Diseases Commons^™

Mepolizumab Improves Outcomes In Patients With Crswnp With One Or More Prior Nasal Polyp Surgeries, Joseph K. Han, Joaquim Mullol, Martin Wagenmann, Laura Walrave, Lingjiao Zhang, Ana R. Sousa, Peter Howarth, Claire Hopkins

Department of Otolaryngology (ENT) Faculty Publications

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) often undergo multiple nasal surgeries. The Phase III SYNAPSE study (GSK ID:205687; NCT0308579) demonstrated that mepolizumab reduces the need for repeat surgery. We explored whether outcomes differed based on the number of prior surgeries. METHODOLOGY: This post hoc analysis of SYNAPSE stratified patients by history of 1 or more than 1 prior surgery. Patients were randomised to receive mepolizumab or placebo every 4 weeks, alongside standard of care, for 52 weeks. Outcomes included change from baseline in endoscopic nasal polyp (NP) score, visual analogue scale (VAS) scores for nasal obstruction, loss …

Low Utilization Of Intracavernosal Injection And Penile Doppler Ultrasound In The Evaluation Of Erectile Dysfunction And Peyronie's Disease, Joon Yau Leong, Tyler Gaines, Zachary J. Prebay, David Ebbott, Paul H. Chung

Department of Urology Faculty Papers

INTRODUCTION: Despite the diagnostic value of intracavernosal injections (ICI) and penile Doppler ultrasound (PDUS), there remain barriers to widespread clinical adaptation of these methods. The study aimed to evaluate the practice patterns of utilization of ICI and PDUS in the assessment of erectile dysfunction (ED) and Peyronie's disease (PD).

METHODS: Using the TriNetX database (Cambridge, MA, USA), adult (≥18 years) male patients with a diagnosis of ED on oral phosphodiesterase-5 (PDE5) inhibitors were identified. Current Procedural Terminology codes were utilized to identify patients who underwent further evaluation with ICI or PDUS, as well as penile prosthesis placement after PDUS. A …

Subgroup Analyses Of The Phase 3 Focus Study Of Melphalan/Hepatic Delivery System In Patients With Unresectable Metastatic Uveal Melanoma, Jonathan S. Zager, Marlana Orloff, Pier Francesco Ferrucci, Junsung Choi, David J. Eschelman, Evan S. Glazer, Aslam Ejaz, Erika Richtig, Sebastian Ochsenreither, Sunil A. Reddy, Michael C. Lowe, Georgia M. Beasley, Anja Gesierich, Martin Gschnell, Reinhard Dummer, Ana Arance, Stephen William Fenwick, Joseph J. Sacco, Johnny John, Matthew Wheater, Christian H. Ottensmeier

Department of Medical Oncology Faculty Papers

PURPOSE: To assess efficacy and safety in subgroups of patients treated with Melphalan/Hepatic Delivery System (melphalan/HDS), a drug/device combination for liver-directed treatment of metastatic UM (mUM) patients. Previously reported FOCUS study results indicated melphalan/HDS treatment provides a clinically meaningful response rate and favorable benefit-risk ratio in patients with unresectable mUM.

METHODS: Patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) every 6-8 weeks for up to 6 cycles. Post hoc analyses of efficacy and safety were conducted for patient subgroups based on demographic and baseline disease characteristics.

RESULTS: 102 patients with mUM were enrolled; treatment was attempted …

P-15 Peptide Enhanced Bone Graft Improves Time To Fusion In Transforaminal Lumbar Interbody Fusion: A Randomized, Controlled, Investigational Device Exemption Study, James S. Harrop, Michael P. Steinmetz, John E. O'Toole, Christopher D Chaput, Rick C. Sasso, K. Brandon Strenge, Greg Maislin, Jeffrey P. Mullin, Thomas B. Freeman, Anthony Guanciale, Howard Lantner, Michael E. Janssen, David G. Schwartz, John M. Small, Wellington K. Hsu, Paul M. Arnold

Department of Neurosurgery Faculty Papers

STUDY DESIGN: Prospective, multicenter, single-blind, randomized, and controlled pivotal study.

OBJECTIVE: Compare time-to-fusion in patients treated with P-15L (PearlMatrix TM P-15 peptide enhanced bone graft) versus local autograft over 24 months and evaluate changes in pain and quality of life at 24 months relative to baseline.

SUMMARY OF BACKGROUND DATA: P-15L, an FDA-designated breakthrough device, is a composite bone graft with P-15, a 15-amino acid polypeptide that promotes cellular adhesion, proliferation, and differentiation to support bone formation.

METHODS: Patients (22-80 y) with degenerative disc disease were randomized to the investigational (P-15L) or control (local autograft) group during single-level transforaminal lumbar …

Urinothorax And Empyema: Presentation Of An Unusual Complication Of A Rare Condition, Nolan Fox, Nicholas Fox, Shourjo Chakravorty, Neeraj Sinha

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

A 68-year-old male with a history of metastatic bladder cancer and urinary obstruction presented with intractable hiccups and chest pain is presented in this case. He was found to have a unilateral pleural effusion in addition to ipsilateral renal metastasis abutting the diaphragm. Imaging revealed empyema. Thoracentesis revealed positive cultures and a lack of malignant cells on cytology. Comorbid urinary obstruction and urinary tract infection suggested the rare diagnosis of an infected urinothorax. Thoracentesis also revealed pleural fluid creatinine greater than serum creatinine, meeting the most specific diagnostic criteria for urinothorax and establishing the diagnosis. Treatment aimed at evacuating the …

Radiogenomic Profiling Of Prostate Tumors Prior To External Beam Radiotherapy Converges On A Transcriptomic Signature Of Tgf-Β Activity Driving Tumor Recurrence, Anson T. Ku, Uma Shankavaram, Shana Y. Trostel, Hong Zhang, Sumeyra Kartal, Houssein A. Sater, Stephanie A. Harmon, Nicole V. Carrabba, Yang Liu, Hyunnam Ryu, James A. Proudfoot, Boon Hao Hong, Bradford J. Wood, Peter A. Pinto, Peter L. Choyke, Mack Roach, Howard M. Sandler, Stephanie L. Pugh, Kenneth L. Zeitzer, Lucas C. Mendez, Nirav S. Kapadia, William A. Hall, Anand B. Desai, Radka S. Stoyanova, Alan Pollack, Elai Davicioni, Melvin L. K. Chua, Baris Turkbey, Adam G. Sowalsky, Deborah E. Citrin

Einstein Health Papers

PURPOSE: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies.

EXPERIMENTAL DESIGN: We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n = 60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI at baseline and 6 months after treatment, with a median follow-up …

Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage In Cpvt, Shanna Hamilton, Radmila Terentyeva, Roland Veress, Fruzsina Perger, Zuzana Nichtova, Mark Bannister, Jinxi Wang, Sage Quiggle, Rachel Battershell, Matthew Gorr, Sandor Györke, Bum-Rak Choi, Christopher George, Andriy Belevych, György Csordás, Dmitry Terentyev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca 2+ ] in the mitochondrial intermembrane space (IMS) and activates the Ca 2+ -sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).

METHODS: We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(Ser2336Leu)(+/-) . We created a new biosensor to measure IMS-[Ca2+ ] …

Incidence And Management Of Adverse Events Associated With Tebentafusp Treatment In Metastatic Uveal Melanoma: Pooled Safety Analysis Of 410 Patients, Takami Sato, Marcus O. Butler, Sophie Piperno-Neumann, Jessica C. Hassel, Paul Nathan, Alexander N. Shoushtari, Piotr Rutkowski, Richard D. Carvajal, Jean-Francois Baurain, Max Schlaak, Josep M. Piulats, Ryan J. Sullivan, Sebastian Ochsenreither, Reinhard Dummer, John M. Kirkwood, Alexandra Ikeguchi, Anthony M. Joshua, Mark R. Middleton, Ramakrishna Edukulla, Constance Pfeiffer, Joseph J. Sacco

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

PURPOSE: We conducted an integrated safety analysis from three clinical studies of tebentafusp, a first-in-class ImmTAC bispecific T-cell engager, which can redirect T cells to target glycoprotein 100-positive cells, in metastatic uveal melanoma.

EXPERIMENTAL DESIGN: HLA-A*02:01-positive patients with unresectable or metastatic uveal melanoma enrolled in three clinical trials (IMCgp100-01, IMCgp100-102, and IMCgp100-202) who received ≥1 dose of tebentafusp were included. Safety data were pooled to evaluate the profile, onset, and management of treatment-related adverse events (TRAE). Adverse events of special interest included cytokine release syndrome (CRS), acute skin reactions (ASR), and liver function test elevations. Primary prophylaxis with medications was …

Dual-Level Pattern Tree For Visual Field Improves Glaucoma Progression And Polygenic Risk Prediction, Luo Song, Lucy Q. Shen, Louis R. Pasquale, Michael V. Boland, Sarah R. Wellik, Carlos Gustavo De Moraes, Ayellet Segre, Janey L. Wiggs, Constance Turman, Jonathan S. Myers, Tobias Elze, Nazlee Zebardast, David S. Friedman, Jae H. Kang, Mengyu Wang

Wills Eye Hospital Papers

PURPOSE: To develop a dual-level pattern tree to characterize visual field (VF) loss subtypes that can be used to better predict glaucoma progression and glaucoma polygenic risk scores (PRSs).

METHODS: This study included 113,030 patients from three datasets, each used for a specific purpose: (1) model training, (2) progression forecasting, and (3) PRS correlations. We applied archetypal analysis to cluster 24-2 VFs into trunk patterns and their branch patterns. The Cox regression model was used to forecast VF progression using mean deviation (MD) slope, MD-fast slope, total deviation (TD) pointwise slope, and visual field index (VFI) slope. Multivariable regression analyses …

Dna Methylation Markers Of Insulin Resistance Surrogate Measures In The Atherosclerosis Risk In Communities (Aric) Study, Jeewoen Shin, Jan Bressler, Megan L Grove, Michael Brown, Elizabeth Selvin, James S Pankow, Myriam Fornage, Alanna C Morrison, Chloé Sarnowski

Faculty, Staff and Student Publications

Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association …

Derivation Of Pluripotent Stem Cell Lines (Rfsci005-A, Rfsci006-A) From Siblings Harboring Identical High-Risk Complement Variants With Discordant Age-Related Macular Degeneration, Naresh Rajendran, Ajeet Singh, Wendy Runyon, Sam Hu, Ritu Kumar, Rinki Ratnapriya, Karl Csaky, Srinivasa R Sripathi

Faculty, Staff and Students Publications

Age-related macular degeneration (AMD) is a complex disease influenced by genetic and environmental factors. Variants in the complement pathway, especially in the CFH gene, increase AMD risk, yet disease severity can differ among individuals with identical high-risk genotypes. We generated induced pluripotent stem cell (iPSC) lines from siblings carrying identical high-risk complement variants but displaying discordant AMD phenotypes. These lines provide a unique platform to study epigenetic, transcriptomic, and environmental factors driving AMD heterogeneity. By comparing differentiated retinal cells, we aim to reveal mechanisms behind variable disease susceptibility and inform personalized therapies for AMD.

Generation Of Ipscs (Rfsci007-A, Rfsci008-A) From A Patient With Early-Onset Bilateral Drusen And A Healthy Sibling For Retinal Disease Modeling, Sonali Singh, Wendy Runyon, Sam Hu, Paige Grona Kennedy, Ajeet Singh, Rinki Ratnapriya, Ritu Kumar, Karl Csaky, Srinivasa R Sripathi

Faculty, Staff and Students Publications

Drusen are extracellular deposits between the retinal pigment epithelium and Bruch's membrane, commonly linked to age-related macular degeneration (AMD). However, their presence in younger individuals offers a unique opportunity to study early disease mechanisms before extensive degeneration. We generated two human induced pluripotent stem cell (hiPSC) lines from siblings' peripheral blood mononuclear cells-one with early-onset bilateral drusen and the other unaffected. This genetically matched iPSC pair enables investigation of early drusen associated pathological changes driving retinal disease development.

The Impact Of Extramedullary And Paraskeletal Plasmacytomas On Treatment Outcomes In Multiple Myeloma Treated With Teclistamab: U.S. Myeloma Immunotherapy Consortium Real-World Experience, Aimaz Afrough, Danai Dima, Beatrice Razzo, Utkarsh Goel, Aishwarya Sannareddy, Oren Pasvolsky, Mariola Vazquez-Martinez, Christopher Ferreri, Rahul Banerjee, Jack Khouri, James Davis, Mahmoud Gaballa, Alex Lieberman-Cribbin, Masooma Rana, Kelley Julian, Faiz Anwer, Leyla Shune, Shaun Dejarnette, Ariel Grajales-Cruz, Evguenia Ouchveridze, Gabriel De Avila, Sandra Susanibar-Adaniya, Andrew Portuguese, Daniel Schrum, Erin Eberwein, Hitomi Hosoya, Lekha Mikkilineni, Gurbakhash Kaur, Joseph Mcguirk, Adriana Rossi, Megan Herr, Omar Castaneda, Frederick Locke, Shahzad Raza, Yi Lin, Shebli Atrash, Douglas Sborov, Peter Voorhees, Shambavi Richard, Alfred Garfall, Surbhi Sidana, Krina Patel, Doris Hansen, Andrew Cowan, Larry Anderson, Hans Lee

Department of Medical Oncology Faculty Papers

Teclistamab, a bispecific antibody targeting B-cell maturation antigen (BCMA), is effective in relapsed or refractory multiple myeloma (RRMM), but its impact on patients with soft tissue plasmacytomas is unclear. We studied 385 RRMM patients treated with teclistamab at 13 U.S. centers through September 2023, with follow-up to April 2024. Soft tissue plasmacytomas were classified as true extramedullary disease (EMD; not contiguous with bone) or paraskeletal plasmacytomas (PSK; contiguous with bone). Patients with the simultaneous presence of both were classified as true-EMD, reflecting its adverse prognosis. Of those, 109 (28%) had true EMD, 33 (9%) had PSK, and 243 (63%) had …

Rabies Virus-Vectored Lyme Disease Vaccine Provides Long-Term Protection Against Tick-Transmitted Borrelia Burgdorferi, Shantel Rios, Bibek Bhattachan, Christoph Wirblich, Anisha Chandwani, Kruthi Vavilikolanu, Jacob F. Myers, Chrysoula Kitsou, Utpal Pal, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Lyme disease (LD) cases have doubled globally. LD is a tick-borne illness caused by the Borrelia burgdorferi sensu lato (Bb). If untreated, Bb can disseminate to distal organs, causing carditis, arthritis, and meningitis. Currently, no FDA-approved human LD vaccine exists on the market. This study used two approaches to incorporate OspA into the rabies virus (RABV) vaccine vector. We used the RABV-glycoprotein tail (RVG tail) and the Hendra virus (HeV) glycoprotein tail (HVG tail) to incorporate OspA, creating BNSP333-OspA-RVG and BNSP333-OspA-HVG, respectively. Both vaccines produced type-1 biased anti-OspA antibodies, but only BNSP333-OspA-HVG induced neutralizing antibodies and protected against Bb infection. …

‘In Texas, Everybody Wants Antibiotics’: Reducing Inappropriate Antibiotic Expectations And Use With A Provider-Patient Communication Tool In Primary Care, Ashley Collazo, Paige Wermuth, Johanan Luna Rodriguez, Kiara Olmeda, Azalia Mancera, Fabrizia Faustinella, Michael K Paasche-Orlow, Roger Zoorob, Barbara Wells Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Background/objective: Patients often expect antibiotics for self-limiting diseases, pressuring providers to prescribe antibiotics unnecessarily. These expectations also contribute to the unsafe practice of taking antibiotics without a prescription (non-prescription use), such as pills retained from prior prescriptions or antibiotics from non-medical sources. Previous work shows that non-prescription use is due to strong, widely held misconceptions regarding the curative power of antibiotics. To reduce unnecessary use of antibiotics, we developed and pilot-tested a patient-focused, bilingual (English and Spanish) educational tool with patient and provider stakeholder input. The tool, a trifold brochure, included information on safe antibiotic use, potential antibiotic harms and …

Chronic Rhinosinusitis Is A Risk Factor For Interstitial Lung Disease In Sjogren’S Syndrome, Brian Schonewald, Christopher Xie, Andrew Engel, Ross Summer, Giorgos Loizidis

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

BACKGROUND: Interstitial lung disease (ILD) is a leading cause of morbidity and mortality in Sjögren's syndrome (SS), but its risk factors remain unclear. Although SS affects both the upper and lower respiratory epithelium, it is unknown whether this occurs simultaneously or separately. In other autoimmune conditions-such as eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis-upper airway disease precedes lower lung involvement by months or even years. We hypothesized that chronic rhinosinusitis (CRS), as an upper airway disease, may be a risk factor for ILD in SS.

METHODS: We analyzed the TriNetX Research Network database to compare incident ILD in SS …

Evaluation Of Integrative Oncology Modalities For Symptom Management: A Mascc/Sio Global Survey, Alexandre Chan, Reem Nasr, Daniela Arcos, Dalia Kagramanov, Chioma Asuzu, Ting Bao, Yin Ting Cheung, Jung Hye Kwon, Judith Lacey, Richard T. Lee, Maryam Lustberg, Beatrice M. Ohaeri, Santosh Rao, Enrique Soto-Perez-De-Celis, Claudia M. Witt, Ana M. Lopez

Kimmel Cancer Center Faculty Papers

BACKGROUND: With growing evidence pointing towards the potential of integrative oncology modalities (IOM) in addressing cancer and cancer-treatment related symptoms, research on IOM utilization and implementation is warranted. This study examines global stakeholder perspectives on integrative oncology (IO) utilization for supportive cancer care.

METHODS: Members of the Multinational Association of Supportive Care in Cancer (MASCC) and the Society for Integrative Oncology (SIO) completed a survey on the utilization of IOM for supportive cancer care. Descriptive statistics were used to assess demographic data, IOM usage patterns, IOM education, and financial considerations for utilizing IOM.

RESULTS: Among 344 participants representing eight geographical …

Risk Of Late-Onset Depression In Long-Term Survivors Of Breast, Prostate, And Colorectal Cancer, Melissa Taylor, Sarah Westvold, Jessica Long, Terry Hyslop, Andrea Silber, Rebecca Forman, Faiza Yasin, Tendai Kwaramba, Shi-Yi Wang, Michael Leapman, Michael Cecchini, Ira Leeds, Lisa Spees, Stephanie Wheeler, Cary Gross, Kevin Oeffinger, Michaela Dinan

Kimmel Cancer Center Faculty Papers

IMPORTANCE: The prevalence of depression is higher in cancer survivors than in the general population. As the long-term cancer survivor population increases, it is increasingly important to understand risk factors for late-onset depression.

OBJECTIVE: To identify risk factors associated with late-onset depression in long-term (5-year) survivors of breast, prostate, or colorectal cancer.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used 2022 linkage of Surveillance, Epidemiology, and End Results (SEER) and Medicare data to identify 5-year survivors of breast, prostate, or colorectal cancer 66 years or older who were enrolled in fee-for-service Medicare and had no previous depression diagnosis. Long-term …

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

Genomic Profiling Of Intraocular Leiomyomas Reveals Recurrent Copy Number Alterations, Vivian Tang, Yubai Chou, Cuyan Demirkesen, Michele M. Bloomer, Joseph B. Crawford, Ahmet M. Sarici, Carol L. Shields, Ralph C. Eagle Jr., Codrin E. Iacob, Walter P. Devine, Tatyana Milman, Melike Pekmezci

Wills Eye Hospital Papers

PURPOSE: Leiomyomas are benign smooth muscle tumors that commonly present in the uterus, soft tissue, skin, and gastrointestinal tract but in rare cases can also arise within the eye. Notably, intraocular leiomyomas often show slightly different histopathologic and immunohistochemical features, referred to as mesectodermal morphology, given their presumed neural crest origin. Genetic and cytogenetic alterations of intraocular leiomyomas, as well as their association with various clinical and histopathologic features, have not been previously studied.

METHODS: We identified eight patients diagnosed with intraocular leiomyoma and performed targeted next-generation sequencing, whole transcriptome RNA sequencing, and chromosomal copy number analysis on those with …

Ocular Bacterial Microbiome Analysis By Next-Generation Sequencing In Patients With Stevens-Johnson Syndrome And Sjögren’S Disease: Associations With Dry Eye Indices, Luciana Frizon, Talita Trevizani Rocchetti, André Frizon, Rafael Jorge Alves De Alcântara, Ana Luisa Hofling-Lima, Cintia S De Paiva, José Álvaro Pereira Gomes

Faculty, Staff and Students Publications

The ocular surface microbiome plays a crucial role in maintaining immune homeostasis, and its disruption may contribute to mucosal inflammation and autoimmunity. This pilot exploratory study investigated and compared the ocular surface bacterial microbiome in patients with Stevens-Johnson syndrome (SJS), Sjögren's disease (SjD), and healthy controls using next-generation sequencing (NGS) and correlated these findings with dry eye parameters. Conjunctival swabs were collected from sixteen individuals: ten with SJS, three with SjD, and three healthy controls. Dry eye parameters were employed to evaluate the dry eye disease. Microbiome profiles were determined by the NGS of the 16S V3-V4 region and analyzed …

Glycerol-3-Phosphate Activates Chrebp, Fgf21 Transcription And Lipogenesis In Citrin Deficiency, Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner

Faculty, Staff and Students Publications

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms …

Effect Of Valemetostat On The Pharmacokinetics Of Midazolam And Digoxin: A Phase 1 Drug-Drug Interaction Study In Patients With Non-Hodgkin Lymphoma, Masaya Tachibana, Steven Horwitz, Eric Jacobsen, Francine Foss, Pamela Allen, Pierluigi Porcu, Tatyana Feldman, Jia Ruan, Jonathan Brammer, Jie Wang, Shinichi Inaba, Yuka Iko, Keiko Nakajima, Yasuyuki Kakurai, Noriaki Kitami, Yang Chen, Yvonne Lau

Department of Medicine Faculty Papers

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2/1, under investigation in non-Hodgkin lymphomas (NHLs) and solid tumors. In vitro, it inhibits cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) when combined with sensitive CYP3A or P-gp substrates. This drug–drug interaction (DDI) sub-study is part of the phase 1 trial of valemetostat monotherapy (DS3201-A-J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P-gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and …

Adherence To Integrative Care, Oncology Healthcare Utilization, Opioid Use And Hospitalization, Eran Ben-Arye, Dan Greenberg, Noah Samuels, Ana Maria Lopez, Tzahit Simon-Tuval

Kimmel Cancer Center Faculty Papers

Research on the relationship between integrative oncology (IO) programs and dispensing of chemotherapy agents and supportive care drugs, and hospitalization rates is limited. The present study examined these outcomes in chemotherapy-treated patients with cancer, comparing patients highly adherent to integrative care (high-AIC) to those with low adherence (low-AIC). Data from patients with cancer treated with taxane and/or platinum-based agents participating in an ongoing prospective, controlled pragmatic trial were examined retrospectively. Patients were referred to an IO consultation and weekly treatments at 3 medical centers in Northern Israel, with high-AIC defined as attending ≥4 sessions at 6 weeks; low-AIC, 0-3 sessions. …

Cd5 Expression In Ctcl And Its Implications For Anti-Cd5 Car T-Cell Therapy, Leena Wardeh, Madeline Williams, Courtney Prestwood, Zachary Wolner, Neda Nikbakht

Department of Dermatology and Cutaneous Biology Faculty Papers

Cutaneous T-Cell Lymphomas (CTCL) are a heterogenous group of T-cell malignancies in the skin and have poor treatment outcomes in advanced stages. CD5, a surface glycoprotein expressed on most mature T cells, has emerged as a promising target for chimeric antigen receptor (CAR) T-cell therapy in systemic T-cell lymphomas. However, its expression profile in CTCL and relevance for targeted therapy remain unclear. Notably, in CTCL, the cell surface expression of receptors, such as CD7 and CD26, tends to become downregulated on the surfaces of malignant T cells In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from patients at …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …

Development And Validation Of Clinical Screening Systems For Cushing Disease In The United States, Jorge E. Salcedo-Sifuentes, Sonal Mehta, Carter M. Suryadevara, Marvin Bergsneider, Kevin C. J. Yuen, Paul A. Gardner, Julie M. Silverstein, Albert H. Kim, James J. Evans, Garni Barkhoudarian, Juan C. Fernandez-Miranda, William T. Couldwell, Robert C. Rennert, Varun R. Kshettry, Kyle C. Wu, Carolina Benjamin, Gabriel Zada, Michael R. Chicoine, Jamie J. Van Gompel, Michael P. Catalino, Michael Karsy, Adam Mamelak, Ildiko Torok, Trevor Low, Won Kim, Donato R. Pacione, Nidhi Agrawal

Department of Neurosurgery Faculty Papers

PURPOSE: Clinical screening systems (CSSs) for Cushing syndrome (CS) validated in Europe have not been evaluated for CS or Cushing disease (CD) in the United States (US). We aimed to evaluate existing CSSs in US patients and develop two new symptom-based CSSs to identify patients with high pre-test probability of disease warranting referral for definitive biochemical workup-one for broad CS screening and one specifically for CD.

METHODS: Data were obtained from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID)-comprising 615 patients who underwent transnasal transsphenoidal resection for CD at one of 11 US pituitary centers, the Centers …

What Community Members With Chronic Illness Teach Future Healthcare Professionals In A Longitudinal Interprofessional Education Program: A Focus Group Study, Rachel White, Maria Brucato, Amber King, Anne B. Mitchell, Nethra S. Ankam

Department of Medicine Faculty Papers

INTRODUCTION: Nearly 50% of Americans have at least one chronic illness. Preparing future healthcare providers for interprofessional collaborative practice (IPCP) and person-centred care through community-based interprofessional education (IPE) can improve outcomes for this growing population. Partial programme theories predict that patients' participation as teachers in health professions education contributes to students' development of patient-centredness. Role theory asserts that behaviours are shaped by assigned roles; therefore, community members with chronic illness who assume roles of health mentors in an IPE curriculum are predicted to teach students about their patient experiences. Yet, this teaching outcome and the lessons health mentors teach in …

Concurrent Local Therapy Extends Clinical Benefit Of Tebentafusp In Metastatic Uveal Melanoma Patients, Tristan L. Lim, Kamaneh Montazeri, Eric Wehrenberg-Klee, Antoine Desilets, Rino S. Seedor, Marlana Orloff, Takami Sato, Michael Caplan, Mariam El-Ashmawy, Benjamin Izar, Shaheer Khan, Inderjit Mehmi, Aleigha Lawless, Theodore S. Hong, Omid Hamid, Richard D. Carvajal, Alexander Shoushtari, Ryan J. Sullivan

Kimmel Cancer Center Faculty Papers

BACKGROUND: Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone.

PATIENTS AND METHODS: This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that …

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

The Brown Foundation: Institute of Molecular Medicine

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