl.DTLVardef@1dac551org.highwire.dtl.DTLVardef@1d071ccorg.highwire.dtl.DTLVardef@1df1a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Identification and molecular characterization of novel viruses in Ugandan cattle

The risk for the emergence of novel viral zoonotic diseases in animals and humans in Uganda is high given its geographical location with high biodiversity. We aimed to identify and characterize viruses in 175 blood samples from cattle selected in Uganda using molecular approaches. We identified 8 viral species belonging to 4 families (Flaviviridae, Peribunyaviridae, Reoviridae and Rhabdoviridae) and 6 genera (Hepacivirus, Pestivirus, Orthobunyavirus, Coltivirus, Dinovernavirus and Ephemerovirus). Four viruses were novel and tetantively named as Zikole virus (Family: Flaviviridae), Zeboroti virus (Family: Reoviridae), Zebtine virus (Family: Rhabdoviridae) and Kokolu virus (Family: Rhabdoviridae). In addition, Bovine hepacivirus, Obodhiang virus, Aedes pseudoscutellaris reovirus and Schmallenberg virus were identified for the first time in Ugandan cattle. We report a broad range of viruses including novel ones in the blood of cattle likely as reservoir hosts for emergence of novel viruses with serious public health implications. HighlightsO_LIPan PCR and High Throughput Sequencing Approaches reveal novel viruses in the blood of cattle. C_LIO_LIIdentified 8 viral species belonging to 4 families: Flaviviridae, Peribunyaviridae, Reoviridae and Rhabdoviridae C_LIO_LI60% of the identified viruses were found in the Ankole cattle breed C_LI

microbiology↗

bioRxiv2020

Four novel Picornaviruses viruses detected in Magellanic Penguins (Spheniscus magellanicus) in Chile

Members of the Picornaviridae comprise a significant burden on the poultry industry, causing diseases such as gastroenteritis and hepatitis. However, with the advent of metagenomics, a number of picornaviruses have now been revealed in apparently healthy wild birds. In this study, we identified four novel viruses belonging to the family Picornaviridae in healthy Magellanic Penguins (Spheniscus magellanicus), a near threatened species found along the coastlines of temperate South America. We collected 107 faecal samples from 72 individual penguins. Twelve samples were initially sequenced by high throughout sequencing with metagenomics approach. All samples were subsequently screened by PCR for these new viruses, and approximately 20% of the penguins were infected with at least one of these viruses, and seven individuals were co-infected with two or more. The viruses were distantly related to members of the genera Hepatoviruses, Tremoviruses and unassigned viruses from Antarctic Penguins and Red-Crowned Cranes. Further, they had more than 60% amino acid divergence from other picornaviruses, and therefore likely constitute novel genera. That these four novel viruses were abundant among the sampled penguins, suggests Magellanic Penguins may be a reservoir for several picornaviruses belonging to different genera. Our results demonstrate the vast undersampling of wild birds for viruses, and we expect the discovery of numerous avian viruses that are related to Hepatoviruses and Tremoviruses in the future. ImportanceRecent work has demonstrated that Antarctic penguins of the genus Pygoscelis are hosts for an array of viral species. However, beyond these Antarctic penguin species, very little is known about the viral diversity or ecology in this highly charismatic avian order. Through metagenomics we identified four novel viruses belonging to the Picornaviridae family in faecal samples from Magellanic Penguins. These highly divergent viruses, each possibly representing novel genera, are related to members of the Hepatovirus, Tremovirus genera, and unassigned picornaviruses described from Antarctic Penguin and Red-crowned Cranes. By PCR these novel viruses were shown to be common in Magellanic Penguins, indicating that penguins may play a key role in their epidemiology and evolution. Overall, we encourage further sampling to reveal virus diversity, ecology, and evolution in these unique avian taxa.

ecology↗

bioRxiv2020

The heart microbiome of insectivorous bats from Central and South Eastern Europe

Host associated microbiome not only may affect the individual health-status or provide insights into the species- or group specific bacterial communities but may act as early warning signs in the assessment of zoonotic reservoirs, offering clues to predict, prevent and control possible episodes of emerging zoonoses. Bats may be carriers and reservoirs of multiple pathogens such as viruses, bacteria and parasites, showing in the same time robust immunity against many of them. The microbiota plays a fundamental role on the induction, training and function of the host immune system and the immune system has largely evolved in order to maintain the symbiotic relationship of the host with these diverse microbes. Thus, expanding our knowledge on bat-associated microbiome it can be usefully in understanding bats outstanding immune capacities. The aim of this study was to investigate the presence of different bacterial communities in heart tissue of insectivorous bats, Nyctalus noctula, Pipistrellus pipistrellus and Rhinoplophus hipposideros, from Central and Eastern Europe using high-throughput sequencing of variable regions of the 16S rRNA. In addition, species-specific PCRs were used to validate the presence of the vector-borne pathogens Bartonella spp. and Rickettsia spp. In this study we identified a wide variety of bacterial groups, with the most abundant phyla being Proteobacteria and Firmicutes. The results showed that at individual level, the year or location had no effect on the diversity and composition of the microbiome, however host species determined both structure and abundance of the bacterial community. We report the presence of vector-borne bacteria Bartonella spp. in samples of N. noctula and indications of Rickettsia spp. in R. hipposideros. Our results provide a first insight into the bacterial community found in heart tissue of bats from Central and South Eastern Europe.

microbiology↗

bioRxiv2020

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, and ERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.

cancer biology↗