Cascadia Journal of Biomedical Research - Articles

Gupta, V.

Czirok, S., Tislér, A., Nagy, G., Tapolyai, M.

Czirok, S., Tislér, A., Nagy, G., Tapolyai, M.

Strouza, A., Lawrence, A., Dimitrova, L., Vissia, E., Chalavi, S., Veltman, D., Reinders, A.

Background Dissociative identity disorder (DID) manifests with distinct trauma-avoidant and trauma-related identity states. Overtly conscious trauma-related knowledge processing is identity state-dependent. Previous research on covertly subconscious knowledge processing in DID lacks subject-specific trauma-related stimuli. Aims Our controlled functional magnetic resonance imaging (fMRI) study explored neural and behavioural differences of overt and covert knowledge processing of individualised self-relevant words in DID. Method Behavioural data were gathered while 56 participants underwent task-based fMRI: 14 with DID, 14 DID simulators and a paired control group of 14 healthy controls and 14 participants with post-traumatic stress disorder. Individuals with DID and simulators participated in a trauma-avoidant and a trauma-related identity state. Reaction times and brain activation following overtly and covertly presented individualised words were statistically analysed. Results Behavioural analyses showed a main effect of consciousness (P < 0.001). Post hoc between-group pairwise comparisons revealed slower reaction times for individuals with DID compared with simulating (P < 0.05) and paired controls (P < 0.05). Neural data analyses showed increased brain activation in frontal and parietal regions within the diagnosed DID group, especially during overt processing. Between-group comparisons mostly showed less pronounced activation in frontal, occipital and temporal areas. Conclusions The present study showed increased cognitive control during overt self-relevant knowledge processing in the trauma-avoidant identity state of DID, in line with previous research. The slower reaction times and increased frontoparietal activation shown in individuals with diagnosed DID, as compared with both control groups, support the notion of cognitive avoidance of trauma-related information in DID and further reinforce the authenticity of DID experiences.

Wen, H., Zheng, S., Zhu, X., Wang, L., Chen, D.

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic malignancy with a complex tumor microenvironment (TME) that shapes disease progression and therapeutic resistance. Despite advances in immune checkpoint inhibitors (ICIs) and targeted therapies, clinical responses remain heterogeneous, underscoring the need for a deeper understanding of RCC immunobiology. This review comprehensively examines the immunosuppressive TME of RCC, emphasizing the roles of cytotoxic and immunosuppressive immune cells, carcinoma-associated fibroblasts (CAFs), abnormal vasculature, and extracellular matrix (ECM) remodeling in fostering immune evasion. This review summarized emerging biomarkers—including PD-L1 expression, tumor mutational burden (TMB), gene mutations, and immune-based subtypes—that may predict ICI response. Furthermore, we evaluate current immunotherapeutic strategies, such as ICIs, combination therapies, and novel approaches targeting immunosuppressive cells and metabolic pathways. While combination therapies have improved outcomes, challenges like toxicity and resistance persist, necessitating biomarker-driven patient stratification and optimized treatment sequencing. Future directions should focus on deciphering TME heterogeneity and developing precision immunotherapy strategies to enhance clinical efficacy in RCC.

Watanabe, S., Marchetti, M., Hartmann, J., Hansen, F.

Age-related hearing loss (ARHL) is the most common cause of hearing loss in the elderly. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme involved in several types of human disease. The present study aimed to investigate the effect of UCHL1 on a hydrogen peroxide (H 2 O 2 )-induced ARHL model in cochlear hair cells and uncover its underlying mechanism. Reverse transcription-quantitative (RT-q)PCR and western blot analysis were used to assess UCHL1 expression in HEI-OC1 cells exposed to H 2 O 2 . Following UCHL1 overexpression in H 2 O 2 -induced HEI-OC1 cells, cell activity was assessed by Cell Counting Kit-8 assay. The content of oxidative stress-associated markers including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and reactive oxygen species (ROS ) was measured using corresponding commercial kits. Cell apoptosis was evaluated by TUNEL assay and western blot analysis. Cell senescence was assessed by senescence-associated β-galactosidase staining and western blot analysis. RT-qPCR and western blot analysis were applied to measure mRNA and protein expression levels, respectively, of specificity protein 1 (Sp1) in H 2 O 2 -treated HEI-OC1 cells. In addition, the association between UCHL1 and Sp1 was verified by luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The mRNA and protein expression levels of UCHL1 were also determined in Sp1-overexpressing cells by RT-qPCR and western blot analysis, respectively. Following Sp1 overexpression in UCHL1-overexpressing H 2 O 2 -treated HEI-OC1 cells, cell activity, oxidative stress, apoptosis and senescence were assessed. Finally, the expression levels of NF-κB signaling-related proteins p-NF-κB p65 and NF-κB p65 were detected using western blot analysis. The results showed that UCHL1 was downregulated in H 2 O 2 -treated HEI-OC1 cells. In addition, UCHL1 overexpression enhanced cell viability and promoted oxidative damage, apoptosis and senescence in H 2 O 2 -induced HEI-OC1 cells. Furthermore, Sp1 was upregulated in H 2 O 2 -treated HEI-OC1 cells. Additionally, luciferase reporter and ChIP assays demonstrated that Sp1 interacted with the UCHL1 promoter to inhibit UCHL1 transcription. Sp1 overexpression reversed the effect of UCHL1 overexpression on cell viability, oxidative stress, apoptosis, senescence and activation of the NF-κB signaling pathway in H 2 O 2- exposed HEI-OC1 cells. Collectively, the results suggested that UCHL1 transcriptional suppression by Sp1 protected cochlear hair cells from H 2 O 2 -triggered senescence and oxidative damage.

Zeng, B., Mechin, I., Mowrey, D., Rivera, G., Nyvall, H., Suresh, S., Burke, J., Harriman, W., Chen, B., Abdiche, Y.

Next-generation antibodies include a growing number of bispecific and multispecific antibodies that are commonly used to redirect the immune system to fight cancer. Herein, we assessed the depth and breadth of epitope coverage as a proxy for functional diversity in human immune repertoires produced by two complementary in vivo platforms utilizing a common light chain, in a chicken (OmniClicTM) or rat (OmniFlic®) host species. We adopted NKp46 as a model to target antigen due to its use in emerging natural killer (NK) immune engagers that are being explored clinically as potentially safer alternatives to traditional CD3-based T cell engagers. To probe the epitope diversity of our antibody repertoires, we performed a detailed high throughput epitope binning study using surface plasmon resonance and corroborated our binning assignments with epitope mapping data deduced from hydrogen deuterium exchange mass spectrometry. Our results revealed broad epitope coverage and nuanced diversity both within and across repertoires, with few epitopes shared, suggesting that the complementary use of OmniClicTM and OmniFlic® produces more comprehensive coverage than either alone. Furthermore, our epitope binning assignments aligned with our complementarity-determining region-based sequence lineage assignments, enabling a direct comparison of sequence diversity across Clic and Flic repertoires despite their use of different scaffolds, a single functionally rearranged V(D)J scaffold versus multiple combinatorially assembled V(D)J scaffolds, respectively. The rich epitope diversity of both OmniClicTM and OmniFlic® yielded multiple candidates for functional NK activators, as determined in an antibody-dependent cellular cytotoxicity assay, demonstrating their value as building blocks in constructing optimized immune engagers.

Sharma, A., Bellini, G., Mahmoud, Y.

Breast cancer have attracted growing attention because of their relevance to both theory and practice. We find a significant association after adjustment for age, sex and baseline severity. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a 23% relative reduction in the primary outcome. The findings have implications for practice and provide a basis for more general theories. Previous work on cardiac fibrosis has produced conflicting results, partly because of differences in design and data. We find a significant association after adjustment for age, sex and baseline severity, and we show that the result is stable under a range of perturbations of the assumptions. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find no evidence of an effect on the secondary outcomes. Together, these results contribute to a more complete picture and open the way to further applications. Postoperative delirium have attracted growing attention because of their relevance to both theory and practice. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a significant association after adjustment for age, sex and baseline severity. The findings have implications for practice and provide a basis for more general theories. Previous work on COVID-19 vaccination has produced conflicting results, partly because of differences in design and data. We find that elevated levels at baseline predicted poor prognosis. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find that elevated levels at baseline predicted poor prognosis. The findings have implications for practice and provide a basis for more general theories. Despite considerable progress in recent years, several fundamental questions about gut microbiota remain open. We find no evidence of an effect on the secondary outcomes. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. We discuss limitations of the present study and outline how the methods can be extended. Understanding asthma in children is of central importance, yet existing approaches rely on restrictive assumptions. We find that elevated levels at baseline predicted poor prognosis, and we show that the result is stable under a range of perturbations of the assumptions. We discuss limitations of the present study and outline how the methods can be extended. Understanding insulin signaling is of central importance, yet existing approaches rely on restrictive assumptions. We find a 23% relative reduction in the primary outcome. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. We find a significant association after adjustment for age, sex and baseline severity, and we show that the result is stable under a range of perturbations of the assumptions. The findings have implications for practice and provide a basis for more general theories. Previous work on insulin signaling has produced conflicting results, partly because of differences in design and data. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a 23% relative reduction in the primary outcome. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a significant association after adjustment for age, sex and baseline severity. We discuss limitations of the present study and outline how the methods can be extended. Despite considerable progress in recent years, several fundamental questions about hepatocellular carcinoma remain open. We find that elevated levels at baseline predicted poor prognosis. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a 23% relative reduction in the primary outcome. These results clarify the role of the underlying mechanisms and suggest several directions for future work. Understanding asthma in children is of central importance, yet existing approaches rely on restrictive assumptions. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find that elevated levels at baseline predicted poor prognosis. These results clarify the role of the underlying mechanisms and suggest several directions for future work. Despite considerable progress in recent years, several fundamental questions about chronic kidney disease remain open. We find a significant association after adjustment for age, sex and baseline severity, and we show that the result is stable under a range of perturbations of the assumptions. We find a distinct transcriptional program in the responding group. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. These results clarify the role of the underlying mechanisms and suggest several directions for future work. Previous work on chronic kidney disease has produced conflicting results, partly because of differences in design and data. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a distinct transcriptional program in the responding group. We find that elevated levels at baseline predicted poor prognosis, and we show that the result is stable under a range of perturbations of the assumptions. Together, these results contribute to a more complete picture and open the way to further applications. Neuroinflammation have attracted growing attention because of their relevance to both theory and practice. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a significant association after adjustment for age, sex and baseline severity. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find that elevated levels at baseline predicted poor prognosis. These results clarify the role of the underlying mechanisms and suggest several directions for future work. Understanding insulin signaling is of central importance, yet existing approaches rely on restrictive assumptions. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a significant association after adjustment for age, sex and baseline severity. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find that elevated levels at baseline predicted poor prognosis. We discuss limitations of the present study and outline how the methods can be extended.

Mahdavi, H., Kaveh, V., Ijadi Nasrabadi, M., Karimi, M., Azizmohammad Looha, M.

Background and Aims Gastrointestinal neuroendocrine neoplasms (g‐NENs) represent a heterogeneous group of tumors with variable prognoses. Inflammation‐based markers, such as the neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR), have emerged as potential prognostic indicators in various malignancies. This study aimed to evaluate the prognostic significance of NLR and PLR in g‐NENs and their associations with histopathological features and survival outcomes. Methods A retrospective, cross‐sectional study was conducted on 80 patients with histologically confirmed g‐NENs from April 2017 to March 2019. Baseline NLR and PLR were calculated, and their relationships with tumor grade, Ki‐67 proliferation index, metastatic status, and survival outcomes were analyzed. Cox regression and logistic regression models were used to determine independent prognostic factors. Results The hazard of death was approximately one‐third in the low NLR group after adjusting for metastasis and tumor grade (HR = 0.33, 95% CI: 0.14–0.80, p < 0.05). Elevated PLR was associated with poor outcomes; however, the difference between the high and low PLR groups was not statistically significant. Higher tumor grades and elevated Ki‐67 indices correlated with worse survival and increased metastatic potential (p < 0.001). No significant associations were observed for CRP or ESR levels with survival. Conclusion Our findings suggest that NLR may serve as an independent and accessible prognostic marker in g‐NENs, potentially offering a cost‐effective tool to support clinical decision‐making. The combined assessment of inflammatory biomarkers and histopathological parameters could improve prognostic accuracy and help guide personalized management strategies in patients with g‐NENs. Nevertheless, these observations should be interpreted with caution due to the retrospective, single‐center design and limited sample size. Future large‐scale, prospective studies are warranted to confirm and expand upon these results.

Kuznetsov, T., Yılmaz, L.

Understanding tumor-infiltrating lymphocytes is of central importance, yet existing approaches rely on restrictive assumptions. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a distinct transcriptional program in the responding group. We find no evidence of an effect on the secondary outcomes. The analysis uses a combination of rigorous arguments and extensive numerical or empirical checks. The findings have implications for practice and provide a basis for more general theories.