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Genome-Wide Association Studies Of Metabolites In Finnish Men Identify Disease-Relevant Loci, Xianyong Yin, Adam E Locke, Erica Young, Liron Ganel, Indraniel Das, Haley Abel, Nathan O Stitziel, Et Al

Open Access Publications

Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.

The Effects Of The Combination Of Mesenchymal Stromal Cells And Nanofiber-Hydrogel Composite On Repair Of The Contused Spinal Cord, Agnes E Haggerty, Ines Maldonado-Lasunción, Yohshiro Nitobe, Kentaro Yamane, Megan M Marlow, Hua You, Chi Zhang, Brian Cho, Xiaowei Li, Sashank Reddy, Hai-Quan Mao, Martin Oudega

Open Access Publications

A bone marrow-derived mesenchymal stromal cell (MSC) transplant and a bioengineered nanofiber-hydrogel composite (NHC) have been shown to stimulate nervous tissue repair in the contused spinal cord in rodent models. Here, these two modalities were combined to assess their repair effects in the contused spinal cord in adult rats. Cohorts of contused rats were treated with MSC in NHC (MSC-NHC), MSC in phosphate-buffered saline (MSC-PBS), NHC, or PBS injected into the contusion site at 3 days post-injury. One week after injury, there were significantly fewer CD68+ cells in the contusion with MSC-NHC and NHC, but not MSC-PBS. The reduction in …

Multimodal Thrombectomy Device For Treatment Of Acute Deep Venous Thrombosis, Usama Ismail, Roger A Rowe, John Cashin, Guy M Genin, Mohamed A Zayed

Open Access Publications

Deep vein thrombosis (DVT) is a potentially deadly medical condition that is costly to treat and impacts thousands of Americans every year. DVT is characterized by the formation of blood clots within the deep venous system of the body. If a DVT dislodges it can lead to venous thromboembolism (VTE) and pulmonary embolism (PE), both of which can lead to significant morbidity or death. Current treatment options for DVT are limited in both effectiveness and safety, in part because the treatment of the DVT cannot be confined to a defined sequestered treatment zone. We therefore developed and tested a novel …

Monospecific And Bispecific Monoclonal Sars-Cov-2 Neutralizing Antibodies That Maintain Potency Against B.1.617, Lei Peng, Yingxia Hu, Madeleine C Mankowski, Ping Ren, Rita E Chen, Michael S Diamond, Et Al

Open Access Publications

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong …

Structural And Molecular Rationale For The Diversification Of Resistance Mediated By The Antibiotic_Nat Family, Peter J Stogios, Emily Bordeleau, Zhiyu Xu, Tatiana Skarina, Elena Evdokimova, Sommer Chou, Luke Diorio-Toth, Alaric W D'Souza, Sanket Patel, Gautam Dantas, Gerard D Wright, Alexei Savchenko

Open Access Publications

The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases. We determined a pan-family antibiogram of 21 Antibiotic_NAT enzymes, including 8 derived from clinical isolates and 13 from environmental metagenomic samples. We find that environment-derived representatives confer high-level, broad-spectrum resistance, including against the atypical …

Therapeutic Drug Monitoring In Perianal Fistulizing Crohn's Disease, Mir Zulqarnain, Parakkal Deepak, Andres J Yarur

Open Access Publications

Perianal fistulas are a common complication of Crohn's disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn's disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is …

A Bayesian Network To Predict The Risk Of Post Influenza Vaccination Guillain-Barré Syndrome: Development And Validation Study, Yun Huang, Chongliang Luo, Ying Jiang, Jingcheng Du, Cui Tao, Yong Chen, Yuantao Hao

Open Access Publications

BACKGROUND: Identifying the key factors of Guillain-Barré syndrome (GBS) and predicting its occurrence are vital for improving the prognosis of patients with GBS. However, there are scarcely any publications on a forewarning model of GBS. A Bayesian network (BN) model, which is known to be an accurate, interpretable, and interaction-sensitive graph model in many similar domains, is worth trying in GBS risk prediction.

OBJECTIVE: The aim of this study is to determine the most significant factors of GBS and further develop and validate a BN model for predicting GBS risk.

METHODS: Large-scale influenza vaccine postmarketing surveillance data, including 79,165 US …

Maternal Obesogenic Diet Enhances Cholestatic Liver Disease In Offspring, Michael D Thompson, Holly Hinrichs, Austin Faerber, Phillip I Tarr, Nicholas O Davidson

Open Access Publications

Human and animal model data show that maternal obesity promotes nonalcoholic fatty liver disease in offspring and alters bile acid (BA) homeostasis. Here we investigated whether offspring exposed to maternal obesogenic diets exhibited greater cholestatic injury. We fed female C57Bl6 mice conventional chow (CON) or high fat/high sucrose (HF/HS) diet and then bred them with lean males. Offspring were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 2 weeks to induce cholestasis, and a subgroup was then fed CON for an additional 10 days. Additionally, to evaluate the role of the gut microbiome, we fed antibiotic-treated mice cecal contents from CON or HF/HS offspring, …

Sorl1 Polymorphisms In Mexican Patients With Alzheimer's Disease, Danira Toral-Rios, Elizabeth Ruiz-Sánchez, Nancy Lucero Martínez Rodríguez, Marlene Maury-Rosillo, Óscar Rosas-Carrasco, Fernando Becerril-Pérez, Francisco Mena-Barranco, Rosa Carvajal-García, Daniela Silva-Adaya, Yair Delgado-Namorado, Gerardo Ramos-Palacios, Carmen Sánchez-Torres, Victoria Campos-Peña

Open Access Publications

The present study evaluated the risk effect of 12 Single Nucleotide Polymorphisms in the SORL1 gene in the Mexican population using Late-Onset Alzheimer's Disease (LOAD) and control subjects. Considering APOE as the strongest genetic risk factor for LOAD, we conducted interaction analyses between single nucleotide polymorphisms (SNPs) and the APOE genotype.

METHODS: Patients were interviewed during their scheduled visits at neurologic and geriatric clinics from different institutions. The LOAD diagnosis included neurological, geriatric, and psychiatric examinations, as well as the medical history and neuroimaging. Polymorphisms in

RESULTS: The A/A genotype in rs1784933 might be associated with an increased LOAD risk. …

Constructing An Adapted Cascade Of Diabetes Care Using Inpatient Admissions Data: Cross-Sectional Study, Irene Ryan, Cynthia Herrick, Mary F E Ebeling, Randi Foraker

Open Access Publications

BACKGROUND: The diabetes mellitus cascade of care has been constructed to evaluate diabetes care at a population level by determining the percentage of individuals diagnosed and linked to care as well as their reported glycemic control.

OBJECTIVE: We sought to adapt the cascade of care to an inpatient-only setting using the electronic health record (EHR) data of 81,633 patients with type 2 diabetes.

METHODS: In this adaptation, linkage to care was defined as prescription of diabetes medications within 3 months of discharge, and control was defined as hemoglobin A

RESULTS: We found that out of 81,633 patients, 28,716 (35.2%) were …

Neutrophil-Vascular Interactions Drive Myeloperoxidase Accumulation In The Brain In Alzheimer's Disease, Leon C D Smyth, Et Al

Open Access Publications

INTRODUCTION: Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain.

MATERIALS AND METHODS: We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD.

RESULTS: There was an increase in neutrophils in AD …

Micrornas In Pulmonary Hypertension, From Pathogenesis To Diagnosis And Treatment, Junhua Xu, John Linneman, Yanfeng Zhong, Haoyang Yin, Qinyi Xia, Kang Kang, Deming Gou

Open Access Publications

Pulmonary hypertension (PH) is a fatal and untreatable disease, ultimately leading to right heart failure and eventually death. microRNAs are small, non-coding endogenous RNA molecules that can regulate gene expression and influence various biological processes. Changes in microRNA expression levels contribute to various cardiovascular disorders, and microRNAs have been shown to play a critical role in PH pathogenesis. In recent years, numerous studies have explored the role of microRNAs in PH, focusing on the expression profiles of microRNAs and their signaling pathways in pulmonary artery smooth muscle cells (PASMCs) or pulmonary artery endothelial cells (PAECs), PH models, and PH patients. …

Locommotion: A Prospective, Non-Interventional, Multinational Study Of Real-Life Current Standards Of Care In Patients With Relapsed And/Or Refractory Multiple Myeloma, Maria-Victoria Mateos, Katja Weisel, Ravi Vij, Et Al

Open Access Publications

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median …

Increasing Dorsal Tilt In Distal Radius Fractures Does Not Increase Median Nerve Strain, Chukwuka Obiofuma, Christopher Dy, Leanne E Iannucci, Spencer P Lake, David Brogan

Open Access Publications

Although extensive research shows an association between distal radius fractures and the development of median nerve related pathologies such as carpal tunnel syndrome, none directly track how the resulting angular deformity relates to likelihood of development of median nerve pathology.

Methods: Median nerve strain was measured with a custom-built system using a camera, optical markers, and a proprietary segmentation algorithm. After initial validation of the system in a cadaver model, our system was used to assess strain in 10 cadaver arms with a simulated distal radius fracture and increasing dorsal angulation. The measured strain at each angle was then analyzed …

Spherical Nucleic Acids As Precision Therapeutics For The Treatment Of Cancer—From Bench To Bedside, Akanksha S Mahajan, Alexander H Stegh

Open Access Publications

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their "free" form. Early phase …

Facing The Realities Of Pragmatic Design Choices In Environmental Health Studies: Experiences From The Household Air Pollution Intervention Network Trial, William Checkley, Victor G Davila-Roman, Et Al

Open Access Publications

No abstract provided.

Predictors Of Humoral Response To Sars-Cov-2 Mrna Vaccine Bnt162b2 In Patients Receiving Maintenance Dialysis, Li Tingting, Sumanth Gandra, Kimberly A. Reske, Margaret A. Olsen, Silvana Bommarito, Candace Miller, Karl G. Hock, Claire A. Ballman, Christina Su, Na Le Dang, Jennie H. Kwon, David K. Warren, Victoria J. Fraser, Christopher W. Farnsworth

Open Access Publications

No abstract provided.

Conditional Loss Of Ikkα In Osterix + Cells Has No Effect On Bone But Leads To Age-Related Loss Of Peripheral Fat, Jennifer L Davis, Nitin Kumar Pokhrel, Linda Cox, Nidhi Rohatgi, Roberta Faccio, Deborah J Veis

Open Access Publications

NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly …

Movement Through Chemotherapy Delay To Initiation Among Breast Cancer Patients: A Qualitative Analysis, Ashley J Housten, Catalina Malinowski, Edna Paredes, Cassandra L Harris, Lorna H Mcneill, Mariana Chavez-Macgregor

Open Access Publications

Purpose: (Neo) adjuvant chemotherapy decreases the risk of recurrence and improves overall survival among breast cancer patients; however, delays in chemotherapy initiation are associated with adverse health outcomes. The causes of delay are complex and include interrelated social, economic, cultural, environmental, and health system factors. Project Start was a qualitative study designed to assess and identify the multilevel factors contributing to the barriers and facilitators of initiating chemotherapy.

Patients and Methods: Women diagnosed with primary invasive breast cancer who experienced ≥60 day delay in (neo) adjuvant chemotherapy initiation were included. Participants completed semi-structured interviews exploring barriers and facilitators to starting …

The Bacterial Microbiota Regulates Normal Hematopoiesis Via Metabolite-Induced Type 1 Interferon Signaling, Hannah Yan, Forrest C Walker, Arushana Ali, Hyojeong Han, Lin Tan, Lucas Veillon, Philip L Lorenzi, Megan T Baldridge, Katherine Y King

Open Access Publications

Antibiotic therapy, especially when administered long term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota. We reported previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined. We sought to identify the cell type(s) through which STAT1 promotes microbiota-mediated hematopoiesis and to elucidate which upstream signaling pathways trigger STAT1 signaling. Using conditional knockout and chimeric mice, we …

Solving Neurodegeneration: Common Mechanisms And Strategies For New Treatments, Lauren K Wareham, Albert A Davis, Et Al

Open Access Publications

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for …

A Phase Ii Trial Of An Alternative Schedule Of Palbociclib And Embedded Serum Tk1 Analysis, Jairam Krishnamurthy, Jingqin Luo, Rama Suresh, Foluso Ademuyiwa, Caron Rigden, Timothy Rearden, Katherine Clifton, Katherine Weilbaecher, Ashley Frith, Anna Roshal, Mathew Cherian, Tracy Summa, Brittney Haas, Shana Thomas, Leonel Hernandez-Aya, Lindsey Peterson, Cynthia X Ma, Et Al

Open Access Publications

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase …

Mitochondrial Phenotypes In Genetically Diverse Neurodegenerative Diseases And Their Response To Mitofusin Activation, Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy, Gerald W Dorn Ii

Open Access Publications

Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect …

Predicting Mitochondrial Dynamic Behavior In Genetically Defined Neurodegenerative Diseases, Gerald W Dorn Ii, Xiawei Dang

Open Access Publications

Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich's ataxia, dominant optic atrophy, and Alzheimer's, Huntington's, and Parkinson's diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to …

Nanoluc Reporters Identify Col4a5 Nonsense Mutations Susceptible To Drug-Induced Stop Codon Readthrough, Kohei Omachi, Hirofumi Kai, Michel Roberge, Jeffrey H Miner

Open Access Publications

Alport syndrome, a disease of kidney, ear, and eye, is caused by pathogenic variants in the

Cryo-Em Analysis Of Ebola Virus Nucleocapsid-Like Assembly, Yan Wang, Jennifer M Binning, Grigore D Pintilie, Wah Chiu, Gaya K Amarasinghe, Daisy W Leung, Zhaoming Su

Open Access Publications

This protocol describes the reconstitution of the filamentous Ebola virus nucleocapsid-like assembly

Generation Of Human Induced Pluripotent Stem Cell-Derived Cerebral Organoids For Cellular And Molecular Characterization, Corina Anastasaki, Anna F Wilson, Alexander S Chen, Michelle L Wegscheid, David H Gutmann

Open Access Publications

Human induced pluripotent stem cell (hiPSC)-derived cerebral organoids (COs) can serve as an

Dissecting The Cellular Landscape And Transcriptome Network In Viral Myocarditis By Single-Cell Rna Sequencing, Ninaad Lasrado, Nicholas Borcherding, Rajkumar Arumugam, Timothy K Starr, Jay Reddy

Open Access Publications

Coxsackievirus B3 (CVB3)-induced myocarditis is commonly employed to study viral pathogenesis in mice. Chronically affected mice may develop dilated cardiomyopathy, which may involve the mediation of immune and nonimmune cells. To dissect this complexity, we performed single-cell RNA sequencing on heart cells from healthy and myocarditic mice, leading us to note significant proportions of myeloid cells, T cells, and fibroblasts. Although the transcriptomes of myeloid cells were mainly of M2 phenotype, the Th17 cells, CTLs, and Treg cells had signatures critical for cytotoxic functions. Fibroblasts were heterogeneous expressing genes important in fibrosis and regulation of inflammation and immune responses. The …

A Novel Fusion Protein Scaffold 18/12/Txm Activates The Il-12, Il-15, And Il-18 Receptors To Induce Human Memory-Like Natural Killer Cells, Celia C Cubitt, Ethan Mcclain, Michelle Becker-Hapak, Jennifer A Foltz, Pamela Wong, Julia A Wagner, Carly C Neal, Nancy D Marin, Lynne Marsala, Mark Foster, Timothy Schappe, Patrick Soon-Shiong, John Lee, Melissa M Berrien-Elliott, Todd A Fehniger

Open Access Publications

Natural killer (NK) cells are cytotoxic innate lymphoid cells that are emerging as a cellular immunotherapy for various malignancies. NK cells are particularly dependent on interleukin (IL)-15 for their survival, proliferation, and cytotoxic function. NK cells differentiate into memory-like cells with enhanced effector function after a brief activation with IL-12, IL-15, and IL-18. N-803 is an IL-15 superagonist composed of an IL-15 mutant (IL-15N72D) bound to the sushi domain of IL-15Rα fused to the Fc region of IgG1, which results in physiological trans-presentation of IL-15. Here, we describe the creation of a novel triple-cytokine fusion molecule, 18/12/TxM, using the N-803 …

Adherence Enables Neisseria Gonorrhoeae To Overcome Zinc Limitation Imposed By Nutritional Immunity Proteins, Jocelyn C Ray, Asya Smirnov, Stavros A Maurakis, Simone A Harrison, Eugene Ke, Walter J Chazin, Cynthia Nau Cornelissen, Alison K Criss

Open Access Publications

Neisseria gonorrhoeae (Gc) must overcome the limitation of metals such as zinc to colonize mucosal surfaces in its obligate human host. While the zinc-binding nutritional immunity proteins calprotectin (S100A8/A9) and psoriasin (S100A7) are abundant in human cervicovaginal lavage fluid, Gc possesses TonB-dependent transporters TdfH and TdfJ that bind and extract zinc from the human version of these proteins, respectively. Here we investigated the contribution of zinc acquisition to Gc infection of epithelial cells of the female genital tract. We found that TdfH and TdfJ were dispensable for survival of strain FA1090 Gc that was associated with Ect1 human immortalized epithelial …