Dartmouth Institute for Health Policy and Clinical Practice
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Proteomic-based strategies to determine aberrant signaling in cancer
No full textProteomics and phosphoproteomics have emerged as powerful tools to elucidate the intricate molecular underpinnings that drive cancer development by quantifying changes in protein and post-translational modification abundances. Throughout my thesis work, I have advanced these techniques to map cancer signaling networks on a global scale. Among breast cancer subtypes, triple-negative (TNBC) remains the most challenging to treat, with poorer clinical outcomes attributed to tumor heterogeneity and yet unidentified, oncogenic driver proteins for therapeutic targeting. To identify potential targeted treatment strategies, we employed mass spectrometry-based quantitative proteomics to analyze 55 formalin-fixed paraffin- embedded TNBC tumor specimens. Unsupervised hierarchical clustering of relative protein abundances identified four distinct subtypes. Functional annotation analyses designated the subtypes as: Immune-active (IMA), Immune-suppressed (IMS), Luminal androgen receptor (LAR), and Mesenchymal (MES). These protein-based subtypes correlated strongly with several clinicopathological features, including significantly high and low tumor-infiltrating lymphocyte scores for the IMA and IMS subtypes, respectively. DNA methylation analysis for inferred cell-type deconvolution of the tumor microenvironment corroborated these findings. Finally, to establish a foundation for pre-clinical investigations into each subtype, we assigned representative cell line models.
To expand beyond proteomic analyses, my research also focused on dissecting the regulatory mechanisms underlying phosphorylation-dependent signaling in cancer cells. Protein phosphorylation is an essential regulatory mechanism of cell signaling that is deregulated in many cancers. In eukaryotic cells, most phosphosites are dephosphorylated by members of the Phosphoprotein Phosphatase (PPP) family. However, no selective PPP inhibitor exists to study their individual functions. Here, we utilized endogenous tagging of genomic loci with an auxin-inducible degron system to investigate specific PPP signaling in cancer. Using Protein Phosphatase 6 (PP6) as an example, we demonstrated how inducible protein degradation can be employed to discover dephosphorylation sites and elucidate PP6 biology. Upon auxin-induced degradation of PP6, we performed quantitative mass spectrometry-based proteomics and phosphoproteomics to identify PP6 substrates in colorectal cancer cells. Consistently, we identified candidate PP6-dependent phosphosites on proteins that mediate MAPK and Hippo signaling. Finally, we demonstrated that PP6 opposes the activation of LATS1 by dephosphorylating Threonine 35 site on MOB1, thereby inhibiting the tumor-suppressive activity of the Hippo pathway
Appalachia Winter/Spring 2025: Complete Issue
Get PDFWinter/Spring 2025 - Volume LXXVI, Number 1 - Issue #259. The Humanity of Machines: Stories of drones, helicopters, and snowcats in the mountains
The Long Way Home: Getting Water
Get PDFFrom the outlet of Ethan Pond in New Hampshire’s White Mountains, waterlogged memories of moose, children, and swimmers resurface
When Powder Skis Became a Thing: A Winter\u27s Tale of Engineers and Unbroken Fields of White
Get PDFPowder skiing used to be the domain of an adventurous fringe element, but with the manufacturing of specialized skis, it is now a mainstream pursuit
A Comparative Mathematical Analysis of Ice Modulation Measurement Techniques: Unifying Thermal Hysteresis, Freezing Point Depression, and Colligative Effects
No full textThermal hysteresis (TH) measurement techniques for ice binding proteins (IBPs) have historically lacked standardization, making cross-study comparisons challenging and potentially impeding development of these materials for practical applications. This study provides a comprehensive comparison of three measurement techniques: differential scanning calorimetry (DSC), microlitre osmometry, and cryostage microscopy. Through systematic experimentation with Wild Type III Antifreeze Protein (AFP) at varying concentrations (10μM, 100μM, 1mM), along with cell lysate AFP and Pseudomonas syringe ice nucleating protein (INP), mathematical relationships were established between measurement techniques, and cryostage microscopy was identified as the most reproducible and reliable method. Regression analysis revealed strong relationships between measurement techniques, with distinct mathematical relationships: a logarithmic relationship between cryostage microscopy and microlitre osmometry (y = 0.8241ln(x) + 0.8983, R² = 0.9949), and between DSC and microlitre osmometry (y = 0.4542ln(x) + 0.6029, R² = 1.0000). The relationship between cryostage microscopy and DSC also showed a strong logarithmic relationship (y = 0.6809ln(x) + 1.2083, R² = 0.9993. Factorial analysis revealed that both concentration (0.525) and measurement technique (0.167) had significant effects on TH values, exceeding the significance threshold of 0.153 (α=0.05). Cryostage microscopy consistently produced lower TH values (mean ~0.45 °C) compared to microlitre osmometry (0.6 °C TH), likely representing more accurate measurements due to guaranteed single crystal observation. The technique demonstrated perfect reproducibility across trials while maintaining high equipment precision (±0.01 °C). Additionally, cryostage microscopy was compatible with all sample types, while microlitre osmometry failed with cell lysate and Pseudomonas syringae samples, likely due to nucleating behavior. These findings establish cryostage microscopy as the most reliable and reproducible measurement technique due to its unique combination of direct visual observation, single crystal measurement capability, and high precision. The mathematical relationships discovered provide a framework for converting between measurement techniques while highlighting the importance of standardizing cryostage microscopy for future TH measurements. Such standardization would significantly improve the reliability and comparability of TH measurements across the field
Neural representations of valence and arousal in Kung Fury
Get PDFEmotions are a core component of human experience and behavior, yet after decades of scientific research, it is still difficult to uncover the neural substrates related to emotion. Recent advances in neuroscience have examined how we interpret emotional signals from static images of facial expressions, but less work has sought to understand how the brain constructs our emotional experiences (Chen, 2020). To investigate such idiosyncratic experiences across participants, we employed naturalistic stimuli to model the real-time, reliable changes in activity that correspond to changes in emotional experience. A primary element of emotional experience is core affect, defined as the mental representation of bodily changes, which when experienced as feelings (or with conscious awareness), constitute a degree of hedonic valence and arousal (Lindquist et al., 2012). Previous studies in affective neuroscience have discovered neural representations of valence and arousal with findings linked to amygdala, insula, thalamus, orbitofrontal cortex, cingulate cortex, and subsections of the prefrontal cortex, but no previous study has utilized the movie Kung Fury in uncovering rich and reliable brain responses. Do neural representations of emotions generalize to unseen movies? Our results suggest that valence elicits robust activity in visual cortices, the intraparietal sulcus, and the cuneus, while arousal elicits activity in the precuneus, posterior cingulate cortex, and intraparietal sulcus, both subsets of regions implicated in the saliency and default mode network respectively. Our findings suggest that our brain utilizes a constellation of brain regions to construct our everyday emotional experiences
Beware the Wandering Woman: Depictions of Female Spatial Transgression in Athenian Public Dramas of the 5th and 4th Centuries BCE
Get PDFThis paper explores how ancient Greek literature and culture construct autonomous, mobile women as threats to the ideological and spatial order of the polis. Referencing mythological precedents and closely reading Classical texts, I propose the category of “excepted women” to address the threads of female transgression woven throughout this extensive literary corpus. Focusing on figures who transgress imposed spatial boundaries, I examine how such women are positioned as disruptors of gendered norms and civic stability, thus reflecting deep cultural anxieties about female agency and movement into spaces coded as masculine. The paper engages theoretical frameworks from Althusser and Butler to analyze how these women are figured in particular texts; operating with the dual levels of interpellation inherent to a state-sponsored, publicly-staged drama, the 5th century plays Agamemnon (Aeschylus) and Ecclesiazusae (Aristophanes) are examined closely and seen to clearly depict the female rearticulation of ideological norms through spatial transgression. In this analysis, the excepted woman becomes a figure through which Greek culture negotiates the limits of gendered space and power—she is always seen to have the potential to unsettle or exceed these boundaries. In tracing the movement of the excepted woman, this paper illuminates the cultural and conceptual mechanisms by which femininity was policed, performed, and persistently imagined as a site of instability in ancient Greece
Colonization-Persistence Trade-offs in the Human Microbiome
Get PDFUnderstanding how diverse microbial taxa coexist in the human body without competitively excluding one another remains a key challenge in microbiome ecology. One proposed explanation is the colonization-persistence trade-off, where species with high colonization ability are poor persisters, and vice versa. We test for this trade-off across human associated microbial communities among many individuals and in multiple body sites using a large-scale participant-level meta-analysis of longitudinal microbiome datasets curated from the MGnify database. We applied island biogeography-based models to calculate effective colonization and persistence rates for microbial families and genera across 606 individuals over twenty-six studies. Regression of the log-transformed colonization and persistence rates of different taxa revealed a widespread, significantly negative relationship across all body habitats (gut, skin, oral, respiratory, and vaginal), consistent with the predicted trade-off. We also found that this relationship varies with body habitat, disease state, and temporal variability. The oral microbiome was found to have a shallower (less negative) slope between colonization and persistence, indicating that the cost for persistence is lower for species with high colonization ability. Disease states were associated with a stronger trade-off (slope closer to -1) than healthy individuals, except in the vaginal microbiome where disease was associated with a weaker trade off. High temporal variability in community composition was also associated with a weaker trade-off signal. At the family level, colonization and persistence rates were context dependent, with some taxa acting as colonizers in one habitat and persisters in another. Our findings suggest that the colonization-persistence trade-off structures the diversity of human-associated microbial communities