Digital Commons Network^™

Registered Replication Report: A Large Multilab Cross-Cultural Conceptual Replication Of Turri Et Al. (2015), Braeden Hall, Kathleen Schmidt, Jordan Wagge, Savannah C. Lewis, Sophia C. Weissgerber, Felix Kiunke, ..., Andree Hartanto

Research Collection School of Social Sciences

According to the justified true belief (JTB) account of knowledge, people can truly know something only if they have a belief that is both justified and true (i.e., knowledge is JTB). This account was challenged by Gettier, who argued that JTB does not explain knowledge attributions in certain situations, later called “Gettier-type cases,” wherein protagonists are justified in believing something to be true, but their belief was correct only because of luck. Laypeople may not attribute knowledge to protagonists with justified but only luckily true beliefs. Although some research has found evidence for these so-called Gettier intuitions, Turri et al. …

Selves As Worlds, Worlds As Selves: A Review Of Worlds We Are (2023), Emerald F. Manlapaz

Akda: The Asian Journal of Literature, Culture, Performance

No abstract provided.

Small-Molecule Ccr4 Antagonists In Cutaneous T-Cell Lymphoma, José S Enriquez, Xiaohong Wang, Loka Reddy Velatooru, Wei Han, Pedram Bijani, Xiao Ni

Faculty, Staff and Student Publications

Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor-4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. Although small-molecule CCR4 antagonists have been studied in other diseases involving CCR4⁺ Th2 cells and regulatory T cells, their effects in CTCL …

Characterization Of Stealth Liposome-Based Nanoparticles Encapsulating Acat1/Soat1 Inhibitor F26: Potential Therapeutics For Niemann-Pick Type C And Other Neurodegenerative Diseases., Junghoon Lee

Dartmouth College Ph.D Dissertations

Cholesterol dysregulation is implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Niemann-Pick type C disease (NPCD). This study focused on evaluating the potent ACAT1 inhibitor, F26, as a therapeutic strategy for NPCD. F26 demonstrated superior ACAT1 inhibition and efficacy compared to the previously studied inhibitor, F12511, both in vitro and in vivo. Notably, F26 exhibited enhanced pharmacokinetic properties, including prolonged duration of action and better brain retention, making it a more promising candidate for treating neurodegenerative diseases.

F26 was encapsulated in a liposome-based nanoparticle system, DSPE-PEG2000 with phosphatidylcholine (PC), for enhancing its …

Selected Aspects Of The Organization Of Tourism And Recreation In Natural Areas With Different Status Of Legal Protection, Marcin Pasek, Dominik Borek

internetowy Kwartalnik Antymonopolowy i Regulacyjny (internet Quarterly on Antitrust and Regulation)

An important place in the strategy of promoting health of modern societies, especially in the post-pandemic world, is played by orienting recommendations on how to spend free time towards tourism and recreation in the natural environment. The utilitarian nature of this type of activity is associated with the need to respect legal provisions, relating to the use of statutory forms of nature conservation, as well as non-statutory protection areas. The aim of the study is to characterize the tourist-recreational use in both of the abovementioned types of ecological habitats, and to indicate the similarities and differences in the conditions of …

Behavioral And Neural Evidence For Perceptual Inference Of Position, Sharif Saleki

Dartmouth College Ph.D Dissertations

Extensive neuroscientific research has advanced our knowledge of the mechanisms involved in the detection and recognition of visual stimuli. However, to guide flexible behavior in a changing world, the brain must also construct stable and coherent perceptual representations from retinal images that are often ambiguous. To resolve ambiguities and uncertainties, the visual system combines its input with other sources of information such as context and prior knowledge to infer the most likely interpretation of a scene. Thus, perception is inherently an inferential process that goes beyond simple detection or recognition of stimuli. Although inference has been studied in many areas …

The Role Of The Basolateral Nuclear Complex & Central Nucleus Of The Amygdala In Fear-Conditioned Responses To External Stimuli And Anxiety Responses, Oluwaseyi A. Adelakun

Senior Theses

This thesis reviews the role of the amygdala, particularly the basolateral nuclear complex (BLA) and central nucleus (CeA), in fear-conditioned responses and generalized anxiety disorder (GAD). By investigating the neurological and physiological mechanisms that influence the amygdala’s fear and anxiety responses, further connections can be made between this region and other notable brain regions, like the prefrontal cortex (PFC). We review both human and rodent models to explore the overlap between the two and explore various therapeutic interventions that regulate amygdalar activity and therefore mitigate anxiety symptoms. Key research into the patient SM, who lacks fear responses due to bilateral …

Participant Engagement And Preference Study For Clinical Outcomes Associated With Atrial Fibrillation: The Pearl-Af Study, Shelby D. Reed, Josephine L. Harrington, Daniel P. Morin, Samir F. Saba, Jay Alan Montgomery, Robert W. Harrison, Daniel R. Frisch, Thomas Viethen, Miriam Tamm, Jessica Xiao, Hardi Mundl, Rosa Coppolecchia, Jui-Chen Yang, Matthew J. Wallace, Juan Marcos Gonzalez, Manesh R. Patel

Division of Cardiology Faculty Papers

Background: Quantifying patients’ preferences for health outcomes associated with atrial fibrillation (AF) and its treatments offers a replicable approach to considering the patient perspective in regulatory decision-making. Objective: The authors conducted a preference survey to estimate the relative importance of AF-related events for use in clinical trial analyses to estimate net health benefits with anticoagulants. Methods: The survey included nontechnical descriptions of three severities of stroke, systemic embolism, myocardial infarction (MI) with or without subsequent heart failure (HF), major bleeding, clinically relevant nonmajor bleeding, and death. A best-worst scaling question format was used in which patients were shown 10 sets …

El Campanario (Volume 1, Issue 1), St. Mary's University

Honors Program Newsletters

No abstract provided.

Blurring Boundaries: A Proposed Research Agenda For Ethical, Legal, Social, And Historical Studies At The Intersection Of Infectious And Genetic Disease, Seethal Jose, Juli Bollinger, Gail Geller, Jeremy Greene, Leslie Meltzer Henry, Brian Hutler, Eric Thomas Juengst, Jeffrey Kahn, Anna Mastroianni, Graham Mooney

Articles

Contemporary understanding of the mechanisms of disease increasingly points to examples of “genetic diseases” with an infectious component and of “infectious diseases” with a genetic component. Such blurred boundaries generate ethical, legal, and social issues and highlight historical contexts that must be examined when incorporating host genomic information into the prevention, outbreak control, and treatment of infectious diseases.

Augmented Reality (Ar) And Virtual Reality (Vr)-Based Data Visualization Frameworks For The Manufacturing Industry, Nitol Saha

Theses and Dissertations

Industry 4.0 is transforming the manufacturing industry by integrating digital technologies throughout the production lifecycle, leading to the development of smart factories. The integration of Augmented Reality (AR) and Virtual Reality (VR) alongside smart manufacturing is transforming traditional industry practices by establishing a robust cyber-physical infrastructure, enhanced data visualization, and improved task execution. This thesis aims to develop AR and VR-based data visualization frameworks for the manufacturing industry, focusing on detailed implementation strategies, initial results, and key findings of these frameworks. One major focus of these frameworks is the generalization of the technological assets so that these frameworks can be …

Impacts Of Ing4-Deficiency On Hematopoietic Stem And Progenitor Cells & Characterizing The Concerns Of Novice Stem Graduate Teaching Assistant, Georgina Alice Anderson

Theses and Dissertations

The hematopoietic compartment is tasked with the establishment and maintenance of the entire blood program in steady-state and in response to stress. Key to this process are hematopoietic stem cells (HSCs), which possess the unique ability to self-renew and differentiate to replenish blood cells throughout an organism’s lifetime. Recent work has illustrated the vast mechanisms involved in regulating stress-induced hematopoiesis, including cytokine-mediated lineage bias, gene signature changes in aged HSCs associated with chronic inflammation, the impact of clonal hematopoiesis and stress tolerance. Inhibitor of Growth 4 (Ing4) has been identified as a critical regulator of HSC homeostasis. We show that …

Mitochondrial Function In The Maternal Brain: A New Perspective On Gestational Stress And Pathology Of Postpartum Depression, Erin Rene Gorman-Sandler

Theses and Dissertations

Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to avoidance and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Chronic mild unpredictable (CMUS) stress during late gestation …

Plankton Dynamics In A Temperate Estuary:Size Structure And Trophic Implications, Nayan Mallick

Theses and Dissertations

Estuarine ecosystems provide goods and services to around 45% of the entire human population. In recent times, these ecosystems have been severely affected by multiple stressors such as pollution, eutrophication, harmful algal blooms, sea level rise, and, most importantly, climate change. Increasing temperature associated with climate change can have pervasive impacts throughout the ecosystem’s functions and processes. Plankton, a conspicuous member of estuarine food web, are among the first to respond to the changes in temperature due to their high sensitivity to changing environmental conditions.

In this dissertation, I investigated the plankton dynamics in an estuarine ecosystem through a combination …

Popular Justice Or Populist Justice? Penal Populism And Its Impact On Democracy, Kuan-Wu Chen

Theses and Dissertations

Populism, a pervasive phenomenon in contemporary politics, manifests as an anti-establishment, anti-pluralistic, morally charged framing that advocates for direct rule between leader and populace. Among its variants, penal populism emerges as a particularly concerning manifestation. It is characterized by a leader's deployment of panicking, punitive, and politically targeted rhetoric to enhance social control and accrue political capital rather than address crime prevention. This research argues that penal populism poses the most significant threat to democratic rule, as evidenced by theoretical, framing, and mobilization analyses. A novel categorization of populist variants is proposed based on dimensions of social categorization and exclusivity. …

The Dengue Vaccine Initiative: A Bibliometric Analysis Of Research Publications, Festus Mulakoli, Abednego Ongeso, Horatius Musembi

School of Nursing & Midwifery, East Africa

Dengue fever has become a significant public health problem in tropical and subtropical regions and affects millions of people annually. Approximately 390 million people worldwide are estimated to be infected with dengue every year, of which 96 million develop dengue fever. Recently, there has been a noticeable increase in dengue cases, primarily in areas with tropical and subtropical climates. Vaccines have been developed to prevent or reduce the severity of the disease. This study reviews the number of publications on dengue vaccines and related topics worldwide. We aimed to evaluate the research output and create a narrative on global vaccine …

Unveiling Similarities In The Code Of Life: A Detailed Exploration Of Dna Sequence Matching Algorithm, Mahmoud Y. Shams, Romany M. Farag, Dalia A. Aldawody, Huda E. Khalid, Ahmed K. Essa, Hazem M. El-Bakry, A. A. Salama

Neutrosophic Systems with Applications

Identifying similar DNA sequences is crucial in various biological research endeavors. This paper delves into the intricate workings of a specific algorithm designed for this purpose. We provide a systematic explanation, exploring how the algorithm handles user input, reads stored DNA sequences, utilizes the Word2Vec model for vector representation, and calculates sequence similarity using diverse metrics like Cosine Similarity and Neutrosophic Distance. Additionally, the paper explores the incorporation of neutrosophic values to account for uncertainty in the comparisons. Finally, we discuss the extraction of results, including matched sequences, similarity scores, and accuracy measures. This in-depth exploration provides a clear understanding …

An Approach To Multi-Attribute Decision-Making Based On Single-Valued Neutrosophic Hesitant Fuzzy Aczel-Alsina Aggregation Operator, Raiha Imran, Kifayat Ullah, Zeeshan Ali, Maria Akram

Neutrosophic Systems with Applications

A single-valued Neutrosophic hesitant fuzzy set (SVNHFS) is a combination of a single-valued neutrosophic set (SVNS) and hesitant fuzzy set (HFS) that has been developed to address insufficient, unreliable, and vague environments in which each element has several possible options determined by the truthiness, indeterminacy and falsity value. By considering this, in this paper, we have proposed the Aczel-Alsina aggregation operator (AAAO) for SVNHFS, which is more flexible t-norm and t-conorm than the other and due to the flexible nature of parameters to solve Multi-Attribute decision making (MADM) problems. Further, the score function, accuracy function, and certainty function of SVNHFS …

Cellular Prion Protein Acts As Mediator Of Amyloid Beta Uptake By Caveolin-1 Causing Cellular Dysfunctions In Vitro And In Vivo, Angela Da Silva Correia, Matthias Schmitz, Anna-Lisa Fischer, Susana Da Silva Correia, Franco L Simonetti, Gesine Saher, Roberto Goya-Maldonado, Amandeep Singh Arora, Andre Fischer, Tiago F Outeiro, Inga Zerr

Faculty, Staff and Student Publications

Introduction: Cellular prion protein (PrPC) was implicated in amyloid beta (Aβ)-induced toxicity in Alzheimer's disease (AD), but the precise molecular mechanisms involved in this process are unclear.

Methods: Double transgenic mice were generated by crossing Prnp knockout (KO) with 5xFAD mice, and light-sheet microscopy was used for whole brain tissue analyses. PrPC-overexpressing cells were developed for in vitro studies, and microscopy was used to assess co-localization of proteins of interest. Surface-plasmon resonance (SPR) was used to investigate protein-binding characteristics.

Results: In vivo, PrPC levels correlated with reduced lifespan and cognitive and motor function, and its ablation disconnected behavior deficits from …

Dual Targeting Macrophages And Microglia Is A Therapeutic Vulnerability In Models Of Pten-Deficient Glioblastoma, Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen

Faculty, Staff and Student Publications

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent …

Challenges And Opportunities For Early Phase Clinical Trials Of Novel Drug-Radiotherapy Combinations: Recommendations From Nrg Oncology, The American Society For Radiation Oncology (Astro), The American College Of Radiology (Acr), The Sarah Cannon Research Institute, And The American College Of Radiation Oncology (Acro), Zachary S Zumsteg, Siddharth Sheth, Salma K Jabbour, Krishnan R Patel, Randall J Kimple, Terence M Williams, Meng Xu-Welliver, Pedro A Torres-Saavedra, Arta M Monjazeb, Jyoti Mayadev, Steven E Finkelstein, John M Buatti, Sandip P Patel, Steven H Lin

Faculty, Staff and Student Publications

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.

Collision Tumor: Multinodular And Vacuolating Neuronal Tumor With Isocitrate Dehydrogenase-Mutant Diffuse Astrocytoma, Vinodh A Kumar, Alejandro Perez, Angela L Young, Julia Jones, Barbara J O'Brien, Frederick F Lang, Jason T Huse, Gregory N Fuller

Faculty, Staff and Student Publications

Herein, we report a case of a collision tumor involving a multinodular and vacuolating neuronal tumor (MVNT) and a diffuse astrocytoma. A collision tumor between these two entities has not previously been reported. The patient is a 35-year-old woman who presented with new-onset hearing loss and ringing in her right ear. Magnetic resonance imaging identified a non-enhancing mass involving the gray matter and subcortical white matter of the left middle frontal gyrus. Additionally, tiny clustered nodules were noted along the underlying subcortical ribbon and superficial subcortical white matter of the left superior frontal gyrus. The patient underwent a left frontal …

A Single-Cell Atlas Of The Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications In Pancreas Regeneration And Exocrine Pathogenesis, Ángel Fernández, Joan Casamitjana, Adrián Holguín-Horcajo, Katarina Coolens, Loris Mularoni, Li Guo, Olga Hartwig, Tim Düking, Noemi Vidal, Lincoln N Strickland, Lorenzo Pasquali, Jennifer M Bailey-Lundberg, Ilse Rooman, Yue J Wang, Meritxell Rovira

Faculty, Staff and Student Publications

Background & aims: Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells, terminal, intercalated, intracalated ducts, and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized; therefore, our understanding of the role of ductal cells in pancreas regeneration and exocrine pathogenesis has been hampered by the limited knowledge and unexplained diversity within the ductal network.

Methods: We used single cell RNA sequencing to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells …

Persistent Microbial Infections And Idiopathic Pulmonary Fibrosis – An Insight Into Non-Typeable Haemophilus Influenza Pathogenesis, Dong Hun Lee, Minseong Kim, Sarah S Chang, Raham Lee, Andrew J Jang, Juyoung Kim, Jing Ma, Michael J Passineau, Raymond L Benza, Harry Karmouty-Quintana, Wilbur A Lam, Benjamin T Kopp, Roy L Sutliff, C Michael Hart, Changwon Park, Bum-Yong Kang

Faculty, Staff and Student Publications

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH) but the molecular mechanisms regulating EndoMT remain to be defined. We demonstrate that the axis of the transcription factors PPARγ (Peroxisome Proliferator-Activated Receptor gamma) and ETV2 (ETS variant 2) play important roles in the pathogenesis of PH. Decreased levels of the expression of PPARγ and ETV2 along with reduced endothelial and increased EndoMT markers are consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced-EndoMT cells. Etv2 +/- mice spontaneously developed PH and right …

A Molecular Switch From Tumor Suppressor To Oncogene In Er+Ve Breast Cancer: Role Of Androgen Receptor, Jak-Stat, And Lineage Plasticity, Sarah Asemota, Wendy Effah, Jeremiah Holt, Daniel Johnson, Linnea Cripe, Suriyan Ponnusamy, Thirumagal Thiyagarajan, Yekta Khosrosereshki, Dong-Jin Hwang, Yali He, Brandy Grimes, Martin D Fleming, Frances E Pritchard, Ashley Hendrix, Meiyun Fan, Abhinav Jain, Hyo Young Choi, Liza Makowski, D Neil Hayes, Duane D Miller, Lawrence M Pfeffer, Balaji Santhanam, Ramesh Narayanan

Faculty, Staff and Student Publications

Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in …

Inulin-Gel-Based Oral Immunotherapy Remodels The Small Intestinal Microbiome And Suppresses Food Allergy, Kai Han, Fang Xie, Olamide Animasahun, Minal Nenwani, Sho Kitamoto, Yeji Kim, May Thazin Phoo, Jin Xu, Fulei Wuchu, Kehinde Omoloja, Abhinav Achreja, Srinadh Choppara, Zhaoheng Li, Wang Gong, Young Seok Cho, Hannah Dobson, Jinsung Ahn, Xingwu Zhou, Xuehui Huang, Xinran An, Alexander Kim, Yao Xu, Qi Wu, Soo-Hong Lee, Jessica J O'Konek, Yuying Xie, Yu Leo Lei, Nobuhiko Kamada, Deepak Nagrath, James J Moon

Faculty, Staff and Student Publications

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells …

The Tragedy Of Our Trajectory, Marisola Xhelili Ciaccio

Dissertations (1934 -)

In this project, I argue that the trajectory of Western European civilization has resulted in increasingly tragic predicaments that are not to be taken as given features of being human. Though both Ancient Western and Eastern wisdom traditions concur that suffering is a part of life, the point of living is not to suffer but to learn to overcome it and flourish. But because the purported successes of Western “progress” necessarily depend on structural oppression, and oppression produces superfluous sufferings that interfere with our capacities to actualize our freedom and flourish, they ultimately make us all worse-off. Reflecting on such …

Il-22 Resolves Masld Via Enterocyte Stat3 Restoration Of Diet-Perturbed Intestinal Homeostasis, Peng Zhang, Junlai Liu, Allen Lee, Irene Tsaur, Masafumi Ohira, Vivian Duong, Nicholas Vo, Kosuke Watari, Hua Su, Ju Youn Kim, Li Gu, Mandy Zhu, Shabnam Shalapour, Mojgan Hosseini, Gautam Bandyopadhyay, Suling Zeng, Cristina Llorente, Haoqi Nina Zhao, Santosh Lamichhane, Siddharth Mohan, Pieter C Dorrestein, Jerrold M Olefsky, Bernd Schnabl, Pejman Soroosh, Michael Karin

Faculty, Staff and Student Publications

The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous …

Astrocyte-Induced Cdk5 Expedites Breast Cancer Brain Metastasis By Suppressing Mhc-I Expression To Evade Immune Recognition, Arseniy E Yuzhalin, Frank J Lowery, Yohei Saito, Xiangliang Yuan, Jun Yao, Yimin Duan, Jingzhen Ding, Sunil Acharya, Chenyu Zhang, Abigail Fajardo, Hao-Nien Chen, Yongkun Wei, Yutong Sun, Lin Zhang, Yi Xiao, Ping Li, Philip L Lorenzi, Jason T Huse, Huihui Fan, Zhongming Zhao, Mien-Chie Hung, Dihua Yu

Faculty, Staff and Student Publications

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to …

Targeting The Peripheral Neural-Tumour Microenvironment For Cancer Therapy, Dan Yaniv, Brandi Mattson, Sebastien Talbot, Frederico O Gleber-Netto, Moran Amit

Faculty, Staff and Student Publications

As the field of cancer neuroscience expands, the strategic targeting of interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment, comparable to the advent of our current understanding of tumour immunology. Cancer cells actively release growth factors that stimulate tumour neo-neurogenesis, and accumulating evidence indicates that tumour neo-innervation propels tumour progression, inhibits tumour-related pro-inflammatory cytokines, promotes neovascularization, facilitates metastasis and regulates immune exhaustion and evasion. In this Review, we give an up-to-date overview of the dynamics of the tumour microenvironment with an emphasis on tumour innervation by the peripheral …