Umeå University's logo

Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.

Contamination of plastic particles in environmental and biological systems raises concerns regarding their potential negative impacts. Human exposure to microplastics (MPs) and nanoplastics (NPs) is increasing; however, some potential adverse health effects might remain unclear, due to analytical challenges in detecting trace concentrations. To address this, we propose a workflow for NPs assessment in biological samples combining three complimentary methods, namely inductively coupled plasma mass spectrometry (ICP-MS), X-ray fluorescence imaging (XFI), and imaging mass cytometry (IMC) to detect palladium-doped NPs (Pd-NPs). This approach was used to quantify the temporal distribution and accumulation of Pd-NPs in mouse models under different experimental conditions, dosages, and time frames. Acute exposure showed a clear particle excretion from the gastrointestinal tract into feces, while subchronic exposure led to tissue accumulation. This workflow enhances our ability to analyze and study NP uptake and biodistribution mechanisms down to the nanoscale in complex biological samples.

In this study, we investigate the efficacy of optical photothermal infrared (O-PTIR) spectroscopy, also known as mid-infrared photothermal (MIP) microscopy, for label-free and nondestructive detection of micro- and nanoplastics (MNPs) down to diameters of 200 nm in mammalian tissues. Experiments with both in vitro three-dimensional cell cultures derived from HTC116 colorectal cancer cell line and in vivo mouse tissue models were conducted. Spherical polystyrene particles served as reliable model systems for evaluating spatial resolution limits and quality of spectra. Our findings demonstrate the superior resolution of O-PTIR in imaging individual particles of 200 nm in mouse kidney tissues, surpassing the capabilities of traditional Fourier transform infrared (FTIR) spectroscopy. Furthermore, we apply a semiautomated image analysis that incorporates machine learning algorithms to accelerate the detection process, thus improving throughput and minimizing the potential for human error. The results confirm that O-PTIR is able to provide high-quality, artifact-free spectral images in a contact-less manner and significantly outperforms traditional infrared spectroscopy in terms of spatial resolution and signal-to-noise ratio in complex biological matrices.

Background: To validate the clinical utility of a previously identified circulating tumor DNA methylation marker (meth-ctDNA) panel for disease detection and survival outcomes, meth-ctDNA markers were compared to PSA levels and PSMA PET/CT findings in men with different stages of prostate cancer (PCa).

Methods: 122 PCa patients who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT and plasma sampling (03/2019–08/2021) were analyzed. cfDNA was extracted, and a panel of 8 individual meth-ctDNA markers was queried. PET scans were qualitatively and quantitatively assessed. PSA and meth-ctDNA markers were compared to PET findings, and their relative prognostic value was evaluated.

Results: PSA discriminated best between negative and tumor-indicative PET scans in all (AUC 0.77) and hormone-sensitive (hsPC) patients (0.737). In castration-resistant PCa (CRPC), the meth-ctDNA marker KLF8 performed best (AUC 0.824). CHST11 differentiated best between non- and metastatic scans (AUC 0.705) overall, KLF8 best in hsPC and CRPC (AUC 0.662, 0.85). Several meth-ctDNA markers correlated low to moderate with the tumor volume in all (5/8) and CRPC patients (6/8), while PSA levels correlated moderately to strongly with the tumor volume in all groups (all p < 0.001). CRPC overall survival was independently associated with LDAH and PSA (p = 0.0168, p < 0.001).

Conclusion: The studied meth-ctDNA markers are promising for the minimally-invasive detection and prognostication of CRPC but do not allow for clinical characterization of hsPC. Prospective studies are warranted for their use in therapy response and outcome prediction in CRPC and potential incremental value for PCa monitoring in PSA-low settings.

Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis¹. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions1^1,2,3. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism⁴. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-α (HIF1α) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases⁵.

Nano- and microplastics (NMPs) are increasingly raising concerns about their potential health effects. Traditional methods for detection and characterization of NMPs in tissue require elaborate sample preparation, such as labelling or time-consuming tissue digestion. In this contribution we report on the application of optical photothermal infrared spectroscopy (O-PTIR) for localization and identification of plastic particles smaller than 1 µm. We show that the method can be applied to routine clinical tissue samples, preserving tissue architecture while accurately locating NMPs. Since this technique is label-free, contactless and non-destructive it can be applied prior to routine histopathology. We present results on various types of clinical samples, among them 3D cell cultures, mouse kidney tissue and human colon tissue.

Microplastic (MP) pollution is increasingly acknowledged as a critical environmental and public health issue. This study sought to establish a robust, clinically compatible method for detecting MP particles in deparaffinized formalin-fixed paraffin-embedded (FFPE) human colon tissue sections, using protocols compatible with routine clinical pathology. We employed mid-infrared photothermal (MIP) microscopy—also referred to as optical photothermal infrared (OPTIR) spectroscopy—as a non-destructive, high-resolution technique for chemical characterization and spatial mapping of polymer particles in intact FFPE samples. Following OPTIR analysis, identical sections underwent hematoxylin and eosin (H&E) staining to facilitate precise histopathological evaluation in defined regions of interest. Using this integrated workflow, we detected and localized polyethylene (PE), polystyrene (PS), and polyethylene terephthalate (PET) particles (21 PE particles, 1 PS particle, and 1 PET fiber) within distinct tissue areas. Subsequent histological assessment revealed characteristic inflammatory features near to these identified MP particles. To our knowledge, this represents the first demonstration of a diagnostic workflow that enables combined infrared spectroscopic and histopathological analysis of MPs in routinely processed human FFPE tissue. This approach offers a promising avenue to elucidate the role of microplastic accumulation in human disease and supports further investigation into potential mechanistic links between MP exposure and inflammatory processes in the colon.

Introduction: Sinonasal squamous cell carcinoma (SNSCC) is a rare malignancy with limited data on effective treatment modalities in the recurrent and/or metastatic (r/m) setting. While immune checkpoint inhibitors (ICIs) have shown promise in treating head and neck cancers, in general, their effects in SNSCC remain poorly understood. Furthermore, SNSCC patients are frequently excluded from clinical trials, limiting the evidence base for ICI efficacy in this specific subgroup. Therefore, our study evaluated the efficacy and safety of single-agent ICI therapy in r/m SNSCC.

Methods: We conducted a retrospective multicenter analysis of all r/m SNSCC patients treated with single-agent ICIs from July 2018 to December 2023 at two tertiary reference centers.

Results: A total of 18 patients received either Pembrolizumab (n = 8) or Nivolumab (n = 10) for r/m SNSCC. The overall response rate (ORR) to immunotherapy was 11.1% (2/18), with a disease control rate (DCR) of 27.8% (5/18) and a mean PFS and OS of 11.7 (95% CI: 2.3–21.0) months and 18.9 (95% CI: 8.3–29.5) months respectively. Two (11.1%) immune-related adverse events led to treatment discontinuation. Univariable analysis revealed high pathological grading (p = 0.049) as a negative prognostic factor for PFS. In an exploratory comparison with a larger cohort of 121 patients with r/m SCC of the larynx, oropharynx, hypopharynx, or oral cavity receiving ICI therapy, outcomes in SNSCC appeared broadly similar, with no statistically significant differences in PFS (p = 0.153), OS (p = 0.152), ORR (p = 0.401), or DCR (p = 0.359).

Conclusion: Immunotherapy may represent a treatment option for patients with SNSCC. Given the limited sample size, these results should be interpreted with caution. Our findings highlight the urgent need to include SNSCC patients in future prospective trials to clarify the role of immunotherapy in this underrepresented population.

Background Prognosis and quality of life in patients with advanced cutaneous T-cell lymphoma (CTCL), particularly in those with Sézary syndrome (SS) or advanced-stage mycosis fungoides (MF), are poor. Monoclonal antibodies or antibody–drug conjugates (ADCs) have been added into CTCL treatment algorithms, but the spectrum of antibody-targetable cell surface antigens in T-cell non-Hodgkin lymphomas (T-NHLs) is limited.

Objectives To evaluate the expression of the major histocompatibility complex class II chaperone CD74 in common subtypes of CTCL by various methods, and to explore the efficacy of targeting CD74 in CTCL cells with an anti-CD74 ADC in vitro and in vivo.

Methods We comprehensively investigated the expression of CD74 in well-defined CTCL cell lines by polymerase chain reaction, immunoblotting and flow cytometry. More than 140 primary CTCL samples of all common subtypes were analysed by immunohistochemistry, flow cytometry, immunofluorescence and ‘co-detection by indexing’ (CODEX) multiplexed tissue imaging, as well as by single-cell RNA sequencing (scRNAseq) analyses. DNA methylation of CTCL cell lines was interrogated by the generation of genome-wide methylation profiling. The effect of a maytansinoid-conjugated humanized ADC against CD74 was investigated in CTCL cell lines in vitro, alone or in combination with gemcitabine, and in vivo after xenotransplantation of CTCL cell lines in NOD-scid Il2rgnull mice.

Results We demonstrated that CD74 is widely and robustly expressed in CTCL cells. In addition, CD74 expression in SS and MF was confirmed by scRNAseq data analysis and was correlated in CTCL cell lines with CD74 DNA hypomethylation. CD74 was rapidly internalized in CTCL cells and CD74 targeting by the ADC STRO-001 efficiently killed CTCL-derived cell lines. Finally, targeting of CD74 synergized with conventional chemotherapy in vitro and eradicated murine xenotransplants of CTCL cell lines in vivo.

Conclusions CD74 is expressed in common CTCL subtypes. Targeting CD74 efficiently killed CTCL cells in vitro and in vivo. We therefore suggest the targeting of CD74 to be a highly promising treatment strategy for CTCL.

Microplastics comprise a heterogeneous group of polymer particles that vary in chemical properties, size, and shape, that may influence their environmental and in vivo behavior. Numerous in vitro and in vivo studies show induction of oxidative stress and metabolic disturbances. Valid critique regarding unrealistically high concentrations or additives within standard materials calls some results into question. Here, we present a novel protocol for the detergent-free production of polyethylene terephthalate (PET) and biodegradable poly(butylenadipat-co-terephthalat) (PBAT) micro- and nanoplastic particles (MNPs) as model microplastics for research. The particles were produced by dissolution precipitation from trifluoroacetic acid (TFA) for PET or tetrahydrofuran (THF)/ethanol for PBAT. Different PET sources were investigated for MNPs production. PET MNPs in the size range of 170–1000 nm with up to 80 % yield were produced from pellets as starting material. Particle size can be adjusted by ultrasounding. The non-toxic concentration range for two commonly used detergents was assessed by means of MTT assay. PET particles with a Zeta-potential of −45 were stable in aqueous suspension with and without detergents at neutral pH. Biodegradable PBAT particles in the micro- and nanometer range were produced by adapting the PET precipitation protocol. These high-yield production protocols provide additive-free authentic PET and PBAT MNPs for research.