Faculty Bibliography

BACKGROUND:Primary central nervous system lymphoma (PCNSL) is a highly aggressive subtype of non-Hodgkin lymphoma that is confined to the central nervous system. PCNSL is associated with a poor 5-year survival rate of 30-40%, partly due to a high recurrence rate of 60%. A comprehensive understanding of the molecular signatures and mechanisms underlying drug resistance in PCNSL is crucial, as it has significant implications for therapeutic strategies. METHODS:A cohort of 56 newly diagnosed PCNSL patients was generated. The tumor specimens were obtained by biopsy. A combined approach, including single-cell transcriptomics and B-cell receptor sequencing, transcriptome-informed multiplex immunohistochemistry, and ex-vivo drug response assays, was applied to reveal the transcriptional and immune microenvironment landscape of PCNSL. RESULTS:We identify four main B cell subtypes, each characterized by distinct transcriptomic profiles, from malignant B cells in PCNSL. Among these subtypes, plasmablast-like lymphoma cells (PBLCs), characterized by upregulated genes typically associated with plasma cell differentiation, comprise 1.3%-8.1% of malignant B cells and correlate with poor prognosis in PCNSL. PBLCs exhibit reduced expression of CD20, Bruton tyrosine kinase, and FAS, resulting in drug resistance and immune evasion. In addition, PBLCs elevate the expression of critical transcription factors, including XBP1 and PRDM1, to maintain their phenotype. Clinical drugs, such as Lenalidomide, demonstrate potential cytotoxic effects on PBLCs. CONCLUSIONS:These findings highlight PBLCs as a distinct subtype of malignant B cells that plays a critical role in the multidrug resistance of PCNSL and reveal the molecular signature of PBLCs that can be targeted for therapy.

Ferroptosis is a form of regulated cell death characterized by iron accumulation and increased lipid peroxidation, primarily counteracted by a range of antioxidant molecules, including glutathione (GSH), glutathione peroxidase 4 (GPX4), ubiquinone, tetrahydrofolate, and nuclear respiratory factor 2. Furthermore, the process of ferroptosis is intricately influenced by the opposing actions of the p53 tumor suppressor gene and activated transcription factors 3 and 4, which can either facilitate or hinder ferroptotic cell death depending on the cellular context. This form of cell death is significantly associated with various pancreatic disorders, including both acute and chronic pancreatitis, as well as diabetes mellitus. In this review, we thoroughly investigate the mechanisms underlying ferroptosis, focusing on iron overload, lipid peroxidation, and the regulatory molecules involved in ferroptosis modulation (notably the system xc-/GSH/GPX4 axis), along with the relevant signaling pathways. We also examine the role of ferroptosis in non-neoplastic pancreatic diseases such as pancreatitis and diabetes mellitus while identifying novel therapeutic agents that target ferroptosis, potentially paving the way for innovative treatment strategies for pancreatic conditions.

Solute carrier family 7 member 11 (SLC7A11), or xCT, is a cystine-glutamate antiporter crucial for maintaining cellular antioxidant capacity through the uptake of cystine, which is vital for glutathione synthesis. This protein plays an important role in regulating ferroptosis, an iron-dependent form of cell death. Fibrosis, a pathological condition characterized by the excessive accumulation of fibrous connective tissue, is a health challenge because it can lead to organ dysfunction and failure. Emerging evidence links SLC7A11 to the regulation of fibrosis through its involvement in ferroptosis and other mechanisms. This review aims to explore the effects of SLC7A11 on fibrotic diseases in various organs. We will delve into both ferroptosis-dependent and -independent pathways and propose therapeutic strategies that target SLC7A11 to mitigate fibrosis, emphasizing the need for cell-type-specific interventions. This review provides a foundational understanding for the development of targeted treatments involving SLC7A11 for managing fibrotic diseases.

Digestive-system cancers represent major threats to human health; however, the mechanisms underlying tumorigenesis and radiochemotherapy resistance have remained elusive. Therefore, an urgent need exists for identifying key drivers of digestive system tumorigenesis and novel targeted therapeutics. The checkpoint kinase 2 (Chk2) regulates cell-cycle progression, and Chk2 dysregulation or Chk2 mutations can lead to the development of various cancers, which makes Chk2 an important research topic. This review summarizes the roles of Chk2 in DNA-damage responses, cell-cycle regulation, autophagy, and homeostasis maintenance. We describe relationships between tumorigenesis and cell-cycle dysregulation induced by Chk2 mutations. In addition, we summarize evidence indicating that Chk2 can serve as a novel therapeutic target, based on its contributions to radiochemotherapy-resistance reversion and progress made in developing antitumor agents against Chk2. The prevailing evidence supports the conclusion that further research on Chk2 will provide a deeper understanding of digestive-system tumorigenesis and should suggest novel therapeutic targets.

People with blindness and low vision (pBLV) encounter substantial challenges when it comes to comprehensive scene recognition and precise object identification in unfamiliar environments. Additionally, due to the vision loss, pBLV have difficulty in accessing and identifying potential tripping hazards independently. Previous assistive technologies for the visually impaired often struggle in real-world scenarios due to the need for constant training and lack of robustness, which limits their effectiveness, especially in dynamic and unfamiliar environments, where accurate and efficient perception is crucial. Therefore, we frame our research question in this paper as: How can we assist pBLV in recognizing scenes, identifying objects, and detecting potential tripping hazards in unfamiliar environments, where existing assistive technologies often falter due to their lack of robustness? We hypothesize that by leveraging large pretrained foundation models and prompt engineering, we can create a system that effectively addresses the challenges faced by pBLV in unfamiliar environments. Motivated by the prevalence of large pretrained foundation models, particularly in assistive robotics applications, due to their accurate perception and robust contextual understanding in real-world scenarios induced by extensive pretraining, we present a pioneering approach that leverages foundation models to enhance visual perception for pBLV, offering detailed and comprehensive descriptions of the surrounding environment and providing warnings about potential risks. Specifically, our method begins by leveraging a large-image tagging model (i.e., Recognize Anything Model (RAM)) to identify all common objects present in the captured images. The recognition results and user query are then integrated into a prompt, tailored specifically for pBLV, using prompt engineering. By combining the prompt and input image, a vision-language foundation model (i.e., InstructBLIP) generates detailed and comprehensive descriptions of the environment and identifies potential risks in the environment by analyzing environmental objects and scenic landmarks, relevant to the prompt. We evaluate our approach through experiments conducted on both indoor and outdoor datasets. Our results demonstrate that our method can recognize objects accurately and provide insightful descriptions and analysis of the environment for pBLV.

The novel COVID-19 pneumonia caused by the SARS-CoV-2 virus poses a significant threat to human health. Scientists have made significant efforts to control this virus, consequently leading to the development of novel research methods. Traditional animal and 2D cell line models might not be suitable for large-scale applications in SARS-CoV-2 research owing to their limitations. As an emerging modelling method, organoids have been applied in the study of various diseases. Their advantages include their ability to closely mirror human physiology, ease of cultivation, low cost, and high reliability; thus, they are considered to be a suitable choice to further the research on SARS-CoV-2. During the course of various studies, SARS-CoV-2 was shown to infect a variety of organoid models, exhibiting changes similar to those observed in humans. This review summarises the various organoid models used in SARS-CoV-2 research, revealing the molecular mechanisms of viral infection and exploring the drug screening tests and vaccine research that have relied on organoid models, hence illustrating the role of organoids in remodelling SARS-CoV-2 research.

The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel's state. Moreover, we discovered a protonation-independent voltage activation of the PAC channel that appears to operate through an ion-flux gating mechanism. Through scanning-mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel's proton gating while sparing the voltage-dependent gating. This proton-sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton-sensing mechanisms in the PAC channel that may inspire potential drug development.

INTRODUCTION/UNASSIGNED:Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among all solid tumors. Tumorigenesis is promoted by the oncogene KRAS, and KRAS mutations are prevalent in patients with PDAC. Therefore, a comprehensive understanding of the interactions between KRAS mutations and PDAC may expediate the development of therapeutic strategies for reversing the progression of malignant tumors. Our study aims at establishing and validating a prediction model of KRAS mutations in patients with PDAC based on survival analysis and mRNA expression. METHODS/UNASSIGNED:A total of 184 and 412 patients with PDAC from The Cancer Genome Atlas (TCGA) database and the International Cancer Genome Consortium (ICGC), respectively, were included in the study. RESULTS/UNASSIGNED:After tumor mutation profile and copy number variation (CNV) analyses, we established and validated a prediction model of KRAS mutations, based on survival analysis and mRNA expression, that contained seven genes: CSTF2, FAF2, KIF20B, AKR1A1, APOM, KRT6C, and CD70. We confirmed that the model has a good predictive ability for the prognosis of overall survival (OS) in patients with KRAS-mutated PDAC. Then, we analyzed differential biological pathways, especially the ferroptosis pathway, through principal component analysis, pathway enrichment analysis, Gene Ontology (GO) enrichment analysis, and gene set enrichment analysis (GSEA), with which patients were classified into low- or high-risk groups. Pathway enrichment results revealed enrichment in the cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450, and viral protein interaction with cytokine and cytokine receptor pathways. Most of the enriched pathways are metabolic pathways predominantly enriched by downregulated genes, suggesting numerous downregulated metabolic pathways in the high-risk group. Subsequent tumor immune infiltration analysis indicated that neutrophil infiltration, resting CD4 memory T cells, and resting natural killer (NK) cells correlated with the risk score. After verifying that the seven gene expression levels in different KRAS-mutated pancreatic cancer cell lines were similar to that in the model, we screened potential drugs related to the risk score. DISCUSSION/UNASSIGNED:This study established, analyzed, and validated a model for predicting the prognosis of PDAC based on risk stratification according to KRAS mutations, and identified differential pathways and highly effective drugs.

It is estimated that 20 million people in the United States have gallbladder disease. Of the patients who present to the Emergency Department (ED) with abdominal pain, 3-10% have acute cholecystitis. Point-of-care ultrasound (POCUS) evaluation of the biliary system is a valuable tool to diagnose gallbladder disease and can greatly expedite the diagnostic evaluation of patients. One source of error in POCUS of the gallbladder is imaging nearby structures that can mimic the gallbladder, such as the duodenum.