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Cerebrospinal fluid (CSF)-directed therapies are gaining importance in neuro-oncology, but long-term CSF access in preclinical murine models remains limited by anatomical constraints. This technical feasibility study evaluates the Transcranial Cisternal Port (TCP), a skull-anchored cannula that provides repeated access to the intrathecal space. The procedure is performed by: making an incision over the craniocervical junction and exposing the cisterna magna; performing a craniostomy on the interparietal bone and placing a guide cannula through it; verifying placement by threading a wire through the cannula and visualizing it within the cisterna magna; securing the cannula in place using surgical adhesive; skin closure and inserting a mandrin to maintain patency. The TCP was validated via Evans blue dye injection, and long-term outcomes were assessed over 3 weeks in 43 athymic nude mice. Evans blue dye distribution was observed throughout the cisterna magna, basal cisterns, and perivascular spaces. All animals recovered uneventfully without device-related complications. Functional retention was 93% at day 7, 86% at day 14, and 86% at day 21. Failure was related to intraluminal clogging ( n  = 4) and adhesive bonding of the dummy to the guide cannula ( n  = 2). Revision surgery was successful in all cases. The TCP provides a skull-anchored access route to the murine CSF, enabling reliable intrathecal delivery. Cannula patency remains a limitation in some animals. Future iterations might mitigate this by improving guide cannula design. Overall, these findings establish the TCP as a scalable, functionally robust platform for modeling intrathecal regimens in preclinical studies.

Background Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N -butyl- N -(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. Methods Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. Results We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. Conclusions Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

Bispecific T cell engagers (BTEs) induce MHC‐independent cytotoxicity by bridging T cells to tumor cells via binding a T cell–activating receptor and a tumor‐associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin‐13 receptor alpha 2 (IL13RA2), a tumor‐associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen‐dependent cytokine release and cytotoxicity against IL13RA2‐positive GBM cells. In vivo, hBTE showed robust target‐specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off‐target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2‐expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2‐expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors. This study reports the development of a fully humanized bispecific T cell engager targeting IL13RA2, a tumor‐associated antigen enriched in glioblastoma. This off‐the‐shelf immunotherapy drives potent, antigen‐dependent T cell activation and tumor killing, and prolongs survival in experimental GBM and other solid tumors models without detectable off‐target toxicity.

Subarachnoid hemorrhage (SAH) is a devastating form of stroke that disproportionately affects younger individuals and often results in long-term disability, even among those who achieve favorable outcomes on traditional clinical scales. This scoping review uses the PRISMA-ScR protocol to evaluate independent studies from 1980 to 2025 and synthesizes current evidence on sleep and cognitive dysfunction in SAH survivors, highlighting their prevalence, impact, and gaps in assessment and management. A total of 2243 publications were screened across three databases (PubMed, EMBASE, and Web of Science), which resulted in 115 studies analyzed for review. Sleep disturbances—including insomnia, hypersomnia, and sleep apnea—are common across all phases of recovery and are closely linked to fatigue, mood disorders, and impaired cognitive function. Cognitive deficits, particularly in memory, executive function, and attention, persist in most survivors and are significant barriers to return to work and reintegration. Despite their clinical relevance, these domains are underrepresented in SAH research and inadequately captured by standard outcome measures such as the modified Rankin Scale. Compared to moderate-to-severe traumatic brain injury (TBI), the SAH literature lacks standardized assessment tools, longitudinal data, and interventional studies. Neuroinflammation may underlie both sleep and cognitive sequelae, offering a potential therapeutic target. This review underscores the need for patient-centered outcome measures, integrated sleep and cognitive assessments, and targeted interventions to improve long-term brain health in SAH survivors.

Traumatic Brain Injury (TBI) is a debilitating condition that poses a significant public health concern. Historically linked to motor vehicle accidents, the epidemiology of TBI has evolved. Falls now emerge as the predominant cause, particularly among older adults. Sport-related TBIs have also garnered increased attention due to concerns regarding long-term neurological sequelae. To date, therapeutic interventions remain limited and have yet to yield substantial clinical benefits. Cell-based therapies offer promising avenues for neural repair and regeneration: endogenous stem cell therapies capitalize on endogenous pools that can be triggered by the injury and further enhanced by therapeutic approaches. In contrast, exogenous cell therapies provide an exogenous source of cells. However, challenges such as age-related decline in neurogenesis, age-related inflammation, and the heterogeneity of TBI present significant hurdles to overcome. Moreover, translating stem cell research from the laboratory to clinical applications necessitates the adherence to good manufacturing practice standards, which presents distinct obstacles. Addressing these challenges requires a multifaceted approach, including careful patient selection in clinical trials, appropriate experimental models, and the optimization of therapeutic techniques. Ultimately, a combination of strategies is likely to yield the most promising outcomes in the pursuit of effective TBI therapies.

Background and purpose Spinal cerebrospinal fluid (CSF) leaks may cause a myriad of symptoms, most common being orthostatic headache. In addition, ventral spinal CSF leaks are a possible etiology of superficial siderosis (SS), a rare condition characterized by hemosiderin deposits in the central nervous system (CNS). The classical presentation of SS involves ataxia, bilateral hearing loss, and myelopathy. Unfortunately, treatment options are scarce. This study was undertaken to evaluate whether microsurgical closure of CSF leaks can prevent further clinical deterioration or improve symptoms of SS. Methods This cohort study was conducted using data from a prospectively maintained database in two large spontaneous intracranial hypotension (SIH) referral centers in Germany and Switzerland of patients who meet the modified International Classification of Headache Disorders, 3rd edition criteria for SIH. Patients with spinal CSF leaks were screened for the presence of idiopathic infratentorial symmetric SS of the CNS. Results Twelve patients were included. The median latency between the onset of orthostatic headaches and symptoms attributed to SS was 9.5 years. After surgical closure of the underlying spinal CSF leak, symptoms attributed to SS improved in seven patients and remained stable in three. Patients who presented within 1 year after the onset of SS symptoms improved, but those who presented in 8–12 years did not improve. We could show a significant association between patients with spinal longitudinal extrathecal collections and SS. Conclusions Long‐standing untreated ventral spinal CSF leaks can lead to SS of the CNS, and microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with SS in a time‐dependent manner. Long‐standing untreated ventral spinal cerebrospinal fluid (CSF) leaks can lead to superficial siderosis of the central nervous system. Microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with superficial siderosis in a time‐dependent manner. Therefore, searching for spinal CSF leaks in all patients with superficial siderosis with a thorough workup is strongly recommended.

Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. It arises from mutational changes in immunoglobulin light chains. To explore whether these mutations may affect the structure of the formed fibrils, we determine and compare the fibril structures from several patients with cardiac AL amyloidosis. All patients are affected by light chains that contain an IGLV3-19 gene segment, and the deposited fibrils differ by the mutations within this common germ line background. Using cryo-electron microscopy, we here find different fibril structures in each patient. These data establish that the mutations of amyloidogenic light chains contribute to defining the fibril architecture and hence the structure of the pathogenic agent. Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. Here the authors analyse the structures of AL amyloid fibrils with different light chain mutations and show that the mutations contribute to defining the fibril structure in different patients.

Systemic ALys amyloidosis is a debilitating protein misfolding disease that arises from the formation of amyloid fibrils from C-type lysozyme. We here present a 2.8 Å cryo-electron microscopy structure of an amyloid fibril, which was isolated from the abdominal fat tissue of a patient who expressed the D87G variant of human lysozyme. We find that the fibril possesses a stable core that is formed by all 130 residues of the fibril precursor protein. There are four disulfide bonds in each fibril protein that connect the same residues as in the globularly folded protein. As the conformation of lysozyme in the fibril is otherwise fundamentally different from native lysozyme, our data provide a structural rationale for the need of protein unfolding in the development of systemic ALys amyloidosis. Here the authors perform the reconstruction and analysis of pathological ALys amyloid fibrils extracted from fat tissue from a patient carrying the D87G variant. They reveal an intact amyloid fibril with no evidence of proteolysis and four intact disulphide bonds.

Systemic AA amyloidosis is a debilitating protein misfolding disease in humans and animals. In humans, it occurs in two variants that are called ‘vascular’ and ‘glomerular’, depending on the main amyloid deposition site in the kidneys. Using cryo electron microscopy, we here show the amyloid fibril structure underlying the vascular disease variant. Fibrils purified from the tissue of such patients are mainly left-hand twisted and contain two non-equal stacks of fibril proteins. They contrast in these properties to the fibrils from the glomerular disease variant which are right-hand twisted and consist of two structurally equal stacks of fibril proteins. Our data demonstrate that the different disease variants in systemic AA amyloidosis are associated with different fibril morphologies. This study reports the cryo-EM structures of AA amyloid fibrils from two patients with vascular AA amyloidosis. The findings imply that different disease variants in systemic amyloidosis are associated with different fibril structures.

The therapeutic efficacy of mesenchymal stromal cells (MSCs) has been shown to rely on their immunomodulatory and regenerative properties. In order to obtain sufficient numbers of cells for clinical applications, MSCs have to be expanded ex vivo. Expansion media with xenogeneic-free (XF) growth-promoting supplements like human platelet lysate (PL) or serum- and xenogeneic-free (SF/XF) formulations have been established as safe and efficient, and both groups provide different beneficial qualities. In this study, MSCs were expanded in XF or SF/XF media as well as in mixtures thereof. MSCs cultured in these media were analyzed for phenotypic and functional properties. MSC expansion was optimal with SF/XF conditions when PL was present. Metabolic patterns, consumption of growth factors, and secretome of MSCs differed depending on the type and concentration of supplement. The lactate per glucose yield increased along with a higher proportion of PL. Many factors in the supernatant of cultured MSCs showed distinct patterns depending on the supplement (e.g., FGF-2, TGFβ, and insulin only in PL-expanded MSC, and leptin, sCD40L PDGF-AA only in SF/XF-expanded MSC). This also resulted in changes in cell characteristics like migratory potential. These findings support current approaches where growth media may be utilized for priming MSCs for specific therapeutic applications.