Digital Commons Network^™

Imipridones Inhibit Tumor Growth And Improve Survival In An Orthotopic Liver Metastasis Mouse Model Of Human Uveal Melanoma, Chandrani Chattopadhyay, Janos Roszik, Rajat Bhattacharya, Md Alauddin, Iqbal Mahmud, Sirisha Yadugiri, Mir Mustafa Ali, Fatima S Khan, Varun Vijay Prabhu, Philip L Lorenzi, Bo Wei, Elizabeth Burton, Rohini R Morey, Rossana Lazcano, Michael A Davies, Sapna P Patel, Elizabeth A Grimm

Faculty, Staff and Student Publications

Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.

Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.

Results: CLPP expression was detected in primary …

Targeting The Glutamine-Arginine-Proline Metabolism Axis In Cancer, Di Wang, Jiang-Jie Duan, Yu-Feng Guo, Jun-Jie Chen, Tian-Qing Chen, Jun Wang, Shi-Cang Yu

Faculty, Staff and Student Publications

Metabolic abnormalities are an important feature of tumours. The glutamine-arginine-proline axis is an important node of cancer metabolism and plays a major role in amino acid metabolism. This axis also acts as a scaffold for the synthesis of other nonessential amino acids and essential metabolites. In this paper, we briefly review (1) the glutamine addiction exhibited by tumour cells with accelerated glutamine transport and metabolism; (2) the methods regulating extracellular glutamine entry, intracellular glutamine synthesis and the fate of intracellular glutamine; (3) the glutamine, proline and arginine metabolic pathways and their interaction; and (4) the research progress in tumour therapy …

Physiology And Genomics At The Bottom Of The World: Genome To Phenome, Amy Christine Klink

UNLV Theses, Dissertations, Professional Papers, and Capstones

Mammals are exposed to a suite of physiological challenges based on the environment in which they inhabit. Animal individuals can overcome challenges associated with the dynamic nature of their habitat through variation in phenotypic traits. The plasticity of a phenotype relies on an individual’s genome and the transcription factors that act on regulatory elements. Species living in Antarctica display physiological specializations to withstand harsh conditions, such as severe cold temperatures, shifts in available ice habitat, and annual fluctuations in daylight. To explore the connections between an individual’s genome and its phenotype, we investigated two physiologies of the Antarctic Weddell seal …

Mammalian Mitochondrial Inorganic Polyphosphate (Polyp) And Cell Signaling: Crosstalk Between Polyp And The Activity Of Ampk, Renata T. Da Costa, Anna Nichenko, Matheus M. Perez, Malgorzata Tokarska-Schlattner, Sheida Kavehmoghaddam, Vedangi Hambardikar, Ernest R. Scoma, Erin L. Seifert, Uwe Schlattner, Joshua C. Drake, Maria E. Solesio

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

UNLABELLED: Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged.

OBJECTIVE: In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics.

METHODS: To conduct our studies, …

Validation Studies Of The Flash-Tv System To Passively Measure Children’S Tv Viewing, Anil Kumar Vadathya, Tatyana Garza, Uzair Alam, Alex Ho, Salma M A Musaad, Alicia Beltran, Jennette P Moreno, Tom Baranowski, Nimah Haidar, Sheryl O Hughes, Jason A Mendoza, Ashok Veeraraghavan, Joseph Young, Akane Sano, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

TV viewing is associated with health risks, but existing measures of TV viewing are imprecise due to relying on self-report. We developed the Family Level Assessment of Screen use in the Home (FLASH)-TV, a machine learning pipeline with state-of-the-art computer vision methods to measure children's TV viewing. In three studies, lab pilot (n = 10), lab validation (n = 30), and home validation (n = 20), we tested the validity of FLASH-TV 3.0 in task-based protocols which included video observations of children for 60 min. To establish a gold-standard to compare FLASH-TV output, the videos were labeled by trained staff …

Complement Immune System In Pulmonary Hypertension-Cooperating Roles Of Circadian Rhythmicity In Complement-Mediated Vascular Pathology, Hunter Devaughn, Haydn E Rich, Anthony Shadid, Priyanka K Vaidya, Marie-Francoise Doursout, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

Originally discovered in the 1890s, the complement system has traditionally been viewed as a "compliment" to the body's innate and adaptive immune response. However, emerging data have shown that the complement system is a much more complex mechanism within the body involved in regulating inflammation, gene transcription, attraction of macrophages, and many more processes. Sustained complement activation contributes to autoimmunity and chronic inflammation. Pulmonary hypertension is a disease with a poor prognosis and an average life expectancy of 2-3 years that leads to vascular remodeling of the pulmonary arteries; the pulmonary arteries are essential to host homeostasis, as they divert …

An Annotated Biobank Of Triple Negative Breast Cancer Patient-Derived Xenografts Featuring Treatment-Naïve And Longitudinal Samples Throughout Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Hancock, Sabrina Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Students Publications

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial ( NCT02276443 ) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models …

Strategies To Enhance Diagnostic Capabilities For The New Drug-Resistant Tuberculosis (Dr-Tb) Drugs, Antonia Morita Iswari Saktiawati, Anca Vasiliu, Francesca Saluzzo, Onno W Akkerman

Faculty, Staff and Students Publications

The global burden of drug-resistant tuberculosis (DR-TB) continues to challenge healthcare systems worldwide. There is a critical need to tackle DR-TB by enhancing diagnostics and drug susceptibility testing (DST) capabilities, particularly for emerging DR-TB drugs. This endeavor is crucial to optimize the efficacy of new therapeutic regimens and prevent the resistance and overuse of these invaluable weapons. Despite this urgency, there remains a lack of comprehensive review of public health measures aimed at improving the diagnostics and DST capabilities. In this review, we outline strategies to enhance the capabilities, especially tailored to address the challenges posed by resistance to new …

Blood Matters: The Hematological Signatures Of Coronavirus Infection, Ayelen Toro, Ana P Arévalo, Marianoel Pereira-Gómez, Agustina Sabater, Eric A Zizzi, Paula Perbolianachis, Gaston Pascual, Sofia Lage-Vickers, Jorge L Pórfido, Ines Achinelli, Rocio Seniuk, Juan Bizzotto, Pablo Sanchis, Alvaro Olivera, Alejandro Leyva, Pilar Moreno, Alicia Costábile, Alvaro Fajardo, Federico Carrión, Martín Fló, Natalia Olivero-Deibe, Fernando Rodriguez, Nicolas Nin, Nicolas Anselmino, Estefania Labanca, Elba Vazquez, Javier Cotignola, Daniel F Alonso, Maria P Valacco, Marcelo Marti, Francesco Gentile, Artem Cherkasov, Martina Crispo, Gonzalo Moratorio, Geraldine Gueron

Faculty, Staff and Student Publications

Recent developments have broadened our perception of SARS-CoV-2, indicating its capability to affect the body systemically beyond its initial recognition as a mere respiratory pathogen. However, the pathways of its widespread are not well understood. Employing a dual-modality approach, we integrated findings from a Murine Hepatitis Virus (MHV) infection model with corroborative clinical data to investigate the pervasive reach of Coronaviruses. The novel presence of viral particles within red blood cells (RBCs) was demonstrated via high-resolution transmission electron microscopy, with computational modeling elucidating a potential heme-mediated viral entry mechanism via Spike protein affinity. Our data affirm viral localization in RBCs, …

Comparison Of Toxic Element Cadmium Levels In Female Patients With ‎Benign And ‎‎‎Malignant Uterine Tumors‎ By Flame Atomic Absorption ‎Spectrometry ., Hiba Ghmeedh Adhab, Liwaa Hussein Mahdi, Eman M. Al-Hilo

Maaen Journal for Medical Sciences

Cadmium is a toxic heavy metal known to be associated with various health issues, including cancer. Elevated blood cadmium levels can be a concern and may require medical evaluation and intervention. Some studies describing the etiology of cancer have focused on heavy metals, however, there is little information available for uterine cancer. This study assessed the levels of cadmium in the serum of 60 women with benign and malignant uterine tumors. Blood samples were obtained and analyzed using FAAS spectrometry in Najaf City, Iraq. Serum cadmium levels exhibited higher concentration in patients with malignant uterine tumors than those with benign …

Functions Of Tam Receptors And Ligands Protein S And Gas6 In Atherosclerosis And Cardiovascular Disease, Teagan Prouse, Samarpan Majumder, Rinku Majumder

School of Medicine Faculty Publications

Atherosclerosis and cardiovascular disease are associated with high morbidity and mortality in industrialized nations. The Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases is involved in the amplification or resolution of atherosclerosis pathology and other cardiovascular pathology. The ligands of these receptors, Protein S (PS) and growth arrest specific protein 6 (Gas6), are essential for TAM receptor functions in the amplification and resolution of atherosclerosis. The Axl-Gas6 interaction has various effects on cardiovascular disease. Mer and PS dampen inflammation, thereby protecting against atherosclerosis progression. Tyro3, the least studied TAM receptor in cardiovascular disease, appears to protect against fibrosis …

Multiple Factors Regulate The Expression Of Sufcdsub In Streptococcus Mutans, Kassapa Ellepola, Lauren C. Guillot, Bradley Comeaux, Yiran Han, Jessica K. Kajfasz, Jacob P. Bitoun, Grace Spatafora, Jose A. Lemos, Zezhang T. Wen

School of Dentistry Faculty Publications

Introduction: The sufCDSUB gene cluster, encoding the sole iron-sulfur (Fe-S) cluster assembly system in S. mutans, was recently shown to be up-regulated in response to oxidative stressors and Fe limitation. Methods: In this study, luciferase reporter fusion assays, electrophoretic gel mobility shift assays (EMSA) and in vitro transcription assays (IVT) were used to dissect the cis- and trans-acting factors that regulate the expression of sufCDSUB. Results and discussion: Results showed deletion of perR, for the only Fur-family transcriptional regulator in S. mutans, resulted in > 5-fold increases in luciferase activity under the control of the sufCDSUB promoter (P < 0.01), as compared to the parent strain, UA159 when the reporter strains were grown in medium with no supplemental iron. Site-directed mutagenesis of a PerR-box in the promoter region led to elevation of the reporter activity by >1.6-fold (P < 0.01). In an EMSA, recombinant PerR (rPerR) was shown to bind to the cognate sufCDSUB promoter leading to mobility retardation. On the other hand, the reporter activity was increased by > 84-fold …

Septal Wall Synthesis Is Sufficient To Change Ameba-Like Cells Into Uniform Oval-Shaped Cells In Escherichia Coli L-Forms, Masafumi Hayashi, Chigusa Takaoka, Koichi Higashi, Ken Kurokawa, William Margolin, Taku Oshima, Daisuke Shiomi

Faculty, Staff and Student Publications

A cell wall is required to control cell shape and size to maintain growth and division. However, some bacterial species maintain their morphology and size without a cell wall, calling into question the importance of the cell wall to maintain shape and size. It has been very difficult to examine the dispensability of cell wall synthesis in rod-shaped bacteria such as Escherichia coli for maintenance of their shape and size because they lyse without cell walls under normal culture conditions. Here, we show that wall-less E. coli L-form cells, which have a heterogeneous cell morphology, can be converted to a …

Modulation Of Energetic And Lipid Pathways By Curcumin As A Potential Chemopreventive Strategy In Human Prostate Cancer Cells, Michele Pellegrino, Maria Antonietta Occhiuzzi, Fedora Grande, Ilaria Stefania Pagani, Stefano Aquaro, Paola Tucci

Staff and Researcher Publications

In Western industrialized countries, prostate cancer (PCa) is the second most common malignant disease and prevalent cause of death for men. Epidemiological studies have shown that curcumin (CUR) either prevents PCa initiation or delays its progression to a more aggressive and treatment-refractory form, thus reducing related mortality. Our previous studies have proven the anticancer, antioxidant, and anti-inflammatory properties of CUR on PCa cells. However, there are few reports of the effect of CUR on energy and lipid pathways in PCa. Herein, we show that CUR can modulate the two metabolic energy pathways, increasing glycolytic reserve and reducing oxidative phosphorylation. Moreover, …

Comparing Neoantigen Cancer Vaccines And Immune Checkpoint Therapy Unveils An Effective Vaccine And Anti-Trem2 Macrophage-Targeting Dual Therapy, Sunita Keshari, Alexander S Shavkunov, Qi Miao, Akata Saha, Tomoyuki Minowa, Martina Molgora, Charmelle D Williams, Mehdi Chaib, Anna M Highsmith, Josué E Pineda, Sayan Alekseev, Elise Alspach, Kenneth H Hu, Marco Colonna, Kristen E Pauken, Ken Chen, Matthew M Gubin

Faculty, Staff and Student Publications

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines …

Γ -Aapeptides Targeting Amyloid-Β Pathway And Neural Repair For Alzheimer’S Disease Treatment, Ning Shen

USF Tampa Graduate Theses and Dissertations

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and progressive neuronal degeneration. Despite extensive research, no treatments have been able to effectively halt or reverse the progression of the disease. This study aimed to evaluate the therapeutic potential of two novel γ-AApeptides, HW-C9 and 125-6b, in AD treatment, assessing both their individual and combined effects. HW-C9 was designed to inhibit Aβ aggregation, while 125-6b was developed to promote neuronal growth and repair. Initially, the therapeutic effects of HW-C9 and 125-6b were assessed both in vitro and in vivo. The results showed that HW-C9 …

Cocaine-Induced Dna-Dependent Protein Kinase Relieves Rnap Ii Pausing By Promoting Trim28 Phosphorylation And Rnap Ii Hyperphosphorylation To Enhance Hiv Transcription, Adhikarimayum Lakhikumar Sharma, Priya Tyagi, Meenata Khumallambam, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus. The finding that cocaine increases the nuclear localization of the DNA-PK provides further support to our observation of enhanced DNA-PK recruitment at the HIV long terminal repeat (LTR) following cocaine exposure. By activating and facilitating the nuclear localization of the DNA-PK, cocaine effectively orchestrates multiple stages …

Identification Of Lrp1+Cd13+ Human Periosteal Stem Cells That Require Lrp1 For Bone Repair, Youngjae Jeong, Lorenzo Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Faculty, Staff and Students Publications

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, podoplanin (PDPN) and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs, selectively expressed identified markers low density lipoprotein receptor-related protein 1 (LRP1) and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential …

Dobbs And Sterilization Decision-Making: Understanding The Coercive Spillover Effects In Reproductive Choice, Thomas Wilson Williams

Pace Law Review

The Supreme Court majority in Dobbs v. Jackson Women’s Health Organization argued their decision would have limited impact beyond abortion rights. This Article examines how Dobbs and subsequent state abortion restrictions are likely to increase women’s reliance on permanent sterilization procedures, particularly among already marginalized populations. Drawing on emerging data and historical context, I argue that some post-Dobbs sterilizations should be understood as effectively coerced by state policies, implicating reproductive justice concerns and potentially undermining fundamental rights established in Skinner v. Oklahoma. Then, I demonstrate how interdisciplinary bioethics frameworks and methodologies can help courts better understand the full …

Firearm Access, Carriage And Use In An Ethnically Diverse Sample Of Young Adults In Texas, Usa, Yu Lu, Elizabeth Baumler, Annalyn Saludares Demello, Leila Wood, Hillary Mcguire, Jeff R Temple

Faculty, Staff and Student Publications

Background Despite the high rates of firearm ownership and firearm-related injuries and mortalities in Southern US states, understandings on the factors contributing to these are lacking.

Methods Using wave 10 (2021) data from a longitudinal study, we examined firearm-related experiences among 636 ethnically diverse young adults (mean age=26 years; 62% female) in Texas, USA.

Results Just over half of participants had ready access to firearms, with 22.3% having carried a firearm outside of their home, 4.9% having been threatened with a firearm by a romantic partner and 4.4% by a non-romantic partner. More firearm access and carriage were reported in …

Insights Into Human Norovirus Cultivation In Human Intestinal Enteroids, Khalil Ettayebi, Gurpreet Kaur, Ketki Patil, Janam Dave, B Vijayalakshmi Ayyar, Victoria R Tenge, Frederick H Neill, Xi-Lei Zeng, Allison L Speer, Sara C Di Rienzi, Robert A Britton, Sarah E Blutt, Sue E Crawford, Sasirekha Ramani, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are a significant cause of epidemic and sporadic acute gastroenteritis worldwide. The lack of a reproducible culture system hindered the study of HuNoV replication and pathogenesis for almost a half-century. This barrier was overcome with our successful cultivation of multiple HuNoV strains in human intestinal enteroids (HIEs), which has significantly advanced HuNoV research. We optimized culture media conditions and generated genetically modified HIE cultures to enhance HuNoV replication in HIEs. Building upon these achievements, we now present new insights into this culture system, which involve testing different media, unique HIE lines, and additional virus strains. HuNoV infectivity …

Plasmodium Berghei Liver Stage Parasites Exploit Host Gabarap Proteins For Tfeb Activation, Jacqueline Schmuckli-Maurer, Annina F Bindschedler, Rahel Wacker, Oliver M Würgler, Ruth Rehmann, Timothy Lehmberg, Leon O Murphy, Thanh N Nguyen, Michael Lazarou, Jlenia Monfregola, Andrea Ballabio, Volker T Heussler

Duncan NRI Faculty and Staff Publications

Plasmodium, the causative agent of malaria, infects hepatocytes prior to establishing a symptomatic blood stage infection. During this liver stage development, parasites reside in a parasitophorous vacuole (PV), whose membrane acts as the critical interface between the parasite and the host cell. It is well-established that host cell autophagy-related processes significantly impact the development of Plasmodium liver stages. Expression of genes related to autophagy and lysosomal biogenesis is orchestrated by transcription factor EB (TFEB). In this study, we explored the activation of host cell TFEB in Plasmodium berghei-infected cells during the liver stage of the parasite. Our results …

Limosilactobacillus Reuteri Ameliorates Maternal Separation Stress In Newborn Mice And Alters Subsequent Adult Behaviour, Z. M. Saleh, B. Okeugo, V. R. Venna, F. W. Blixt, V. A. Quaicoe, E. S. Park, S. Giorgberidze, Meng Luo, Christopher M. Taylor, J. M. Rhoads, Y. Liu

School of Medicine Faculty Publications

Maternal separation (MS) in mice results in behavioral deficits and gut microbiota dysbiosis that all persist into adulthood. Limosilactobacillus reuteri DSM 17938 modulates gut microbiota, alters systemic metabolites, and facilitates immune regulation. To assess the effect of DSM 17938 on biochemical and behavioural stress-associated changes, newborn mice were exposed to unpredictable MS (MSU) daily from day 7 to day 20 of life, with intragastric administration of DSM 17938 or PBS as control. Body weight, brain levels of cholecystokinin (CCK), glial fibrillary acidic protein (GFAP), corticosterone, and stool microbiota were assessed at day 21. Behaviour tests including Y-maze (YMT), Tail Suspension …

Isolation, Discrimination, And Feeling “Constant Guilt”: A Mixed-Methods Analysis Of Female Physicians’ Experience With Fertility, Family Planning, And Oncology Careers, Sarah Marion, Shraddha M Dalwadi, Aleksandra Kuczmarska-Haas, Erin F Gillespie, Michelle S Ludwig, Emma B Holliday, Bridgette Thom, Fumiko Chino, Anna Lee

Faculty, Staff and Students Publications

Introduction: Family planning among female physicians is harmed by high risks of infertility, workload burden, poor family leave policies, and gender discrimination. Many women report feeling unsupported in the workplace, despite national policies to protect against unfair treatment.

Methods: This secondary analysis applied a modified version of the rigorous and accelerated data reduction technique to conduct a thematic analysis of comments to an open-ended prompt. Comments were coded by multiple trained researchers then grouped and merged into illustrative themes via qualitative techniques.

Results: Of 1004 responses to the quantitative survey, 162 physicians completed the open-ended prompt. Initial codes (n = …

Sample Multiplexing For Retinal Single-Cell Rna Sequencing, Justin Ma, Ting-Kuan Chu, Maria Polo-Prieto, Yong H Park, Yumei Li, Rui Chen, Graeme Mardon, Benjamin J Frankfort, Nicholas M Tran

Faculty, Staff and Students Publications

Rare cell populations can be challenging to characterize using microfluidic single-cell RNA sequencing (scRNA-seq) platforms. Typically, the population of interest must be enriched and pooled from multiple biological specimens for efficient collection. However, these practices preclude the resolution of sample origin together with phenotypic data and are problematic in experiments in which biological or technical variation is expected to be high (e.g., disease models, genetic perturbation screens, or human samples). One solution is sample multiplexing whereby each sample is tagged with a unique sequence barcode that is resolved bioinformatically. We have established a scRNA-seq sample multiplexing pipeline for mouse retinal …

Epigenome Reprogramming Through H3k27 And H3k4 Trimethylation As A Resistance Mechanism To Dna Methylation Inhibition In Brafv600e-Mutated Colorectal Cancer, Hey Min Lee, Ajay Kumar Saw, Van K Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Micheal Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai

Faculty, Staff and Student Publications

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.

Experimental design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.

Results: A profound reduction of DNA …

Assessing Mechanical Agency During Apical Apoptotic Cell Extrusion, Sommer Anjum, Llaran Turner, Youmna Atieh, George T Eisenhoffer, Lance A Davidson

Faculty, Staff and Student Publications

Homeostasis is necessary for epithelia to maintain barrier function and prevent the accumulation of defective cells. Unfit, excess, and dying cells in the larval zebrafish tail fin epidermis are removed via controlled cell death and extrusion. Extrusion coincides with oscillations of cell area, both in the extruding cell and its neighbors. Here, we develop a biophysical model of this process to explore the role of autonomous and non-autonomous mechanics. We vary biophysical properties and oscillatory behaviors of extruding cells and their neighbors along with tissue-wide cell density and viscosity. We find that cell autonomous processes are major contributors to the …

Low-Molecular Weight Cyclin E Confers A Vulnerability To Pkmyt1 Inhibition In Triple-Negative Breast Cancer, Mi Li, Amriti R Lulla, Yan Wang, Spyros Tsavaschidis, Fuchenchu Wang, Cansu Karakas, Tuyen D T Nguyen, Tuyen N Bui, Marc A Pina, Mei-Kuang Chen, Sofia Mastoraki, Asha S Multani, Natalie W Fowlkes, Aysegul Sahin, C Gary Marshall, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low-molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1-S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 …

Oral Acute And Sub-Acute Toxic Effects Of HydroalcoholicTerminalia ChebulaRetz AndAchillea WilhelmsiiExtracts In Balb/C Mice, Mahnaz Jafari, Kourosh Manochehri Naeini, Zahra Lorigooini, Rasool Namjoo

BioMedicine

Background: This study examined the acute and sub-acute toxic effects ofTerminalia chebulaandAchillea wilhelmsiiextracts on the murine model.

Methods: In both phases, mice were assigned to intervention and control groups. At the end of study, the liver, kidney, and heart tissues were collected for histopathological studies.

Results: In the acute phase of the study, the safe dose was ≤5000 mg/kg for both extracts. In sub-acute phase, LD50 (95% CI) ofAchillea wilhelmsiiextract was determined ≥5000 mg/kg and that ofTerminalia chebulaextract 2754.436 (2438-3114) mg/kg. The highest dose ofT. chebulaextract induced few histopathological changes.

Conclusion: It will be useful to gain information on the …

The Potential Therapeutic Effect For Melatonin And Mesenchymal Stem Cells On Hepatocellular Carcinoma, Yasser Mohamed, Mohamed A. Basyony, Nabila I. El-Desouki, Walied S. Abdo, Mohammed A. El-Magd

BioMedicine

Background/aim: Herein, we investigated the potential therapeutic effect of Melatonin (Mel) and/or mesenchymal stem cells (MSCs) on rat model of HCC.

Materials and Methods: Female mature rats were divided into 5 groups (n= 10/group): normal (Nor), HCC group intraperitoneally injected with 200 mg/kg DEN, and 3 treated groups; HCC + Mel (Mel) group given Mel intraperitoneally 20 mg/kg, twice a week, HCC + MSCs (MSCs) group intravenously injected by 1 × 10⁶ cells, and HCC + MSCs (Mel +MSCs) group.

Results: Rats in HCC group showed most deteriorated effect in form of increased mortality and relative liver weight, elevated …