Medical Specialties Commons^™

Egfr-Phosphorylated Gdh1 Harmonizes With Rsk2 To Drive Creb Activation And Tumor Metastasis In Egfr-Activated Lung Cancer, Jihoon Kang, Jaemoo Chun, Jung Seok Hwang, Chaoyun Pan, Jie Li, Austin C Boese, Isabelle Young, Courteney M Malin, Yibin Kang, Don L Gibbons, Gabriel Sica, Haian Fu, Suresh S Ramalingam, Lingtao Jin, Sumin Kang

Faculty, Staff and Student Publications

The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 …

Super-Enhanced Marco Variant Drives Triple-Negative Breast Cancer Progression, Weei-Chin Lin, Fang-Tsyr Lin

Faculty, Staff and Students Publications

No abstract provided.

Issues In Melanoma Detection: Semisupervised Deep Learning Algorithm Development Via A Combination Of Human And Artificial Intelligence, Xinyuan Zhang, Ziqian Xie, Yang Xiang, Imran Baig, Mena Kozman, Carly Stender, Luca Giancardo, Cui Tao

Faculty, Staff and Student Publications

BACKGROUND: Automatic skin lesion recognition has shown to be effective in increasing access to reliable dermatology evaluation; however, most existing algorithms rely solely on images. Many diagnostic rules, including the 3-point checklist, are not considered by artificial intelligence algorithms, which comprise human knowledge and reflect the diagnosis process of human experts.

OBJECTIVE: In this paper, we aimed to develop a semisupervised model that can not only integrate the dermoscopic features and scoring rule from the 3-point checklist but also automate the feature-annotation process.

METHODS: We first trained the semisupervised model on a small, annotated data set with disease and dermoscopic …

Gabapentin Disrupts Binding Of Perlecan To The Α 2Δ1 Voltage Sensitive Calcium Channel Subunit And Impairs Skeletal Mechanosensation, Perla C Reyes Fernandez, Christian S Wright, Adrianna N Masterson, Xin Yi, Tristen V Tellman, Andrei Bonteanu, Katie Rust, Megan L Noonan, Kenneth E White, Karl J Lewis, Uma Sankar, Julia M Hum, Gregory Bix, Danielle Wu, Alexander G Robling, Rajesh Sardar, Mary C Farach-Carson, William R Thompson

Faculty, Staff and Student Publications

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along …

Mapping Single-Cell Transcriptomes In The Intra-Tumoral And Associated Territories Of Kidney Cancer, Ruoyan Li, John R Ferdinand, Kevin W Loudon, Georgina S Bowyer, Sean Laidlaw, Francesc Muyas, Lira Mamanova, Joana B Neves, Liam Bolt, Eirini S Fasouli, Andrew R J Lawson, Matthew D Young, Yvette Hooks, Thomas R W Oliver, Timothy M Butler, James N Armitage, Tev Aho, Antony C P Riddick, Vincent Gnanapragasam, Sarah J Welsh, Kerstin B Meyer, Anne Y Warren, Maxine G B Tran, Grant D Stewart, Isidro Cortés-Ciriano, Sam Behjati, Menna R Clatworthy, Peter J Campbell, Sarah A Teichmann, Thomas J Mitchell

Faculty, Staff and Student Publications

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell …

Place Cells Dynamically Refine Grid Cell Activities To Reduce Error Accumulation During Path Integration In A Continuous Attractor Model, Jose A Fernandez-Leon, Ahmet Kerim Uysal, Daoyun Ji

Faculty, Staff and Students Publications

Navigation is one of the most fundamental skills of animals. During spatial navigation, grid cells in the medial entorhinal cortex process speed and direction of the animal to map the environment. Hippocampal place cells, in turn, encode place using sensory signals and reduce the accumulated error of grid cells for path integration. Although both cell types are part of the path integration system, the dynamic relationship between place and grid cells and the error reduction mechanism is yet to be understood. We implemented a realistic model of grid cells based on a continuous attractor model. The grid cell model was …

A Text-Based Smoking Cessation Intervention For Sexual And Gender Minority Groups: Protocol For A Feasibility Trial, Irene Tami-Maury, Rebecca Klaff, Allison Hussin, Nathan Grant Smith, Shine Chang, Lorna Mcneill, Lorraine R Reitzel, Sanjay Shete, Lorien C Abroms

Faculty, Staff and Student Publications

BACKGROUND: Smoking among sexual and gender minority (SGM) groups, which include lesbian, gay, bisexual, transgender, and queer individuals, has been reported to be highly prevalent. This is attributed to several factors, including minority-specific stress and targeted tobacco marketing. Therefore, this population is at an increased risk for tobacco-related diseases. SMS text messaging programs have been found to be effective for smoking cessation and appeal to traditionally hard-to-reach populations over other interventions. It has also been suggested that targeted and tailored interventions could be more effective among SGM smokers because they can be designed to assure a safe, validating health care …

High-Frequency Ultrasound In Patients With Seronegative Rheumatoid Arthritis, Junkui Wang, Miao Wang, Qinghua Qi, Zhibin Wu, Jianguo Wen

Faculty, Staff and Student Publications

This study aimed to investigate the value of high-frequency ultrasound (HFUS) in differentiation of the seronegative rheumatoid arthritis (SNRA) and osteoarthritis (OA) and in the diagnosis of SNRA. 83 patients diagnosed with SNRA (SNRA group) and 40 diagnosed with OA (OA group) who received HFUS were retrospectively analyzed. The grayscale (GS) scores, power Doppler (PD) scores, and bone erosion (BE)scores were recorded, and added up to calculate the total scores of US variables. The correlations of the total scores of US variables with the 28-joint disease activity score (DAS28), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were analyzed. The …

G-Rich Motifs Within Phosphorothioate-Based Antisense Oligonucleotides (Asos) Drive Activation Of Fxn Expression Through Indirect Effects, Feng Wang, Ezequiel Calvo-Roitberg, Julia M Rembetsy-Brown, Minggang Fang, Jacquelyn Sousa, Zachary J Kartje, Pranathi Meda Krishnamurthy, Jonathan Lee, Michael R Green, Athma A Pai, Jonathan K Watts

Faculty, Staff and Student Publications

Friedreich's ataxia is an incurable disease caused by frataxin (FXN) protein deficiency, which is mostly induced by GAA repeat expansion in intron 1 of the FXN gene. Here, we identified antisense oligonucleotides (ASOs), complementary to two regions within the first intron of FXN pre-mRNA, which could increase FXN mRNA by ∼2-fold in patient fibroblasts. The increase in FXN mRNA was confirmed by the identification of multiple overlapping FXN-activating ASOs at each region, two independent RNA quantification assays, and normalization by multiple housekeeping genes. Experiments on cells with the ASO-binding sites deleted indicate that the ASO-induced FXN activation was driven by …

Efficacy Of Cabozantinib In Metastatic Mit Family Translocation Renal Cell Carcinomas, Jonathan Thouvenin, Omar Alhalabi, Maria Carlo, Lucia Carril-Ajuria, Laure Hirsch, Nieves Martinez-Chanza, Sylvie Négrier, Luca Campedel, Dylan Martini, Delphine Borchiellini, Jad Chahoud, Massimo Lodi, Philippe Barthélémy, Elshad Hasanov, Andrew W Hahn, Thierry Gil, Srinivas R Viswanathan, Ziad Bakouny, Pavlos Msaouel, Mehmet Asim Bilen, Toni K Choueiri, Laurence Albiges, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear.

Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS).

Results: Fifty-two patients with metastatic TRCC treated in …

Inhibition Of The Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib In Loss-Of-Function Notch1-Mutant Head And Neck Cancer, Faye M Johnson, Filip Janku, Mohamed A Gouda, Hai T Tran, Jitesh D Kawedia, Debora Schmitz, Hendrik Streefkerk, J Jack Lee, Clark R Andersen, Defeng Deng, Seema Rawal, Pooja A Shah, Adel K El-Naggar, Jason M Johnson, Mitchell J Frederick

Faculty, Staff and Student Publications

BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC.

METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry.

RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, …

Consistency Of Efficacy Results Across Various Clinical Measures And Statistical Methods In The Lecanemab Phase 2 Trial Of Early Alzheimer’S Disease, Shobha Dhadda, Michio Kanekiyo, David Li, Chad J Swanson, Michael Irizarry, Scott Berry, Lynn D Kramer, Donald A Berry

Faculty, Staff and Student Publications

BACKGROUND: Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) …

Clinical Trial Development In Tp53-Mutated Locally Advanced And Recurrent And/Or Metastatic Head And Neck Squamous Cell Carcinoma, Cristina P Rodriguez, Hyunseok Kang, Jessica L Geiger, Barbara Burtness, Christine H Chung, Curtis R Pickering, Carole Fakhry, Quynh Thu Le, Sue S Yom, Thomas J Galloway, Erica Golemis, Alice Li, Jeffrey Shoop, Stuart Wong, Ranee Mehra, Heath Skinner, Nabil F Saba, Elsa R Flores, Jeffrey N Myers, James M Ford, Rachel Karchin, Robert L Ferris, Charles Kunos, Jean M Lynn, Shakun Malik

Faculty, Staff and Student Publications

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as …

Genotype Classification Of Moraxella Bovis Using Maldi-Tof Ms Profiles, Hannah G. Olson, John Dustin Loy, Michael L. Clawson, Emily L. Wynn, Matthew M. Hille

Nebraska Center for Virology: Faculty Publications

Moraxella bovis (M. bovis) is regarded as a causative agent of infectious bovine keratoconjunctivitis (IBK), the most common ocular disease of cattle. Recently, whole genome sequencing identified the presence of two distinct genotypes within M. bovis that differ in chromosome content, potential virulence factors, as well as prophage and plasmid profiles. It is unclear if the genotypes equally associate with IBK or if one is more likely to be isolated from IBK lesions. We utilized 39 strains of M. bovis that had previously undergone whole genome sequencing and genotype classification to determine the utility of matrix-assisted laser desorption/ionization …

Potential Probiotic Properties Of Exopolysaccharide-Producing Lacticaseibacillus Paracasei Eps Da-Bacs And Prebiotic Activity Of Its Exopolysaccharide, Min-Gyu Lee, Huijin Joeng, Jaein Shin, Suin Kim, Chaeeun Lee, Youngbo Song, Byung-Hoo Lee, Hyoung-Geun Park, Tae-Ho Lee, Hai-Hua Jiang, Young-Sun Han, Bong-Gyeong Lee, Ho-Jin Lee, Min-Ju Park, Yun-Ju Jun, Young-Seo Park

Faculty, Staff and Student Publications

Exopolysaccharide (EPS)-producing Lacticaseibacillus paracasei EPS DA-BACS was isolated from healthy human feces and its probiotic properties, as well as the structure and prebiotic activity of the EPS from this strain were examined. EPS from L. paracasei EPS DA-BACS had a ropy phenotype, which is known to have potential health benefits and is identified as loosely cell-bounded glucomannan-type EPS with a molecular size of 3.7 × 106 Da. EPS promoted the acid tolerance of L. paracasei EPS DA-BACS and provided cells with tolerance to gastrointestinal stress. The purified EPS showed growth inhibitory activity against Clostridium difficile. L. paracasei EPS DA-BACS cells …

An Elf4 Hypomorphic Variant Results In Nk Cell Deficiency, Sandra Andrea Salinas, Emily M Mace, Matilde I Conte, Chun Shik Park, Yu Li, Joshua I Rosario-Sepulveda, Sanjana Mahapatra, Emily K Moore, Evelyn R Hernandez, Ivan K Chinn, Abigail E Reed, Barclay J Lee, Alexander Frumovitz, Richard A Gibbs, Jennifer E Posey, Lisa R Forbes Satter, Akaluck Thatayatikom, Eric J Allenspach, Theodore G Wensel, James R Lupski, H Daniel Lacorazza, Jordan S Orange

Faculty, Staff and Students Publications

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models …

Lpa Disruption With Aav-Crispr Potently Lowers Plasma Apo(A) In Transgenic Mouse Model: A Proof-Of-Concept Study, Alexandria M Doerfler, So Hyun Park, Julia M Assini, Amer Youssef, Lavanya Saxena, Adam B Yaseen, Marco De Giorgi, Marcel Chuecos, Ayrea E Hurley, Ang Li, Santica M Marcovina, Gang Bao, Michael B Boffa, Marlys L Koschinsky, William R Lagor

Faculty, Staff and Students Publications

Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in …

Targeting Tmem205 Mediated Drug Resistance In Ovarian Clear Cell Carcinoma Using Oncolytic Virus, Uksha Saini, Brentley Q Smith, Kalpana Deepa Priya Dorayappan, Ji Young Yoo, G Larry Maxwell, Balveen Kaur, Ikuo Konishi, David O'Malley, David E Cohn, Karuppaiyah Selvendiran

Faculty, Staff and Student Publications

BACKGROUND: Ovarian clear cell carcinoma (OCCC) accounts for approximately 8-10% of epithelial ovarian cancers in the United States. Although it is rare, OCCC usually presents with treatment challenges and the overall prognosis is far worse than high grade serous ovarian cancer HGSOC. The objective of this study was to examine the therapeutic relevance of combining oncolytic virus with cisplatin for ovarian cancer clear cell carcinoma (OCCC).

RESULTS: We identified that TMEM205, a recently discovered transmembrane protein, contributes to chemoresistance in OCCC cells via the exosomal pathway. Mechanistically, TMEM205 undergoes ligand-independent constitutive endocytosis and co-localizes with Rab11 to contribute to the …

A Gbd 2019 Study Of Health And Sustainable Development Goal Gains And Forecasts To 2030 In Spain, Jeffrey V Lazarus, Alberto Ortiz, Stefanos Tyrovolas, Esteve Fernández, Danielle Guy, Trenton M White, Rui Ma, Simon I Hay, Mohsen Naghavi, Joan B Soriano, Gbd 2019 Spain Collaborators

Faculty, Staff and Student Publications

This study aimed to report mortality, risk factors, and burden of diseases in Spain. The Global Burden of Disease, Injuries, and Risk Factors 2019 estimates the burden due to 369 diseases, injuries, and impairments and 87 risk factors and risk factor combinations. Here, we detail the updated Spain 1990-2019 burden of disease estimates and project certain metrics up to 2030. In 2019, leading causes of death were ischaemic heart disease, stroke, chronic obstructive pulmonary disease, Alzheimer's disease, and lung cancer. Main causes of disability adjusted life years (DALYs) were ischaemic heart disease, diabetes, lung cancer, low back pain, and stroke. …

Heavy Metals In Four Marine Fish And Shrimp Species From A Subtropical Coastal Area: Accumulation And Consumer Health Risk Assessment, Mohammad Belal Hossain, Nurer Zaman Bhuiyan, Abul Kasem, Md Kamal Hossain, Salma Sultana, As-Ad Ujjaman Nur, Jimmy Yu, Mohammed Fahad Albeshr, Takaomi Arai

Faculty, Staff and Student Publications

Trace-element or heavy-metal pollution has emerged as a serious concern in terms of both environmental and human health issues. This study measured six trace and toxic heavy metals (Pb, Cd, Cr, Ni, Cu, and Zn) in four marine fish and shrimp species to assess their accumulation levels and evaluate the risks to human health. The mean concentrations of the metals in fish and shrimp species (Labeo bata, Sillaginopsis panijus, Platycepalus fuscus, and Penaeus monodon) followed the decreasing order of Zn (40.8 ± 9.7 μg/g) > Cu (17.8 ± 7.1 μg/g) > Pb (6.2 ± 1.8 μg/g) > Ni (0.4 ± 0.3 μg/g) > Cd …

Prognostic Significance Of P16 And Its Relationship With Human Papillomavirus Status In Patients With Penile Squamous Cell Carcinoma: Results Of 5 Years Follow-Up, Jad Chahoud, Niki M Zacharias, Rachel Pham, Wei Qiao, Ming Guo, Xin Lu, Angelita Alaniz, Luis Segarra, Magaly Martinez-Ferrer, Frederico Omar Gleber-Netto, Curtis R Pickering, Priya Rao, Curtis A Pettaway

Faculty, Staff and Student Publications

Penile Squamous Cell Carcinoma (PSCC) is associated with high-risk human papillomavirus (HR-HPV). The immunohistochemical (IHC) test for p16INK4a (p16) is highly correlated with HR-HPV expression in other SCCs. To investigate whether the expression of p16 IHC or HR-HPV is associated with survival in PSCC, we conducted a single institution analysis of 143 patients with a diagnosis of PSCC and, available tissue were tested for p16 IHC staining patterns, histological subtype, tumor grade, and lymphovascular invasion (LVI) by an experienced pathologist. HR-HPV status using the Cobas PCR Assay or the RNAScope high-risk HPV in situ hybridization kit were also assessed. Patient …

Alternative Precautionary Measures Yielding Lower C. Diff Infection Rates In Healthcare Facilities, Matthew Kramer

Symposium of Student Scholars

Background: An international healthcare concern is the persistent spread of Clostridium difficile, a Gram-positive spore forming bacterium that is responsible for the most common hospital-acquired infection, amongst patients.

Objective: A systematic review was performed to summarize evidence that the interventions utilized in healthcare facilities which indicate a patient’s precautionary status are insufficient, outdated, and commonly lead to infection in neighboring patient rooms. Databases such as PubMed, NCBI, Google Scholar, and APHA’s Medical Care were searched, covering the period from 2017-2022. Studies were included if their focus concentrated on C. diff and the precautionary measures taken by employees at healthcare …

Isolation And Characterization Of Chi-Like Salmonella Bacteriophages Infecting Two Salmonella Enterica Serovars, Typhimurium And Enteritidis, Addisu D. Teklemariam, Mona G. Alharbi, Rashad R. Al-Hindi, Ibrahim Alotibi, Abdullah A. Aljaddawi, Sheren A. Azhari, Ahmed Esmael

Nebraska Center for Virology: Faculty Publications

Salmonella enterica Serovar Typhimurium and Salmonella enterica Serovar Enteritidis are well-known pathogens that cause foodborne diseases in humans. The emergence of antibiotic-resistant Salmonella serovars has caused serious public health problems worldwide. In this study, two lysogenic phages, STP11 and SEP13, were isolated from a wastewater treatment plant in Jeddah, KSA. Transmission electron microscopic images revealed that both phages are new members of the genus “Chivirus” within the family Siphoviridae. Both STP11 and SEP13 had a lysis time of 90 min with burst sizes of 176 and 170 PFU/cell, respectively. The two phages were thermostable (0 ^◦C …

Expression Of P-Stat3 And C-Myc Correlates With P2-Hnf4Α Expression In Nonalcoholic Fatty Liver Disease (Nafld), Mamoun Younes, Lin Zhang, Baharan Fekry, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

We studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. All 49 biopsies (100%) were positive for nuclear expression of P1-HNF4α. Twenty-eight (57%) cases were positive for P2-HNF4α, 6 (12%) were positive for p-STAT3 and 5 (10%) were positive for c-Myc. All 6 (100%) p-STAT3-positive cases were also positive for P2-HNF4α (p = 0.03). p-STAT3-positive cases were more likely to be positive for c-Myc (67% vs. 2%, p = 0.0003). Four cases were positive for P2-HNF4α, p-STAT3 and c-Myc. p-STAT3 …

A Unified Model Of Age-Related Cardiovascular Disease, Michael Fossel, Joe Bean, Nina Khera, Mikhail G Kolonin

Faculty, Staff and Student Publications

Despite progress in biomedical technologies, cardiovascular disease remains the main cause of mortality. This is at least in part because current clinical interventions do not adequately take into account aging as a driver and are hence aimed at suboptimal targets. To achieve progress, consideration needs to be given to the role of cell aging in disease pathogenesis. We propose a model unifying the fundamental processes underlying most age-associated cardiovascular pathologies. According to this model, cell aging, leading to cell senescence, is responsible for tissue changes leading to age-related cardiovascular disease. This process, occurring due to telomerase inactivation and telomere attrition, …

Author Correction: Disrupted Ca2+ Homeostasis And Immunodeficiency In Patients With Functional Ip3 Receptor Subtype 3 Defects, Julika Neumann, Erika Van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele, François Vermeulen, Susan Schlenner, Isabelle Meyts, David I Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston

Faculty, Staff and Student Publications

This corrects the article "Disrupted Ca²⁺ homeostasis and immunodeficiency in patients with functional IP₃ receptor subtype 3 defects" on page 11.

The Rheumatoid Arthritis Drug Auranofin Lowers Leptin Levels And Exerts Antidiabetic Effects In Obese Mice, Aaron R Cox, Peter M Masschelin, Pradip K Saha, Jessica B Felix, Robert Sharp, Zeqin Lian, Yan Xia, Natasha Chernis, David A Bader, Kang Ho Kim, Xin Li, Jun Yoshino, Xin Li, Gang Li, Zheng Sun, Huaizhu Wu, Cristian Coarfa, David D Moore, Samuel Klein, Kai Sun, Sean M Hartig

Faculty, Staff and Student Publications

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic …

Temporal And Spatial Metabolite Dynamics Impart Control In Adipogenesis, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

The process of adipogenesis is critical for forming new, healthy adipocytes that are capable of storing lipids. In this issue, Sánchez-Ramírez and Ung et al. (2022. J. Cell Biol. https://doi.org/10.1083/jcb.202111137) reveal a novel role for the metabolite nicotinamide adenine dinucleotide in controlling differentiation of mesenchymal stromal cells into adipocytes.

Executive Summary Of The American Radium Society Appropriate Use Criteria For Management Of Uterine Clear Cell And Serous Carcinomas, Tracy Sherertz, Anuja Jhingran, Matthew Biagioli, David Gaffney, Mohamed Elshaikh, Robert L Coleman, Matthew Harkenrider, Elizabeth A Kidd, Shruti Jolly, Catheryn Yashar, Lorraine Portelance, Andrew Wahl, Aradhana Venkatesan, Linna Li, William Small, American Radium Society

Faculty, Staff and Student Publications

Background: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies.

Objective: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas.

Methods: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of …

Federated Learning Enables Big Data For Rare Cancer Boundary Detection, Sarthak Pati, Ujjwal Baid, Brandon Edwards, Micah Sheller, Shih-Han Wang, G Anthony Reina, Patrick Foley, Alexey Gruzdev, Deepthi Karkada, Christos Davatzikos, Chiharu Sako, Satyam Ghodasara, Michel Bilello, Suyash Mohan, Philipp Vollmuth, Gianluca Brugnara, Chandrakanth J Preetha, Felix Sahm, Klaus Maier-Hein, Maximilian Zenk, Martin Bendszus, Wolfgang Wick, Evan Calabrese, Jeffrey Rudie, Javier Villanueva-Meyer, Soonmee Cha, Madhura Ingalhalikar, Manali Jadhav, Umang Pandey, Jitender Saini, John Garrett, Matthew Larson, Robert Jeraj, Stuart Currie, Russell Frood, Kavi Fatania, Raymond Y Huang, Ken Chang, Carmen Balaña, Jaume Capellades, Josep Puig, Johannes Trenkler, Josef Pichler, Georg Necker, Andreas Haunschmidt, Stephan Meckel, Gaurav Shukla, Spencer Liem, Gregory S Alexander, Joseph Lombardo, Joshua D Palmer, Adam E Flanders, Adam P Dicker, Haris I Sair, Craig K Jones, Archana Venkataraman, Meirui Jiang, Tiffany Y So, Cheng Chen, Pheng Ann Heng, Qi Dou, Michal Kozubek, Filip Lux, Jan Michálek, Petr Matula, Miloš Keřkovský, Tereza Kopřivová, Marek Dostál, Václav Vybíhal, Michael A Vogelbaum, J Ross Mitchell, Joaquim Farinhas, Joseph A Maldjian, Chandan Ganesh Bangalore Yogananda, Marco C Pinho, Divya Reddy, James Holcomb, Benjamin C Wagner, Benjamin M Ellingson, Timothy F Cloughesy, Catalina Raymond, Talia Oughourlian, Akifumi Hagiwara, Chencai Wang, Minh-Son To, Sargam Bhardwaj, Chee Chong, Marc Agzarian, Alexandre Xavier Falcão, Samuel B Martins, Bernardo C A Teixeira, Flávia Sprenger, David Menotti, Diego R Lucio, Pamela Lamontagne, Daniel Marcus, Benedikt Wiestler, Florian Kofler, Ivan Ezhov, Marie Metz, Rajan Jain, Matthew Lee, Yvonne W Lui, Richard Mckinley, Johannes Slotboom, Piotr Radojewski, Raphael Meier, Roland Wiest, Derrick Murcia, Eric Fu, Rourke Haas, John Thompson, David Ryan Ormond, Chaitra Badve, Andrew E Sloan, Vachan Vadmal, Kristin Waite, Rivka R Colen, Linmin Pei, Murat Ak, Ashok Srinivasan, J Rajiv Bapuraj, Arvind Rao, Nicholas Wang, Ota Yoshiaki, Toshio Moritani, Sevcan Turk, Joonsang Lee, Snehal Prabhudesai, Fanny Morón, Jacob Mandel, Konstantinos Kamnitsas, Ben Glocker, Luke V M Dixon, Matthew Williams, Peter Zampakis, Vasileios Panagiotopoulos, Panagiotis Tsiganos, Sotiris Alexiou, Ilias Haliassos, Evangelia I Zacharaki, Konstantinos Moustakas, Christina Kalogeropoulou, Dimitrios M Kardamakis, Yoon Seong Choi, Seung-Koo Lee, Jong Hee Chang, Sung Soo Ahn, Bing Luo, Laila Poisson, Ning Wen, Pallavi Tiwari, Ruchika Verma, Rohan Bareja, Ipsa Yadav, Jonathan Chen, Neeraj Kumar, Marion Smits, Sebastian R Van Der Voort, Ahmed Alafandi, Fatih Incekara, Maarten M J Wijnenga, Georgios Kapsas, Renske Gahrmann, Joost W Schouten, Hendrikus J Dubbink, Arnaud J P E Vincent, Martin J Van Den Bent, Pim J French, Stefan Klein, Yading Yuan, Sonam Sharma, Tzu-Chi Tseng, Saba Adabi, Simone P Niclou, Olivier Keunen, Ann-Christin Hau, Martin Vallières, David Fortin, Martin Lepage, Bennett Landman, Karthik Ramadass, Kaiwen Xu, Silky Chotai, Lola B Chambless, Akshitkumar Mistry, Reid C Thompson, Yuriy Gusev, Krithika Bhuvaneshwar, Anousheh Sayah, Camelia Bencheqroun, Anas Belouali, Subha Madhavan, Thomas C Booth, Alysha Chelliah, Marc Modat, Haris Shuaib, Carmen Dragos, Aly Abayazeed, Kenneth Kolodziej, Michael Hill, Ahmed Abbassy, Shady Gamal, Mahmoud Mekhaimar, Mohamed Qayati, Mauricio Reyes, Ji Eun Park, Jihye Yun, Ho Sung Kim, Abhishek Mahajan, Mark Muzi, Sean Benson, Regina G H Beets-Tan, Jonas Teuwen, Alejandro Herrera-Trujillo, Maria Trujillo, William Escobar, Ana Abello, Jose Bernal, Jhon Gómez, Joseph Choi, Stephen Baek, Yusung Kim, Heba Ismael, Bryan Allen, John M Buatti, Aikaterini Kotrotsou, Hongwei Li, Tobias Weiss, Michael Weller, Andrea Bink, Bertrand Pouymayou, Hassan F Shaykh, Joel Saltz, Prateek Prasanna, Sampurna Shrestha, Kartik M Mani, David Payne, Tahsin Kurc, Enrique Pelaez, Heydy Franco-Maldonado, Francis Loayza, Sebastian Quevedo, Pamela Guevara, Esteban Torche, Cristobal Mendoza, Franco Vera, Elvis Ríos, Eduardo López, Sergio A Velastin, Godwin Ogbole, Mayowa Soneye, Dotun Oyekunle, Olubunmi Odafe-Oyibotha, Babatunde Osobu, Mustapha Shu'aibu, Adeleye Dorcas, Farouk Dako, Amber L Simpson, Mohammad Hamghalam, Jacob J Peoples, Ricky Hu, Anh Tran, Danielle Cutler, Fabio Y Moraes, Michael A Boss, James Gimpel, Deepak Kattil Veettil, Kendall Schmidt, Brian Bialecki, Sailaja Marella, Cynthia Price, Lisa Cimino, Charles Apgar, Prashant Shah, Bjoern Menze, Jill S Barnholtz-Sloan, Jason Martin, Spyridon Bakas

Faculty, Staff and Student Publications

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically …