Biology subjects

Nowicki, J.

Publications and source records attributed to Nowicki, J..

4 recordsLinked to original sources

bioRxiv2026

Hypothalamic Cell Type Evolution across Vertebrates

The hypothalamus regulates vital functions and is highly conserved among vertebrates occupying diverse niches, but little is known about the evolution of its cell types. Using comparative single-cell transcriptomics across major vertebrate classes, we identified deeply conserved and clade-specific cell types. While homologous cell types express conserved transcription factors and neuropeptides, their regulatory linkages are often rewired across evolution. The paraventricular nucleus largely retains its neuropeptide expression and responds to dehydration with fine cellular resolution from amphibians to mammals, whereas lamina terminalis neurons are specific to terrestrial vertebrates and exhibit gene expression divergence in cell types activated by dehydration and heat. We propose that a conserved set of keystone cell types sustain essential functions across vertebrates, while flexible gene regulatory programs alongside numerous clade-specific cell types offer evolutionary fluidity.

evolutionary biology↗

bioRxiv2022

GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma

BackgroundAggressive primary brain tumors such as glioblastoma are uniquely challenging to treat. The intracranial location poses barriers to therapy, and the potential for severe toxicity. Effective treatments for primary brain tumors are limited, and 5-year survival rates remain poor. Immune checkpoint inhibitor therapy has transformed treatment of some other cancers but has yet to significantly benefit patients with glioblastoma. Early phase trials of CAR-T cell therapy have demonstrated that this approach is safe and feasible, but with limited evidence of its effectiveness. The choices of appropriate target antigens for CAR-T cell therapy also remain limited. MethodsWe profiled an extensive biobank of patients biopsy tissues and patient-derived early passage glioma neural stem cell lines for GD2 expression using immunomicroscopy and flow cytometry. We then employed an approved clinical manufacturing process to make CAR-T cells from peripheral blood of glioblastoma and diffuse midline glioma patients and characterized their phenotype and function in vitro. Finally, we tested intravenously administered CAR-T cells in an aggressive intracranial xenograft model of glioblastoma and used multicolor flow cytometry, multicolor whole-tissue immunofluorescence and next-generation RNA sequencing to uncover markers associated with effective tumor control. ResultsHere we show that the tumor-associated antigen GD2 is highly and consistently expressed in primary glioblastoma tissue removed at surgery. Moreover, despite glioblastoma patients having perturbations in their immune system, highly functional GD2-specific CAR-T cells can be produced from their peripheral T cells using an approved clinical manufacturing process. Finally, after intravenous administration, GD2-CAR-T cells effectively infiltrated the brain and controlled tumor growth in an aggressive orthotopic xenograft model of glioblastoma. Tumor control was further improved using CAR-T cells manufactured with a clinical retroviral vector encoding an IL-15 transgene alongside the GD2-specific CAR. These CAR-T cells achieved a striking 50% complete response rate by bioluminescence imaging in established intracranial tumors. Markers associated with tumor control included those related to T-cell homing, infiltration, and cytotoxicity. ConclusionsTargeting GD2 using a clinically deployed CAR-T therapy has a sound scientific and clinical rationale as a treatment for glioblastoma and other aggressive primary brain tumors. What is already known on this topicGD2 is a tumor antigen of significant interest for targeting immunotherapy. A single preclinical study has shown the effectiveness of GD2-CAR-T cell therapy in an orthotopic xenograft model of diffuse midline glioma. Similarly, there is one previous preclinical study of GD2-CAR-T therapy in a orthotopic glioblastoma xenograft model but tumor control was achieved only following intracranial injection of CAR-T cells. Given that GD2-CAR-T therapy is already being evaluated clinically for other tumor indications, it is important to establish whether there is an acceptable rationale for its use in brain tumors. What this study addsThis is the first description of a GD2-targeted CAR-T cell therapy that shows antitumor effectiveness in a preclinical model of human glioblastoma following intravenous administration. It is also the first study to investigate the potential effects that the immune profile of glioblastoma patients may have on the feasibility of CAR-T cell manufacturing. How this study might affect research, practice, or policyThe results of this study have led to the initiation of an Australian phase 1 clinical trial program aiming to test GD2-specific CAR-T cells for the treatment of childhood and adult primary brain tumors. The study provides valuable insights into the microenvironmental factors that influence the effectiveness of CAR-T cell therapy for this type of tumor, paving the way for further optimization of CAR-T cell technology for treatment of aggressive primary brain tumors such as glioblastoma.

immunology↗

bioRxiv2017

Butterflyfishes as a System for Investigating Pair Bonding

For many animals, affiliative relationships such as pair bonds form the foundation of society, and are highly adaptive. Animal systems amenable for comparatively studying pair bonding are important for identifying underlying biological mechanisms, but mostly exist in mammals. Better establishing fish systems will enable comparison of pair bonding mechanisms across taxonomically distant lineages that may reveal general underlying principles. We examined the utility of wild butterflyfishes (f: Chaetodontidae; g: Chaetodon) for comparatively studying pair bonding. Stochastic character mapping inferred that within the family, pairing is ancestral, with at least seven independent transitions to group formation and seven transition to solitary behavior from the late Miocene to recent. In six sympatric and wide-spread species representing a clade with one ancestrally reconstructed transition from paired to solitary grouping, we then verified social systems at Lizard Island, Australia. In situ observations confirmed that Chaetodon baronessa, C. lunulatus, and C. vagabundus are predominantly pair bonding, whereas C. rainfordi, C. plebeius, and C. trifascialis are predominantly solitary. Even in the predominantly pair bonding species, C. lunulatus, a proportion of adults (15 %) are solitary. Importantly, inter- and intra-specific differences in social systems do not co-vary with other previously established attributes (geographic occurrence, parental care, diet, or territoriality). Hence, the proposed butterflyfish populations are promising for comparative analyses of pair bonding and its mechanistic underpinnings. Avenues for further developing the system are proposed, including determining whether the utility of these species applies across their geographic disruptions.

ecology↗

bioRxiv2017

Neurobiology of pair bonding in fishes; convergence of neural mechanisms across distant vertebrate lineages

Animals display remarkable variation in social behavior. However, outside of rodents, little is known about the neural mechanisms of social variation, and whether they are shared across species and sexes, limiting our understanding of how sociality evolves. Using coral reef butterflyfishes, we examined gene expression correlates of social variation (i.e., pair bonding vs. solitary living) within and between species and sexes. In several brain regions, we quantified gene expression of receptors important for social variation in mammals: oxytocin (OTR), arginine vasopressin (V1aR), dopamine (D1R, D2R), and mu-opioid (MOR). We found that social variation across individuals of the oval butterflyfish, Chaetodon lunulatus, is linked to differences in OTR,V1aR, D1R, D2R, and MOR gene expression within several forebrain regions in a sexually dimorphic manner. However, this contrasted with social variation among six species representing a single evolutionary transition from pair bonded to solitary living. Here, OTR expression within the supracommissural part of the ventral telencephalon was higher in pair bonded than solitary species, specifically in males. These results contribute to the emerging idea that nonapeptide, dopamine, and opioid signaling is a central theme to the evolution of sociality across individuals, although the precise mechanism may be flexible across sexes and species.

neuroscience↗