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Sirtuin 6 Activation Rescues The Age-Related Decline In Dna Damage Repair In Primary Human Chondrocytes, Michaela E. Copp, Jacqueline Shine, Hannon L. Brown, Kirti R. Nimmala, Oliver B. Hansen, Susan Chubinskaya, John A. Collins, Richard F. Loeser, Brian O. Diekman

Department of Orthopaedic Surgery Faculty Papers

While advanced age is widely recognized as the greatest risk factor for osteoarthritis (OA), the biological mechanisms behind this connection remain unclear. Previous work has demonstrated that chondrocytes from older cadaveric donors have elevated levels of DNA damage as compared to chondrocytes from younger donors. The purpose of this study was to determine whether a decline in DNA repair efficiency is one explanation for the accumulation of DNA damage with age, and to quantify the improvement in repair with activation of Sirtuin 6 (SIRT6). After acute damage with irradiation, DNA repair was shown to be more efficient in chondrocytes from …

Identification Of Ct-Based Non-Invasive Radiomic Biomarkers For Overall Survival Prediction In Oral Cavity Squamous Cell Carcinoma, Xiao Ling, Gregory S. Alexander, Jason Molitoris, Jinhyuk Choi, Lisa Schumaker, Ranee Mehra, Daria A. Gaykalova, Lei Ren

Department of Radiation Oncology Faculty Papers

This study addresses the limited non-invasive tools for Oral Cavity Squamous Cell Carcinoma (OSCC) survival prediction by identifying Computed Tomography (CT)-based biomarkers to improve prognosis prediction. A retrospective analysis was conducted on data from 149 OSCC patients, including CT radiomics and clinical information. An ensemble approach involving correlation analysis, score screening, and the Sparse-L1 algorithm was used to select functional features, which were then used to build Cox Proportional Hazards models (CPH). Our CPH achieved a 0.70 concordance index in testing. The model identified two CT-based radiomics features, Gradient-Neighboring-Gray-Tone-Difference-Matrix-Strength (GNS) and normalized-Wavelet-LLL-Gray-Level-Dependence-Matrix-Large-Dependence-High-Gray-Level-Emphasis (HLE), as well as stage and alcohol usage, …

A Phenotypically Robust Model Of Spinal And Bulbar Muscular Atrophy In Drosophila, Kristin Richardson, Medha Sengupta, Alyson Sujkowski, Kozeta Libohova, Autumn C. Harris, Robert Wessells, Diane E. Merry, Sokol V. Todi

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same safe …

Novel Urine Cell-Free Dna Methylation Markers For Hepatocellular Carcinoma, Selena Lin, Wei Xia, Amy Kim, Dion Chen, Shelby Schleyer, Lin Choi, Zhili Wang, James Hamilton, Harry Luu, Hie-Won Hann, Ting-Tsung Chang, Chi-Tan Hu, Abashai Woodard, Terence Gade, Ying-Hsiu Su

Division of Gastroenterology and Hepatology Faculty Papers

An optimized hepatocellular carcinoma (HCC)-targeted methylation next generation sequencing assay was developed to discover HCC-associated methylation markers directly from urine for HCC screening. Urine cell-free DNA (ucfDNA) isolated from a discovery cohort of 31 non-HCC and 30 HCC was used for biomarker discovery, identifying 29 genes with differentially methylated regions (DMRs). Methylation-specific qPCR (MSqPCR) assays were developed to verify the selected DMRs corresponding to 8 genes (GRASP, CCND2, HOXA9, BMP4, VIM, EMX1, SFRP1, and ECE). Using archived ucfDNA, methylation of GRASP, HOXA9, BMP4, and ECE1, were found to be significantly different (p < 0.05) between HCC and non-HCC patients. The four markers together with previously reported GSTP1 and RASSF1A markers were assessed as a 6-marker panel in an independent training cohort of 87 non-HCC and 78 HCC using logistic regression modeling. AUROC of 0.908 (95% CI, 0.8656-0.9252) was identified for the 6-marker panel with AFP, which was significantly higher than AFP-alone (AUROC 0.841 (95% CI, 0.778-0.904), p = 0.0026). Applying backward selection method, a 4-marker panel was found to exhibit similar performance to the 6-marker panel with AFP having 80% sensitivity compared to 29.5% by AFP-alone at a specificity of 85%. This study supports the potential use of methylated transrenal ucfDNA for HCC screening.

Fluorescent Peptide For Detecting Factor Xiiia Activity And Fibrin In Whole Blood Clots Forming Under Flow, Yue Liu, Jennifer Crossen, Timothy J. Stalker, Scott L. Diamond

Cardeza Foundation for Hematologic Research

Background

During clotting, thrombin generates fibrin monomers and activates plasma-derived transglutaminase factor (F) XIIIa; collagen and thrombin-activated platelets offer thrombin-independent cellular FXIIIa (cFXIIIa) for clotting. Detecting fibrin on collagen and tissue factor surfaces in whole blood clotting typically uses complex reagents like fluorescent fibrinogen or antifibrin antibody.

Objectives

We want to test whether the peptide using the α2- antiplasmin crosslinking mechanism by FXIIIa is a useful tool in both monitoring FXIIIa activity, and visualize and monitor fibrin formation, deposition, and extent of crosslinking within fibrin structures in whole blood clots formed under flow.

Methods

We tested a fluorescent peptide derived …

Negative Pressure Wound Therapy For Complex Oral Wounds, Mykaihla Sternick, James Gates, Allen Champion, Andrew Yampolsky

Department of Oral and Maxillofacial Surgery Faculty Papers

Negative pressure wound therapy provides a nonsurgical treatment option for many types of complex wounds. This therapy utilizes the vacuum-assisted closure device, which decreases air pressure, removes fluid that accumulates within the wound, and aids to facilitate changes that promote healing. Despite the increased use of negative pressure wound therapy in the head and neck region, there is substantially less data available on the management of transoral vacuum-assisted wound closure. Herein, we present a case of a novel approach for the creation and use of a transoral wound vac for a patient with a refractory orocutaneous wound in the setting …

Simultaneous Detection Of Methylation And Genetic Variations Of Bcr-Abl1 Gene By Nanopore Cas9-Targeted Sequencing, Shuilian Xie, Ying Yang, Junjie Zhang, Menglin Zhu, Wang Li, Mengting Li, Yijian Chen, Hailiang Li, Weidan Lun, Weelic Chong, Shaogui Wan

Department of Medicine Faculty Papers

No abstract provided.

Robotic-Assisted Navigation For Stereotactic Neurosurgery: A Cadaveric Investigation Of Accuracy, Time, And Radiation, William Anderson, Francisco Ponce, Michael Kinsman, Sepehr Sani, Brian Hwang, Diana Ghinda, Michael Kogan, Jonathan M Mahoney, Dhara Amin, Margaret Van Horn, Joshua Mcguckin, Dominic Razo-Castaneda, Brandon Bucklen

Department of Neurosurgery Faculty Papers

BACKGROUND AND OBJECTIVES: Despite frequent use, stereotactic head frames require manual coordinate calculations and manual frame settings that are associated with human error. This study examines freestanding robot-assisted navigation (RAN) as a means to reduce the drawbacks of traditional cranial stereotaxy and improve targeting accuracy.

METHODS: Seven cadaveric human torsos with heads were tested with 8 anatomic coordinates selected for lead placement mirrored in each hemisphere. Right and left hemispheres of the brain were randomly assigned to either the traditional stereotactic arc-based (ARC) group or the RAN group. Both target accuracy and trajectory accuracy were measured. Procedural time and the …

Correction Of Spinal Sagittal Alignment After Posterior Lumbar Decompression: Does Severity Of Central Canal Stenosis Matter?, Delano Trenchfield, Yunsoo Lee, Mark J. Lambrechts, Nicholas D'Antonio, Jeremy Heard, John Paulik, Sydney Somers, Jeffrey Rihn, Mark Kurd, David Kaye, Jose Canseco, Alan Hilibrand, Alex Vaccaro, Christopher K Kepler, Gregory Schroeder

Rothman Institute Papers

STUDY DESIGN: This study adopted a retrospective study design.

PURPOSE: Our study aimed to investigate the impact of central canal stenosis severity on surgical outcomes and lumbar sagittal correction after lumbar decompression.

OVERVIEW OF LITERATURE: Studies have evaluated sagittal correction in patients with central canal stenosis after lumbar decompression and the association of stenosis severity with worse preoperative sagittal alignment. However, none have evaluated the impact of spinal stenosis severity on sagittal correction.

METHODS: Patients undergoing posterior lumbar decompression (PLD) of ≤4 levels were divided into severe and non-severe central canal stenosis groups based on the Lee magnetic resonance imaging …

Inhibition Of Neurogenic Inflammatory Pathways Associated With The Reduction In Discogenic Back Pain, Jose A. Canseco, Hannah A. Levy, Brian A. Karamian, Olivia Blaber, Michael Chang, Neil Patel, John G. Curran, Alan S. Hilibrand, Gregory D. Schroeder, Alex R. Vaccaro, Dessislava Z. Markova, David E. Surrey, Christopher K. Kepler

Rothman Institute Papers

STUDY DESIGN: Retrospective cohort study.

PURPOSE: This study aimed to determine whether the initiation of anti-calcitonin gene-related peptide (CGRP inhibitor) medication therapy for migraines was also associated with improvements in back/neck pain, mobility, and function in a patient population with comorbid degenerative spinal disease and migraine.

OVERVIEW OF LITERATURE: CGRP upregulates pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, brain-derived neurotrophic factor, and nerve growth factor in spinal spondylotic disease, which results in disc degeneration and sensitization of nociceptive neurons. Although CGRP inhibitors can quell neurogenic inflammation in migraines, their off-site efficacy as a therapeutic target for discogenic back/neck pain …

Antiseizure Effects Of Peganum Harmala L. And Lavandula Angustifolia, Zahra Rahimian, Seyedhassan Sadrian, Mina Shahisavandi, Hadi Aligholi, Mohammad M. Zarshenas, Alireza Abyar, Zahra Zeraatpisheh, Ali A. Asadi-Pooya

Department of Neurology Faculty Papers

Peganum harmala L. and Lavandula angustifolia are two traditional herbs with probable antiseizure effects. This study evaluated the effects of these two herbal extracts on pentylenetetrazol- (PTZ-) induced seizures in mice. We prepared hydroalcoholic extracts using P. harmala seeds and the aerial parts of L. angustifolia and then randomly divided 190 mice into 19 groups. Normal saline (10 mg/kg), diazepam (2 mg/kg), P. harmala (2.5, 5, 10, 15, 30, 45, and 60 mg/kg), and L. angustifolia (200, 400, 600, and 800 mg/kg) were intraperitoneally (IP) administrated 30 min before an IP administration of PTZ (90 mg/kg). Animals were observed for …

Feasibility Of Electronic Medication Monitoring Among Adolescents And Emerging Adults With Sickle Cell Disease, Aimee Hildenbrand, Katherine Kidwell, Meghan Mcgrady, Constance Mara, Charles Quinn, Lori Crosby

Department of Pediatrics Faculty Papers

Purpose: To examine the feasibility of using MEMS® bottles to assess adherence among adolescents and emerging adults with sickle cell disease.

Patients and Methods: Eighteen non-Hispanic Black participants with HbSS (M = 17.8 years; 61% male) were given a MEMS® bottle to store hydroxyurea (n = 14) or deferasirox (n = 4).

Results: One hundred percent initiated MEMS® use and 61% sustained use through the 18-week study; at follow-up, only 11% returned their bottle on time. Barriers to MEMS® use included medication changes and transition to adult care; facilitators included tip sheets and reminders.

Conclusion: While MEMS® is acceptable to …

Jun Upregulation Drives Aberrant Transposable Element Mobilization, Associated Innate Immune Response, And Impaired Neurogenesis In Alzheimer’S Disease, Chiara Scopa, Samantha Barnada, Maria Cicardi, Mo Singer, Davide Trotti, Marco Trizzino

Farber Institute for Neuroscience Faculty Papers

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death …

Changing The Playbook For Immigrant Health, Cheryl Bettigole, Patricia C. Henwood, Sage Myers, Maura Sammon

Department of Emergency Medicine Faculty Papers

Philadelphia’s response to welcoming Afghan evacuees during the COVID-19 pandemic suggests the need for a new approach to immigrant health care.

Phi-1, An Endogenous Inhibitor Protein For Protein Phosphatase-1 And A Pan-Cancer Marker, Regulates Raf-1 Proteostasis, Jason Kirkbride, Garbo Nilsson, Jee In Kim, Kosuke Takeya, Yoshinori Tanaka, Hiroshi Tokumitsu, Futoshi Suizu, Masumi Eto

Kimmel Cancer Center Faculty Papers

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin-proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed …

Interest In And Barriers To Online Esol Instruction For Adults During And Beyond Covid-19: Exploring Relationships With Sociodemographics And English Proficiency, Jessica G. Cox, Lauren Y. Chen, Harriet Okatch

College of Population Health Faculty Papers

Digital divides mean that marginalized groups such as adults who speak English as a second or other language (ESOL) are less likely to have access to online instruction. Higher levels of English proficiency are associated with better health and employment; therefore, access to ESOL classes is essential. We investigated how sociodemographics and English proficiency relate to adult learners' preferences for, and barriers to, online instruction of ESOL during and beyond the COVID-19 pandemic. Sixty-one adults completed a survey on their pandemic experiences, demographics, and ESOL classes. Analyses showed nonsignificant relationships between interest in online instruction and internet access, education, income, …

Evaluation Of A Balloon Implant For Simultaneous Magnetic Nanoparticle Hyperthermia And High-Dose-Rate Brachytherapy Of Brain Tumor Resection Cavities, Shuying Wan, Dario Rodrigues, Janet Kwiatkowski, Omaditya Khanna, Kevin Judy, Robert Goldstein, Marty Overbeek Bloem, Yan Yu, Sophia Rooks, Wenyin Shi, Mark Hurwitz, Paul Stauffer

Department of Radiation Oncology Faculty Papers

Previous work has reported the design of a novel thermobrachytherapy (TBT) balloon implant to deliver magnetic nanoparticle (MNP) hyperthermia and high-dose-rate (HDR) brachytherapy simultaneously after brain tumor resection, thereby maximizing their synergistic effect. This paper presents an evaluation of the robustness of the balloon device, compatibility of its heat and radiation delivery components, as well as thermal and radiation dosimetry of the TBT balloon. TBT balloon devices with 1 and 3 cm diameter were evaluated when placed in an external magnetic field with a maximal strength of 8.1 kA/m at 133 kHz. The MNP solution (nanofluid) in the balloon absorbs …

Case Report: Durable Response Of Gliomatosis Cerebri With Concurrent Tumor-Treating Fields (Ttfields) And Chemoradiotherapy Treatment, Alex M. Desjarlais, Ryan C. Miller, Ayesha S. Ali, Muneeb Z. Niazi, Louis Cappelli, Jon Glass, Christopher J. Farrell, Wenyin Shi

Department of Radiation Oncology Faculty Papers

Background: Gliomatosis cerebri (GC) is a rare and aggressive form of widely disseminated glioma infiltrating at least 3 lobes of the brain. It is a diffuse pattern of growth seen in glioma rather than a distinct pathological diagnosis based on new Word Health Organization (WHO) classification. Despite this, it is associated with worse prognosis than equally graded gliomas. Tumor treating fields (TTFields) treatment is a more recent advancement in glioma treatment delivered through low energy, intermediate frequency (200 kHz) electromagnetic fields, with multi-modal mechanisms of action. It is Food and Drug Administration (FDA) approved for newly diagnosed and recurrent glioblastoma …

Fundamental Neurochemistry Review: The Role Of Enteroendocrine Cells In Visceral Pain, Annie Londregan, Tyler D. Alexander, Manuel Covarrubias, Scott A. Waldman

Department of Neuroscience Faculty Papers

While visceral pain is commonly associated with disorders of the gut-brain axis, underlying mechanisms are not fully understood. Dorsal root ganglion (DRG) neurons innervate visceral structures and undergo hypersensitization in inflammatory models. The characterization of peripheral DRG neuron terminals is an active area of research, but recent work suggests that they communicate with enteroendocrine cells (EECs) in the gut. EECs sense stimuli in the intestinal lumen and communicate information to the brain through hormonal and electrical signaling. In that context, EECs are a target for developing therapeutics to treat visceral pain. Linaclotide is an FDA-approved treatment for chronic constipation that …

Relationship Between Arm Path, Ball Velocity, And Elbow Varus Torque In Professional Baseball Pitchers, Brittany Dowling, Alexander Hodakowski, Bjorn Olmanson, Matthew Cohn, Patrick Pauley, Nikhil Verma, Gregory Nicholson, Grant Garrigues

Rothman Institute Papers

BACKGROUND: Currently, most pitching instructors suggest a shorter arm path-the total distance the arm travels during pitching. Theoretically, this combination allows for better body segment sequencing, a more efficient energy transfer through the kinetic chain, and increased ball velocity, while limiting elbow varus torque.

HYPOTHESIS: Shorter arm paths would be associated with increased ball velocity and decreased elbow varus torque.

STUDY DESIGN: Descriptive laboratory study.

METHODS: A total of 182 professional pitchers threw 8 to 12 fastball pitches while evaluated by 3-dimensional motion capture (480 Hz). The arm path was calculated as the total distance the hand marker traveled during …

The Iris Registry: A Novel Approach To Clinical Registry Development In Ophthalmology, John C. Lin, Leslie Hyman, Ingrid U. Scott

Wills Eye Hospital Papers

No abstract provided.

Reactive Oxygen Species Behaving Badly: Oxidized Phosphatidylcholines Corrupt Ca2+ Signaling In Airway Smooth Muscle, Deepak A. Deshpande, Raymond B. Penn

Center for Translational Medicine Faculty Papers

No abstract provided.

Human Parechovirus Central Nervous System Infection In A Young Infant Cohort, Aspasia Katragkou, Avni Sheth, Christina Gagliardo, Jessica Aquino, Niva Shah, Eberechi Nwaobasi-Iwuh, Christina Melchionne, Paige Black, Stephanie Chiu, Cecilia Di Pentima

Department of Pediatrics Faculty Papers

In 2022, a surge in cases of pediatric human parechovirus (HPeV) central nervous system infections in young infants was seen at our institution. Despite the dramatic increase in the number of cases seen that year, the clinical features of the illness were similar to prior years. The recent pediatric HPeV surge highlights the need to evaluate treatment options and standardize follow-up to better understand the long-term prognosis of infants with HPeV infection.

Characteristics And Outcomes Of Patients With Pregnancy-Related End-Stage Kidney Disease., Lauren Kucirka, Ana Angarita, Tracy Manuck, Kim Boggess, Vimal Derebail, Mollie Wood, Michelle Meyer, Dorry Segev, Monica Reynolds

Department of Obstetrics and Gynecology Faculty Papers

IMPORTANCE: The incidence of pregnancy-related acute kidney injury is increasing and is associated with significant maternal morbidity including progression to end-stage kidney disease (ESKD). Little is known about characteristics and long-term outcomes of patients who develop pregnancy-related ESKD.

OBJECTIVES: To examine the characteristics and clinical outcomes of patients with pregnancy-related ESKD and to investigate associations between pre-ESKD nephrology care and outcomes.

DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study of 183 640 reproductive-aged women with incident ESKD between January 1, 2000, and November 20, 2020, from the US Renal Data System and maternal data from births captured in the …

Impact Of Comorbid Heart Failure Among Hospitalized Patients With Sarcoidosis: A United States Population-Based Cohort Study, Bruce Adrian Casipit, Kevin Bryan Lo, Carlo Gabriel Casipit, Abdiodun Idowu, Aman Amanullah

Einstein Health Papers

BACKGROUND: There is paucity of data regarding the impact of concomitant heart failure (HF) on the in-hospital outcomes among hospitalized sarcoidosis patients. We aim to investigate the factors associated with concomitant HF and its impact on in-hospital outcomes among hospitalized sarcoidosis patients.

METHODS: We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting this study. Multivariable logistic and linear regression models were used to examine the factors associated with HF and hospital-associated outcomes among patients with sarcoidosis.

RESULTS: A total of 36,864 hospitalized patients with sarcoidosis were identified, of which 24.78 % (n = 9135/36,864) had concomitant HF. Factors …

Cancer Disparities In Southeast Asia: Intersectionality And A Call To Action, Erin Jay G. Feliciano, Frances Dominique V. Ho, Kaisin Yee, Joseph A. Paguio, Michelle Ann B. Eala, Janine Patricia G. Robredo, Kenrick Ng, Jasmine Lim, Khin Thuzar Pyone, Catherine A. Peralta, Jerickson Abbie Flores, J. Seth Yao, Patricia Mae G. Santos, Christian Daniel U. Ang, Gideon Lasco, Jeffrey Shi Kai Chan, Gary Tse, Enrico D. Tangco, T. Peter Kingham, Imjai Chitapanarux, Nirmala Bhoo-Pathy, Gerardo D. Legaspi, Edward Christopher Dee

Einstein Health Papers

No abstract provided.

A Systematic Review Of Noncircular (Rectangle, Oval) Femoral Tunnel Anterior Cruciate Ligament Reconstruction: Does It Improve Outcomes?, S. Ali Ghasemi, Joseph Mccahon, Sangeev J. Herr, James Raphael, Gene Shaffer, Arthur Bartolozzi

Einstein Health Papers

Purpose: The purpose of this study is to systematically review the clinical and biomechanical studies regarding noncircular (rectangular and oval) femoral tunnel anterior cruciate ligament reconstruction (ACLR). We hypothesized that noncircular femoral tunnel ACLR has its advantages in unique situations while maintaining comparable clinical and radiographic outcomes when compared to conventional techniques.

Methods: A systematic review of the literature was performed in PubMed and Scopus databases to identify published articles on the clinical outcomes of noncircular (rectangle and oval) ACLR. The results of the eligible studies were analyzed in terms of instrumented laxity measurements, Lachman test, pivot-shift test, Lysholm and …

Clinical Trials In Cardiogenic Shock: Challenges And Solutions For The Future, Anju Bhardwaj, Sahoor Khan, Shashank Sinha, Preethi Pirlamarla, Rajiv Sankaranarayanan, Alexander Hajduczok, Holger Thiele, Navin Kapur

Division of Cardiology Faculty Papers

No abstract provided.

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M. Kurimchak, Isabella Trachtenberg, Timothy J. Purwin, Jelan I. Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A. Davies, J Silvio Gutkind, Jeffrey L. Benovic, James S. Duncan, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

Functional And Anatomical Connectivity Predict Brain Stimulation’S Mnemonic Effects, Youssef Ezzyat, James E> Kragel, Ethan A. Solomon, Bradley C. Lega, Joshua P. Aronson, Barbara C. Jobst, Robert E. Gross, Michael R. Sperling, Gregory A. Worrell, Sameer A. Sheth, Paul A. Wanda, Daniel S. Rizzuto, Michael J. Kahana

Department of Neurology Faculty Papers

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC …