Medicine and Health Sciences Commons^™

Landscape Of Tb Infection And Prevention Among People Living With Hiv, Anca Vasiliu, Rebecca Abelman, Yousra Kherabi, Antonia Morita Iswari Saktiawati, Alexander Kay

Faculty, Staff and Students Publications

Tuberculosis (TB) is one of the leading causes of mortality in people living with HIV (PLHIV) and contributes to up to a third of deaths in this population. The World Health Organization guidelines aim to target early detection and treatment of TB among PLHIV, particularly in high-prevalence and low-resource settings. Prevention plays a key role in the fight against TB among PLHIV. This review explores TB screening tools available for PLHIV, including symptom-based screening, chest radiography, tuberculin skin tests, interferon gamma release assays, and serum biomarkers. We then review TB Preventive Treatment (TPT), shown to reduce the progression to active …

Using Wearable Sensors To Measure Goal Achievement In Older Veterans With Dementia, Jennifer Freytag, Ram Kinker Mishra, Richard L Street, Angela Catic, Lilian Dindo, Lea Kiefer, Bijan Najafi, Aanand D Naik

Faculty, Staff and Students Publications

Aligning treatment with patients’ self-determined goals and health priorities is challenging in dementia care. Wearable-based remote health monitoring may facilitate determining the active participation of individuals with dementia towards achieving the determined goals. The present study aimed to demonstrate the feasibility of using wearables to assess healthcare goals set by older adults with cognitive impairment. We present four specific cases that assess (1) the feasibility of using wearables to monitor healthcare goals, (2) differences in function after goal-setting visits, and (3) goal achievement. Older veterans (n = 17) with cognitive impairment completed self-report assessments of mobility, then had an …

Tiam1-Mediated Synaptic Plasticity Underlies Comorbid Depression-Like And Ketamine Antidepressant-Like Actions In Chronic Pain, Qin Ru, Yungang Lu, Ali Bin Saifullah, Francisco A Blanco, Changqun Yao, Juan P Cata, De-Pei Li, Kimberley F Tolias, Lingyong Li

Faculty, Staff and Students Publications

Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development. Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. …

A Gating Lever And Molecular Logic Gate That Couple Voltage And Calcium Sensor Activation To Opening In Bk Potassium Channels, Liang Sun, Frank T Horrigan

Faculty, Staff and Students Publications

BK channels uniquely integrate voltage and calcium signaling in diverse cell types through allosteric activation of their K+-conducting pore by structurally distinct V and Ca2+ sensor domains. Here, we define mechanisms and interaction pathways that link V sensors to the pore by analyzing effects on allosteric coupling of point mutations in the context of Slo1 BK channel structure. A gating lever, mediated by S4/S5 segment interaction within the transmembrane domain, rotates to engage and stabilize the open conformation of the S6 inner pore helix upon V sensor activation. In addition, an indirect pathway, mediated by the carboxyl-terminal cytosolic domain (CTD) …

Single Cell Rna Sequencing Of The Adult Drosophila Eye Reveals Distinct Clusters And Novel Marker Genes For All Major Cell Types, Kelvin Yeung, Komal Kumar Bollepogu Raja, Yoon-Kyung Shim, Yumei Li, Rui Chen, Graeme Mardon

Faculty, Staff and Students Publications

The adult Drosophila eye is a powerful model system for phototransduction and neurodegeneration research. However, single cell resolution transcriptomic data are lacking for this tissue. We present single cell RNA-seq data on 1-day male and female, 3-day and 7-day old male adult eyes, covering early to mature adult eyes. All major cell types, including photoreceptors, cone and pigment cells in the adult eye were captured and identified. Our data sets identified novel cell type specific marker genes, some of which were validated in vivo. R7 and R8 photoreceptors form clusters that reflect their specific Rhodopsin expression and the specific Rhodopsin …

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

Faculty, Staff and Students Publications

No abstract provided.

A Path To Translation: How 3d Patient Tumor Avatars Enable Next Generation Precision Oncology, Shree Bose, Margarida Barroso, Milan G Chheda, Hans Clevers, Elena Elez, Salma Kaochar, Scott E Kopetz, Xiao-Nan Li, Funda Meric-Bernstam, Clifford A Meyer, Haiwei Mou, Kristen M Naegle, Martin F Pera, Zinaida Perova, Katerina A Politi, Benjamin J Raphael, Paul Robson, Rosalie C Sears, Josep Tabernero, David A Tuveson, Alana L Welm, Bryan E Welm, Christopher D Willey, Konstantin Salnikow, Jeffrey H Chuang, Xiling Shen

Faculty, Staff and Students Publications

3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here, we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to realize their potential for clinical decision making. 3D-PTAs require standardization criteria and prospective trials to establish clinical benefits. Innovative trial designs that combine omics and 3D-PTA readouts may lead to more accurate clinical predictors, and an integrated platform that combines diagnostic and therapeutic development will accelerate new treatments for patients with refractory disease.

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 …

Trib3 Mediates Fibroblast Activation And Fibrosis Though Interaction With Atf4 In Ipf, Lan Wang, Wenyu Zhao, Cong Xia, Zhongzheng Li, Weiming Zhao, Kai Xu, Ningdan Wang, Hui Lian, Ivan O Rosas, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM …

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 …

Trends In Esophageal Adenocarcinoma And Esophageal Squamous Cell Carcinoma Incidence In The United States From 1992 To 2019, Kyle S Liu, Syed Ahsan Raza, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

Simple Summary

The incidence of esophageal cancer overall has increased in the United States, driven by increasing rates of esophageal adenocarcinoma (EAC). However, whether rates of EAC are still rising is unclear. We examined trends in esophageal cancer overall and within important sub-groups of the population. We found that esophageal squamous cell carcinoma (ESCC) rates have been steadily declining, while EAC rates rose rapidly before stabilizing in 2000. The trend of decreasing incidence of ESCC was observed almost uniformly by age group, sex, and race/ethnicity, while trends in EAC rates varied across these sub-groups. A cohort effect for EAC was …

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

Methylprednisolone For Heart Surgery In Infants - A Randomized, Controlled Trial, Kevin D Hill, Prince J Kannankeril, Jeffrey P Jacobs, H Scott Baldwin, Marshall L Jacobs, Sean M O'Brien, David P Bichel, Eric M Graham, Brian Blasiole, Ashraf Resheidat, Adil S Husain, S Ram Kumar, Jerry L Kirchner, Dianne S Gallup, Joseph W Turek, Mark Bleiweis, Bret Mettler, Alexis Benscoter, Eric Wald, Tara Karamlou, Andrew H Van Bergen, David Overman, Pirooz Eghtesady, Ryan Butts, John S Kim, John P Scott, Brett R Anderson, Michael F Swartz, Patrick I Mcconnell, David F Vener, Jennifer S Li, Stress Network Investigators

Faculty, Staff and Students Publications

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown.

METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite …

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 …

Unfavorable Social Determinants Of Health Are Associated With Higher Burden Of Financial Toxicity Among Patients With Atherosclerotic Cardiovascular Disease In The Us: Findings From The National Health Interview Survey, Javier Valero-Elizondo, Zulqarnain Javed, Rohan Khera, Mauricio E Tano, Ramzi Dudum, Isaac Acquah, Adnan A Hyder, Julia Andrieni, Garima Sharma, Michael J Blaha, Salim S Virani, Ron Blankstein, Miguel Cainzos-Achirica, Khurram Nasir

Faculty, Staff and Students Publications

• D: PMC9727868

Mechanisms Of Irf2bpl-Related Disorders And Identification Of A Potential Therapeutic Strategy, Shrestha Sinha Ray, Debdeep Dutta, Cassandra Dennys, Samantha Powers, Florence Roussel, Pawel Lisowski, Petar Glažar, Xiaojin Zhang, Pipasha Biswas, Joseph R Caporale, Nikolaus Rajewsky, Marc Bickle, Nicolas Wein, Hugo J Bellen, Shibi Likhite, Paul C Marcogliese, Kathrin C Meyer

Faculty, Staff and Students Publications

The recently discovered neurological disorder NEDAMSS is caused by heterozygous truncations in the transcriptional regulator IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation. Moreover, patient astrocytes fail to support neuronal survival in coculture and exhibit aberrant mitochondria and respiratory dysfunction. Treatment with the small molecule copper ATSM (CuATSM) rescues neuronal survival and restores mitochondrial function. Importantly, the in vitro findings are recapitulated in vivo, where co-expression of full-length …

A Cross-Sectional Study Of The Prevalence Of Anal Dysplasia Among Women With High-Grade Cervical, Vaginal, And Vulvar Dysplasia Or Cancer: The Panda Study, Samantha Batman, Craig A Messick, Andrea Milbourne, Ming Guo, Mark F Munsell, Joel Fokom-Domgue, Mila Salcedo, Ashish Deshmukh, Kristina R Dahlstrom, Mallory Ogburn, Anthony Price, Nicole D Fleming, Jolyn Taylor, Aaron Shafer, Lauren Cobb, Keith Sigel, Erich M Sturgis, Elizabeth Y Chiao, Kathleen M Schmeler

Faculty, Staff and Students Publications

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women.

METHODS: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA).

RESULTS: 324 evaluable women were enrolled. …

Selective Vulnerability Of The Intermediate Retinal Capillary Plexus Precedes Retinal Ganglion Cell Loss In Ocular Hypertension, Priyamvada M Pitale, Guofu Shen, Rohini R Sigireddi, Maria Polo-Prieto, Yong H Park, Solomon E Gibson, Peter D Westenskow, Roomasa Channa, Benjamin J Frankfort

Faculty, Staff and Students Publications

Introduction: Glaucoma, a disease of retinal ganglion cell (RGC) injury and potentially devastating vision loss, is associated with both ocular hypertension (OHT) and reduced ocular blood flow. However, the relationship between OHT and retinal capillary architecture is not well understood. In this project, we studied microvasculature damage in mice exposed to mild levels of induced OHT.

Methods: Mild OHT was induced with the microbead model for 2 weeks. At this time point, some retinas were immunostained with CD31 (endothelium), Collagen IV (basement membrane), and RBPMS (RGCs) for z-stack confocal microscopy. We processed these confocal images to distinguish the three retinal …

How I Approach Leishmaniasis: Diagnosis And Treatment In The United States, Tara E Ness, Rachel Martin-Blais, Jill E Weatherhead

Faculty, Staff and Students Publications

Leishmaniasis is a vector-borne disease caused by over 20 species of obligate intracellular protozoa belonging to the genus Leishmania. Leishmaniasis has a global distribution, including in the United States, and can cause a spectrum of clinical syndromes, including cutaneous, mucosal, and visceral diseases depending on host factors and the infecting Leishmania spp. Accurate diagnosis, including Leishmania species identification, is an important step to guide the most appropriate therapeutic intervention. Antileishmanial therapy is dependent on the Leishmania spp. identified, the clinical syndrome, and the child's immune system. However, many treatment regimens for children have been extrapolated from adult clinical trials, which …

Activity Disruption Causes Degeneration Of Entorhinal Neurons In A Mouse Model Of Alzheimer’S Circuit Dysfunction, Rong Zhao, Stacy D Grunke, Caleb A Wood, Gabriella A Perez, Melissa Comstock, Ming-Hua Li, Anand K Singh, Kyung-Won Park, Joanna L Jankowsky

Faculty, Staff and Students Publications

Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Here, we show that entorhinal cortex layer 2 (EC2) neurons are unusually vulnerable to prolonged neuronal inactivity compared with neighboring regions of the temporal lobe, and that reelin + stellate cells connecting EC with the hippocampus are preferentially susceptible within the EC2 population. We demonstrate that neuronal death after silencing can be elicited through multiple independent means of activity inhibition, and that preventing synaptic release, either alone or in combination with electrical shunting, is sufficient to elicit silencing-induced degeneration. Finally, we …

Hyperkalemia And Electrocardiogram Manifestations In End-Stage Renal Disease, Zubaid Rafique, Bryan Hoang, Heba Mesbah, Ryan Pappal, Frank W Peacock, Raul Juarez-Vela, Lukasz Szarpak, Dick C Kuo

Faculty, Staff and Students Publications

Hyperkalemia is one of the more common acute life-threatening metabolic emergencies. The aim of our study is to determine the correlation and accuracy of abnormal ECG parameters as a function of serum potassium concentration in the end-stage renal disease (ESRD) population. We performed a retrospective chart review of emergency department patients presenting with ESRD and receiving emergent hemodialysis treatment. A total of 96 patients, each with five independent ED visits, provided 480 sets of ECGs and electrolytes. Of these, four ECGs were excluded for inability to interpret, leaving a total of 476 patient encounters that met all inclusion criteria. Linear …

Active Dna Demethylation Promotes Cell Fate Specification And The Dna Damage Response, Dongpeng Wang, Wei Wu, Elsa Callen, Raphael Pavani, Nicholas Zolnerowich, Srikanth Kodali, Dali Zong, Nancy Wong, Santiago Noriega, William J Nathan, Gabriel Matos-Rodrigues, Raj Chari, Michael J Kruhlak, Ferenc Livak, Michael Ward, Keith Caldecott, Bruno Di Stefano, André Nussenzweig

Faculty, Staff and Students Publications

Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show that thymidine DNA glycosylase (TDG)-driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. …

Spectrum Of Ddc Variants Causing Aromatic L-Amino Acid Decarboxylase (Aadc) Deficiency And Pathogenicity Interpretation Using Acmg-Amp/Acgs Recommendations, Nastassja Himmelreich, Riccardo Montioli, Sven F Garbade, Jeffrey Kopesky, Sarah H Elsea, Carla Carducci, Carla B Voltattorni, Nenad Blau

Faculty, Staff and Students Publications

Pathogenic variants in dopa decarboxylase (DDC), the gene encoding the aromatic l-amino acid decarboxylase (AADC) enzyme, lead to a severe deficiency of neurotransmitters, resulting in neurological, neuromuscular, and behavioral manifestations clinically characterized by developmental delays, oculogyric crises, dystonia, and severe neurologic dysfunction in infancy. Historically, therapy has been aimed at compensating for neurotransmitter abnormalities, but response to pharmacologic therapy varies, and in most cases, the therapy shows little or no benefit. A novel human DDC gene therapy was recently approved in the European Union that targets the underlying genetic cause of the disorder, providing a new treatment option for patients …

Metabolome And Microbiome Multi-Omics Integration From A Murine Lung Inflammation Model Of Bronchopulmonary Dysplasia, Ahmed El Saie, Chenlian Fu, Sandra L Grimm, Matthew J Robertson, Kristi Hoffman, Vasanta Putluri, Chandra Shekar R Ambati, Nagireddy Putluri, Binoy Shivanna, Cristian Coarfa, Mohan Pammi

Faculty, Staff and Students Publications

BACKGROUND: Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence.

METHODS: C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group).

RESULTS: Microbiome alpha and beta diversity were similar between groups. Metabolic changes included …

Cic Missense Variants Contribute To Susceptibility For Spina Bifida, Xiao Han, Xuanye Cao, Vanessa Aguiar-Pulido, Wei Yang, Menuka Karki, Paula Andrea Pimienta Ramirez, Robert M Cabrera, Ying Linda Lin, Bogdan J Wlodarczyk, Gary M Shaw, M Elizabeth Ross, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased …

Histopathologic And Transcriptomic Phenotypes Of A Conditional Rankl Transgenic Mouse Thymus, Maria M Szwarc, Lan Hai, Vineet K Maurya, Kimal Rajapakshe, Dimuthu Perera, Michael M Ittmann, Qianxing Mo, Yong Lin, Matthew L Bettini, Cristian Coarfa, John P Lydon

Faculty, Staff and Students Publications

Although conventional knockout and transgenic mouse models have significantly advanced our understanding of Receptor Activator of NF-κB Ligand (RANKL) signaling in intra-thymic crosstalk that establishes self-tolerance and later stages of lymphopoiesis, the unique advantages of conditional mouse transgenesis have yet to be explored. A main advantage of conditional transgenesis is the ability to express a transgene in a spatiotemporal restricted manner, enabling the induction (or de-induction) of transgene expression during predetermined stages of embryogenesis or during defined postnatal developmental or physiological states, such as puberty, adulthood, and pregnancy. Here, we describe the K5: RANKL bigenic mouse, in which transgene derived …

Radial Collateral Ligament Injuries Of The Thumb Metacarpophalangeal Joint, Thomas W Mitchell, Scott A Mitchell, Chia Wu

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: Injuries to the radial collateral ligament (RCL) of the thumb are thought to be relatively uncommon, especially when compared to the ulnar collateral ligament. However, the radial collateral ligament is increasingly recognized as critical for the overall stability of the thumb metacarpophalangeal joint. This article sets out to provide a comprehensive review of RCL injuries of the thumb MCP joint, including epidemiology, biomechanics, diagnosis, and treatment.

RECENT FINDINGS: Although traditionally thought to respond well to conservative management, especially when compared to injuries to the ulnar collateral ligament, there is mounting evidence that chronic RCL injury leads to …

Lipid-Lowering Therapy Use And Intensification Among United States Veterans Following Myocardial Infarction Or Coronary Revascularization Between 2015 And 2019, Alexander R Zheutlin, Catherine G Derington, Jennifer S Herrick, Robert S Rosenson, Bharat Poudel, Monika M Safford, Todd M Brown, Elizabeth A Jackson, Mark Woodward, Stephanie Reading, Kate Orroth, Jason Exter, Salim S Virani, Paul Muntner, Adam P Bress

Faculty, Staff and Students Publications

Background: Understanding how statins, ezetimibe, and PCSK9i (proprotein convertase subtilisin/kexin type 9 serine protease inhibitors) are prescribed after a myocardial infarction (MI) or elective coronary revascularization may improve lipid-lowering therapy (LLT) intensification and reduce recurrent atherosclerotic cardiovascular disease events. We described the use and intensification of LLT among US veterans who had a MI or elective coronary revascularization between July 24, 2015, and December 9, 2019, within 12 months of hospital discharge.

Methods: LLT intensification was defined as increasing statin dose, or initiating a statin, ezetimibe, or a PCSK9i, overall and among those with an LDL-C (low-density lipoprotein cholesterol) ≥ …

Early Phase Trial Of Intracystic Injection Of Large Surface Area Microparticle Paclitaxel For Treatment Of Mucinous Pancreatic Cysts, Mohamed Othman, Kalpesh Patel, Somashekar G Krishna, Antonio Mendoza-Ladd, Shelagh Verco, Wasif Abidi, James Verco, Alison Wendt, Gere Dizerega

Faculty, Staff and Students Publications

Background and study aims  Mucinous pancreatic cystic lesions (PCLs) have the potential for malignant transformation, for which the only accepted curative modality is surgery. A novel intracystic therapy with large surface area microparticle paclitaxel (LSAM-PTX) may treat PCLs without local or systemic toxicities. Safety and preliminary efficacy of LSAM-PTX for the treatment of PCLs administered by endoscopic ultrasound-guided fine-needle injection (EUS-FNI) was evaluated.

Patients and methods  Ten subjects with confirmed PCLs (size > 1.5 cm) received intracystic LSAM-PTX via EUS-FNI at volumes equal to those aspirated from the cyst in sequential cohorts at 6, 10, and 15 mg/mL in a standard …

Proteasome Inhibitors Silence Oncogenes In Multiple Myeloma Through Localized Histone Deacetylase 3 (Hdac3) Stabilization And Chromatin Condensation, Laure Maneix, Polina Iakova, Shannon E Moree, Joanne I Hsu, Ragini M Mistry, Fabio Stossi, Premal Lulla, Zheng Sun, Ergun Sahin, Sarvari V Yellapragada, André Catic

Faculty, Staff and Students Publications

Proteasome inhibitors have become the standard of care for multiple myeloma (MM). Blocking protein degradation particularly perturbs the homeostasis of short-lived polypeptides such as transcription factors and epigenetic regulators. To determine how proteasome inhibitors directly impact gene regulation, we performed an integrative genomics study in MM cells. We discovered that proteasome inhibitors reduce the turnover of DNA-associated proteins and repress genes necessary for proliferation through epigenetic silencing. Specifically, proteasome inhibition results in the localized accumulation of histone deacetylase 3 (HDAC3) at defined genomic sites, which reduces H3K27 acetylation and increases chromatin condensation. The loss of active chromatin at super-enhancers critical …