MECHANISMS UNDERLYING THE SENSITIVITY AND RESISTANCE OF GASTRIC CANCER CELLS TO MET INHIBITORS

MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, or RNAi-mediated knockdown of two obligate components of the autophagy pathway (ATG5 and ATG7) blocked cell death induced by crizotinib or RNAi-mediated knockdown of MET, and mechanistic studies localized the effects of autophagy to cytochrome c release from the mitochondria. Overall, the data reveal a novel relationship between autophagy and apoptosis in gastric cancer cells exposed to MET inhibitors. The observations suggest that autophagy inhibitors should not be used to enhance the effects of MET inhibitors in gastric cancer patients

Seeking Solace: Regret, Grief, Anxiety

Seeking Solace: Regret, Grief, Anxiety is a triptych video and artifact piece inspired by the abstract analysis of my dreams. It recognizes worries held within my subconscious and brings them to life through graphic design, photography, and video. The process of creating provides a new perspective of looking at both art and occupational therapy as methods of solving emotional distress. I have recorded over 80 of my dreams in the past year. In these dreams, regret, grief, and anxiety are common themes. These themes are represented in three triptychs that cycle through past, present, and future problems. The cycling of the triptychs simulates the dream cycles one’s brain undergoes during sleep. Corresponding artifacts invite the viewer to interact with this creative healing process. Regret responds to dreams about the struggles with past human relationships. Light serves as a dual symbol expressing both confrontation and forgiveness. The book served as a performative artifact that encouraged me to convert my negative memories into positive experiences. Grief responds to dreams about the loss of a loved one in the present. Through rediscovery and repurposing of past items, it encouraged me to focus on the history and memory of the individual and helped me find comfort in these items. Anxiety responds to dreams about the fear of future events. It utilizes repetition and disorder to describe that I am not fully in control of the future. The balance serves as a visual representation of weighing priorities to find emotional equilibrium. Presenting these personal works in a public setting created a sense of honesty and vulnerability between me and the audience. Physical artifacts encouraged the audience to engage and interact with this therapeutic process. The creation of this body of work was a successful tool of solving emotional distresses due to its repetitive, focused, and expressive nature. Working with previously unexplored media encouraged me to solve problems in new ways. This creative process reduced the amount of bad dreams regarding past regret and present grief. Although helping me cope throughout the process, the works responding to anxiety did not fight off bad dreams as effectively because these events have yet to occur in real life. View video of installation here: https://vimeo.com/16031556

NF2/merlin in hereditary neurofibromatosis 2 versus cancer: biologic mechanisms and clinical associations.

Inactivating germline mutations in the tumor suppressor gene NF2 cause the hereditary syndrome neurofibromatosis 2, which is characterized by the development of neoplasms of the nervous system, most notably bilateral vestibular schwannoma. Somatic NF2 mutations have also been reported in a variety of cancers, but interestingly these mutations do not cause the same tumors that are common in hereditary neurofibromatosis 2, even though the same gene is involved and there is overlap in the site of mutations. This review highlights cancers in which somatic NF2 mutations have been found, the cell signaling pathways involving NF2/merlin, current clinical trials treating neurofibromatosis 2 patients, and preclinical findings that promise to lead to new targeted therapies for both cancers harboring NF2 mutations and neurofibromatosis 2 patients

Stress Induced Remodeling in the Nematode C. elegans

Caenorhabditis elegans is a model organism for studying genetics and neuroscience C. elegans is frequently studied to understand how genes and the environment interact to produce new phenotypes. We take advantage of an organism-wide stress response and genetic tools that provide an excellent model for studying how phenotypes are impacted by stress

Mutational Analysis of the Rotavirus NSP4 Enterotoxic Domain that Binds to Caveolin-1

Background: Rotavirus (RV) nonstructural protein 4 (NSP4) is the first described viral enterotoxin, which induces early secretory diarrhea in neonatal rodents. Our previous data show a direct interaction between RV NSP4 and the structural protein of caveolae, caveolin-1 (cav-1), in yeast and mammalian cells. The binding site of cav-1 mapped to the NSP4 amphipathic helix, and led us to examine which helical face was responsible for the interaction. Methods: A panel of NSP4 mutants were prepared and tested for binding to cav-1 by yeast two hybrid and direct binding assays. The charged residues of the NSP4 amphipathic helix were changed to alanine (NSP446-175-ala6); and three residues in the hydrophobic face were altered to charged amino acids (NSP446-175-HydroMut). In total, twelve mutants of NSP4 were generated to define the cav-1 binding site. Synthetic peptides corresponding to the hydrophobic and charged faces of NSP4 were examined for structural changes by circular dichroism (CD) and diarrhea induction by a neonatal mouse study. Results: Mutations of the hydrophilic face (NSP446-175-Ala6) bound cav-1 akin to wild type NSP4. In contrast, disruption of the hydrophobic face (NSP446-175-HydroMut) failed to bind cav-1. These data suggest NSP4 and cav-1 associate via a hydrophobic interaction. Analyses of mutant synthetic peptides in which the hydrophobic residues in the enterotoxic domain of NSP4 were altered suggested a critical hydrophobic residue. Both NSP4HydroMut112-140, that contains three charged amino acids (aa113, 124, 131) changed from the original hydrophobic residues and NSP4AlaAcidic112-140 that contained three alanine residues substituted for negatively charged (aa114, 125, 132) amino acids failed to induce diarrhea. Whereas peptides NSP4wild type 112 −140 and NSP4AlaBasic112-140 that contained three alanine substituted for positively charged (aa115, 119, 133) amino acids, induced diarrhea. Conclusions: These data show that the cav-1 binding domain is within the hydrophobic face of the NSP4 amphipathic helix. The integrity of the helical structure is important for both cav-1 binding and diarrhea induction implying a connection between NSP4 functional and binding activities

Report: North Dakota Alzheimer’s and dementia state plan: Current status of, and recommendations for, meeting the needs of individuals and families with Alzheimer’s disease and other dementias

North Dakota reports the fourth highest mortality rate for Alzheimer’s disease in the United States (U.S.) at 52.9 per 100,000 North Dakota residents. The rate for the U.S. is 37 per 100,000 residents. Although leading in mortality, North Dakota is one of a few states with a State Plan for Alzheimer’s and Dementia over 12 years old. This plan was written in July of 2007 and is less than two pages. Although it does mention Alzheimer’s and other other dementias, it does not specifically outline a plan to address services for those living with, or supporting those living with, dementia in North Dakota. This current state plan, developed in 2021, reviewed existing data, involved stakeholders and community members, and identified strengths in the current plan as well as opportunities to reach the following vision: Create an inclusive community and health system that understands, respects, and supports persons who are at-risk of or diagnosed with Alzheimer’s and other dementias, and their caregivers

Effects of Original XPC on Newly Weaned Beef Steer Nutrient Digestibility and Response to a Vaccination Challenge

The study was designed to determine the effects of Diamond V Original XPC, a yeast fermentation product, in the diets of newly weaned beef steers on nutrient digestibility and response to a vaccination challenge. Although no overall performance benefit was noted, XPC improved total tract CP digestibility. Steers fed XPC at 14 g/d exhibited lesser concentrations of APP, greater DMI, and more efficient rumination post-vaccination. Further research is needed to determine the optimal supplementation rate of XPC to newly received beef cattle