Medical Molecular Biology Commons^™

Rbm39 Contributes To Mgmt Maintenance In Response To Temozolomide-Induced Dna Damage, Vahid Khalaj, Jack T Adams, Solmaz Aghaamiri, Servando Hernandez Vargas, Tyler M Bateman, Sukhen C Ghosh, Majid Momeny, Ali Azhdarinia

The Brown Foundation: Institute of Molecular Medicine

Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. In this study, we investigated the effect of RNA-binding motif protein 39 (RBM39) downregulation on MGMT protein levels, based on prior observations suggesting an association between these two proteins. Pharmacological depletion or siRNA-mediated knockdown of RBM39 led to a marked reduction in MGMT protein levels in MGMT-expressing cancer cells. We further showed that dual targeting of RBM39 (using indisulam) and MGMT (with O6-benzylguanine) synergistically enhanced MGMT depletion. Functionally, combined indisulam and TMZ treatment significantly …

Prevalence Of Local Ige Elevation And Its Effect On Intranasal Capsaicin Therapy In The Nonallergic Rhinitis Population, Kunal R Shetty, Salman Hasan, Christopher Bankston, Dylan Vance, Elaijah Islam, Gabriella Cruz, Faramarz Ashoori, David Z Allen, William C Yao, Martin J Citardi, Amber U Luong

The Brown Foundation: Institute of Molecular Medicine

No abstract provided.

The Genomes Of Nematode-Trapping Fungi Provide Insights Into The Origin And Diversification Of Fungal Carnivorism, Yani Fan, Minghao Du, Weiwei Zhang, Wei Deng, Ence Yang, Shunxian Wang, Luwen Yan, Liao Zhang, Seogchan Kang, Jacob L Steenwyk, Zhiqiang An, Xingzhong Liu, Meichun Xiang

The Brown Foundation: Institute of Molecular Medicine

Nematode-trapping fungi (NTF), most of which belong to a monophyletic lineage in Ascomycota, cannibalize nematodes and other microscopic animals, raising questions regarding the types and mechanisms of genomic changes that enabled carnivorism and adaptation to the carbon-rich and nitrogen-poor environment created by the Permian-Triassic extinction event. To address these questions, we conducted comparative genomic analyses of 21 NTF and 21 non-NTF. Carnivorism-associated changes include expanded genes for nematode capture, infection, and consumption (e.g., adhesive proteins, CAP superfamily, eukaryotic aspartyl proteases, and serine-type peptidases). Although the link between secondary metabolite (SM) production and carnivorism remains unclear, we found that the number …

The Non-Coding Rna Journal Club: Highlights On Recent Papers-14, El Cheima Mhamedi, Florent Hubé, Suresh K. Alahari, Francisco J. Enguita, Barbara Pardini, Mark W. Feinberg, Laura Poliseno, Beshoy Armanios, Jing Jin, Xiao-Bo Zhong, Nikolaos Sideris, Salih Bayraktar, Leandro Castellano, Gaetano Santulli, Stanislovas S. Jankauskas, Will S. Plewa, Simon J. Conn, Ling Yang, Patrick K. Shiu, Abhishek Kaushik, Alexander Serganov, Gentile, Giuseppe Viglietto, Nicola Amodio, Tijana Mitić, Andrea Caporali

School of Graduate Studies Faculty Publications

The field of non-coding RNA research is advancing at a breathtaking pace, continually uncovering new layers of regulatory complexity and functional diversity [...].

Targeting Gliomas With Beta-Amyloid-Specific Dyes: A Novel Approach For In Vivo Staining And Potential Therapeutic Applications, Lilia Kucheryavykh, Jescelica Ortiz Rivera, Boris Ermolinsky, Vassiliy Tsytsarev, Lynnette Cary, Janaina Alves, Adriana Reyes, Noelis De La Cruz-Rivera, Kevin Rosa Gonzalez, Felix Narvaez Irizarry

School of Integrative Biological & Chemical Sciences Faculty Publications

Gliomas, the most common primary brain tumors, present significant diagnostic and treatment challenges due to their infiltrative nature and heterogeneity. Our previous research revealed that glioma tumors in both animals and humans accumulate beta-amyloid protein (Aβ), detectable through immunohistochemical methods or staining with amyloid-specific dyes. We hypothesize that beta-amyloid-specific dyes could serve as glioma markers, potentially enabling the delineation of glioma tumors or targeted therapeutics delivery. In this study, the specificity and blood-brain barrier permeability of two fluorescent beta-amyloid-specific dyes, Brilliant Blue G (BBG) and BODIPY-based Amyloid Probe-1 (BAP-1), were evaluated in C57Bl/6 mouse glioma implantation models using GL261 and …

Female Cardioprotection In A Mouse Model Of Alcohol-Associated Cardiomyopathy, Joshua M. Edavettal, Meagan Donovan, Nicholas R. Harris, Xavier R. Chapa-Dubocq, Keishla M. Rodríguez-Graciani, Janos Paloczi, Liz Simon, Bysani Chandrasekar, Jason D. Gardner

School of Graduate Studies Faculty Publications

Chronic alcohol misuse is the leading cause of non-ischemic dilated cardiomyopathy, and the molecular mechanisms underlying the development of alcohol-associated cardiomyopathy (ACM), particularly regarding sex-specific susceptibility and mitochondrial contributions, are not fully known. In this study, we utilized a preclinical model of chronic + binge ethanol consumption to investigate sex differences in disease severity and mitochondrial function. Male and female C57BL/6J mice were fed ethanol or control liquid diets for 30 days, with 2 binge episodes on days 10 and 30. Cardiac morphology was assessed via echocardiography and cardiac function via left ventricular pressure-volume catheterization. Mitochondrial function was evaluated ex …

Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration And Mitigates Muscular Dystrophy, Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar

The Brown Foundation: Institute of Molecular Medicine

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen‐related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERRα signaling in pre‐clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative …

Functional Roles Of The Complement Immune System In Cardiac Inflammation And Hypertrophy, Kathryn D Hok, Haydn E Rich, Anthony Shadid, Lavanya Gunamalai, Tingting Weng-Mills, Rajarajan A Thandavarayan, Nirmal K Banda, Marie-Francoise Doursout, Marcos I Restrepo, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation-classical, lectin, and alternative-are implicated in developing cardiac damage, inflammation, and hypertrophy due to …

Escape Of Kdm6a From X Chromosome Is Detrimental To Ischemic Brains Via Irf5 Signaling, Conelius Ngwa, Afzal Misrani, Kanaka Valli Manyam, Yan Xu, Shaohua Qi, Romana Sharmeen, Juneyoung Lee, Long-Jun Wu, Louise Mccullough, Fudong Liu

The Brown Foundation: Institute of Molecular Medicine

The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17–20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the …

Slb-Mssim: A Spectral Library-Based Multiplex Segmented Sim Platform For Single-Cell Proteomic Analysis, Lakmini Senavirathna, Cheng Ma, Van-An Duong, Hong-Yuan Tsai, Ru Chen, Sheng Pan

The Brown Foundation: Institute of Molecular Medicine

Mass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by a multiplex segmented selected ion monitoring (msSIM) technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a …

Investigating Machine Learning Algorithms To Classify Label-Free Images Of Pancreatic Neuroendocrine Neoplasms, Noelle Daigle, Shuyuan Guan, Suzann Duan, Thomas G Knapp, Eung-Joo Lee, Ali Azhdarinia, Sukhen C Ghosh, Solmaz Aghaamiri, Servando Hernandez Vargas, Naruhiko Ikoma, Jeannelyn Estrella, Martin J Schnermann, Tobias Else, Michelle Kang Kim, Juanita L Merchant, Travis W Sawyer

The Brown Foundation: Institute of Molecular Medicine

Significance: Pancreatic neuroendocrine neoplasms (PNENs) are an uncommon cancer whose incidence rate has increased dramatically in recent years. Surgery is the only potentially curative treatment, which relies on both preoperative tumor localization and postoperative margin definition using histopathological examination for decision making. If pathology could be automated, valuable time and resources could be saved.

Aim: In this study, we investigate the ability of machine learning (ML) with handcrafted features, as well as deep learning, to classify label-free microscopy images of PNENs as a first step toward automated pathology of such tumors.

Approach: Patient samples of two different preparation types were …

Serum Endotrophin Relates To Blood Pressure In Young South Asian Women But Not White Women: Evidence Of Ethnic Variation In Its Early Vascular Implications, Ravi Retnakaran, Dawei Bu, Jiajie Pu, Philip W Connelly, Anthony J Hanley, Ningyan Zhang, Zhiqiang An, Bernard Zinman, Philipp E Scherer

The Brown Foundation: Institute of Molecular Medicine

BACKGROUND: Endotrophin is a novel circulating fibroinflammatory protein that has recently been associated with cardiovascular disease (CVD) and all-cause mortality. However, little is known about its role early in the natural history of vascular disease nor whether it exhibits ethnicity-specific variation. Recognizing that South Asians have an elevated risk of ultimately developing CVD, we sought to address these questions by characterizing endotrophin and its physiologic correlates in young South Asian women as compared to White women.

METHODS: From a cohort recruited in pregnancy and followed to 1-year after delivery, we identified 40 participants of South Asian descent and 40 age- …

Association Of Genetic Scores Related To Insulin Resistance With Neurological Outcomes In Ancestrally Diverse Cohorts From The Trans-Omics For Precision Medicine (Topmed) Program, Chloé Sarnowski, Yixin Zhang, Farah Ammous, Lincoln M P Shade, Daniel Dicorpo, Xueqiu Jian, Donna K Arnett, Thomas R Austin, Alexa Beiser, Joshua C Bis, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Charles S Decarli, Harsha Doddapaneni, Josée Dupuis, David W Fardo, Jose C Florez, Stacey Gabriel, Richard A Gibbs, David C Glahn, Namrata Gupta, Hector M González, Kevin A González, Konstantinos Hatzikotoulas, Kathleen M Hayden, Susan R Heckbert, Bertha Hidalgo, Alicia Huerta-Chagoya, Timothy M Hughes, Sharon L R Kardia, Charles L Kooperberg, Lenore J Launer, W T Longstreth, Ravi Mandla, Rasika A Mathias, Andrew P Morris, Thomas H Mosley, Ilya M Nasrallah, Paul Nyquist, Bruce M Psaty, Qibin Qi, Laura M Raffield, Nigel W Rayner, Alexander P Reiner, Claudia L Satizabal, Elizabeth Selvin, Magdalena D R Sevilla-Gonzalez, Albert V Smith, Jennifer A Smith, Kirk Smith, Beverly M Snively, Lorraine Southam, Tamar Sofer, Ken Suzuki, Henry J Taylor, Miriam S Udler, Karine A Viaud-Martinez, Sylvia Wassertheil-Smoller, Alexis C Wood, Lisa R Yanek, Xianyong Yin, Alisa K Manning, Jerome I Rotter, Stephen S Rich, James B Meigs, Myriam Fornage, Sudha Seshadri, Alanna C Morrison, Topmed Neurocognitive Working Group, Topmed Diabetes Working Group

The Brown Foundation: Institute of Molecular Medicine

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P <  0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P <  0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.

Mt1-Mmp Inhibition Rejuvenates Ageing Brain And Rescues Cognitive Deficits In Obesity, Pallavi Asthana, Liguo Li, Lin Lu, Jiayan Wu, Shuo Zhang, Ningning Li, Sheung Kin Ken Wong, Susma Gurung, Yijing Zhang, Yuwan Lin, Yufeng Peng, Zongtang Xu, Kui Ming Chan, Lixiang Zhai, Aiping Lyu, Zhao-Xiang Bian, Xin Ge, Ashok Iyaswamy, Min Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong

The Brown Foundation: Institute of Molecular Medicine

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the …

Ybx1-Mediated Activation Of Srebp2 Drives Sorafenib Resistance Via Cholesterol Biosynthesis In Hepatocellular Carcinoma, Veerababu Nagati, Dennis Kwabiah, Yamile Abuchard, Ana Ayala Pazzi, Shaibir Hussain, Salique H. Shaham, Manish Tripathi

Research Colloquium

Background: Hepatocellular carcinoma (HCC) is an aggressive, largely chemo-resistant cancer with a poor prognosis and is the leading cause of cancer-related deaths worldwide. Currently, there is no effective systemic chemotherapy for HCC. Sorafenib is a multikinase inhibitor commonly used as the first-line treatment for advanced HCC. However, acquired drug resistance significantly limits its clinical effectiveness. The Y-box binding protein (YBX1) is an oncogenic RNA-binding protein found to be upregulated in sorafenib-resistant HCC cells and tissues.

Methods: HCC model SK Hep1, YBX1 overexpression, and knockdown cells were prepared by transient transfection with puromycin selection, and stable cell lines were established through …

Tc-Ptp Enhances Cordycepin-Induced Apoptosis In Human Pancreatic Cancer Cells, Olivia Samaie, Rodrigo Vidales, Lindsey Shim, Murali M. Yallapu, Subhash C. Chauhan, Mushfiq Hassan Shaikh, Dae Joon Kim

Research Colloquium

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy marked by early metastasis, dense desmoplastic stroma, and profound resistance to conventional therapies. Despite the development of combination regimens such as gemcitabine and FOLFIRINOX, outcomes remain dismal, with median survival under one year for metastatic cases. This underscores the urgent need for novel therapeutic approaches that target multiple pathways simultaneously. T-cell protein tyrosine phosphatase (TC-PTP) is one of nonreceptor PTPs that negatively regulates oncogenic signaling pathways, particularly STAT3 and AKT, both of which are constitutively active in many solid tumors. Cordycepin, a nucleoside analogue derived from Cordyceps militaris, has …

Epac1 Deletion Attenuates Müller Glial Pathological Activation And Mitigates Retinal Neurodegeneration In Ischemia-Induced Retinopathy, Shuizhen Shi, Fan Xia, Zhongqiao Lu, Erick Palacios, Fang Mei, Massoud Motamedi, Xiaodong Cheng, Hua Liu, Wenbo Zhang

The Brown Foundation: Institute of Molecular Medicine

Introduction: Ischemia-induced retinopathies, such as retinopathy of prematurity and proliferative diabetic retinopathy, are major causes of vision loss. Both pathological neovascularization and neuronal damage contribute to vision impairment in these conditions, yet current therapies primarily target neovascularization and may further compromise neuronal health.

Objectives: Cyclic AMP (cAMP) is a widely recognized second messenger regulating diverse physiological and pathological processes. Exchange protein directly activated by cAMP (Epac) is a recently identified effector of cAMP signaling. This study aimed to investigate the role of Epac1 in ischemia-induced retinopathy and elucidate its underlying mechanisms using a mouse model of oxygen-induced retinopathy (OIR).

Methods: …

Cetuximab Increases Lgr5 Expression And Augments Lgr5-Targeting Antibody-Drug Conjugate Efficacy In Patient-Derived Colorectal Cancer Models, Peyton C High, Zhengdong Liang, Cara Guernsey-Biddle, Shraddha Subramanian, Yueh-Ming Shyu, Adela M Aldana, Yukimatsu Toh, Kendra S Carmon

The Brown Foundation: Institute of Molecular Medicine

Colorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warrants strategies to improve ADC efficacy. Here, we report that cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody indicated for RASWT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well tolerated …

Somatostatin Receptor 2 Overexpression In Hepatocellular Carcinoma: Implications For Cancer Biology And Therapeutic Applications, Servando Hernandez Vargas, Solmaz Aghaamiri, Jack T Adams, Tyler M Bateman, Belkacem Acidi, Sukhen C Ghosh, Vahid Khalaj, Ahmed O Kaseb, Hop S Tran Cao, Majid Momeny, Ali Azhdarinia

The Brown Foundation: Institute of Molecular Medicine

Background: Somatostatin receptor 2 (SSTR2), a G protein-coupled receptor, is overexpressed in multiple malignancies, including hepatocellular carcinoma (HCC). While SSTR2 has traditionally been viewed as an inhibitory receptor involved in suppressing hormone secretion and cell proliferation, emerging evidence suggests a more complex role in cancer biology. However, the functional implications of SSTR2 expression in HCC remain poorly understood. This study aimed to systematically investigate the molecular landscape associated with SSTR2 expression in HCC and evaluate its potential as a therapeutic target.

Methods: SSTR2 expression patterns across 22 tumor types were assessed using TNMplot, and its expression in HCC was further …

Longitudinal Associations Of Epigenetic Aging With Cognitive Aging In Hispanic/Latino Adults From The Hispanic Community Health Study/Study Of Latinos, Myriam Fornage, Wassim Tarraf, Rui Xia, Adriana Ordonez, Tamar Sofer, Freddie Márquez, Bharat Thyagarajan, Gregory A Talavera, Linda C Gallo, Charles Decarli, Hector M González

The Brown Foundation: Institute of Molecular Medicine

Due to the paucity of longitudinal DNA methylation data (DNAm), especially among Hispanic/Latino adults, the association between changes in epigenetic clocks over time and cognitive aging phenotypes has not been investigated. This longitudinal study included 2671 Hispanic/Latino adults (57 years; 66% women) with blood DNAm data and neurocognitive function assessed at two visits ~7 years apart. We evaluated the associations of 5 epigenetic clocks and their between-visit change with multiple measures of cognitive aging that included a global and domain-specific cognitive function score at each visit, between-visit change in global and domain-specific cognitive function score, and MCI diagnosis at visit …