Investigative Techniques Commons^™

Comparison Of Open And Laparo-Endoscopic Repair Techniques For Patients With Bilateral Inguinal Hernias, Divyansh Agarwal, Tina Bharani, Nora Fullington, Lauren Ott, Kortney Hodgson, Daelyn Mcclain, Kaela Blake, Michael Reinhorn

Department of Surgery Faculty Papers

INTRODUCTION: For primary bilateral inguinal hernias, international guidelines favor a laparoscopic posterior mesh repair due to relatively lower risk of acute and chronic pain, faster recovery, and favorable biomechanical properties compared to open anterior approaches (Lichtenstein, plug and patch, etc.). However, studies comparing open mesh-based bilateral inguinal hernia repairs to bilateral laparoscopic and robotic mesh-based approaches are limited. The Abdominal Core Health Quality Collaborative (ACHQC) registry includes longitudinal data on bilateral inguinal hernia repairs performed via open as well as laparo-endoscopic approaches. We hypothesize that outcomes for bilateral inguinal hernia repair are similar between open and laparo-endoscopic approaches in the …

Association Of Estimated Plasma Volume Status With Invasive Hemodynamics And All-Cause Mortality In Patients With Liver Cirrhosis, Esteban Kosak Lopez, Phuuwadith Wattanachayakul, Jose Manuel Martinez Manzano, Andrew Geller, Simone Jarrett, John Malin, Raul Leguizamon, Tara John, Rasha Khan, Ian Mclaren, Alexander Prendergast, Kevin Lo, Zurab Azmaiparashvili

Einstein Health Papers

BACKGROUND: Estimated plasma volume status (ePVS) correlates with intravascular congestion and prognosis in patients with heart failure. The ePVS relationship with invasive hemodynamic profiling and clinical outcomes in patients with liver cirrhosis (LC) remains unclear.

METHODS: This single-center retrospective cohort study included LC patients who underwent right heart catheterization (RHC) between 2018 and 2023. Estimated plasma volume status (ePVS) was calculated using the Strauss-derived Duarte formula, with patients classified into high (> 5.5%) and low-ePVS (≤ 5.5%) groups. Cox-multivariable analysis was used to determine if ePVS was associated with all-cause mortality within 1 year post-RHC among transplant-free patients.

RESULTS: Of …

Long-Term Non-Conditional And Conditional Metastasis Of Uveal Melanoma By Tumor Size Category In 8034 Patients, Rolika Bansal, Hidayet Sener, Jerry A. Shields, Carol L. Shields

Wills Eye Hospital Papers

PURPOSE: To estimate metastasis of patients with uveal melanoma (UM) based on tumor size categories classified by ultrasonographic thickness as small (0.0-3.0 mm), medium (3.1-8.0 mm), or large (≥8.1 mm) using both non-conditional and conditional analyses.

DESIGN: Retrospective analysis.

METHODS: A retrospective study of 8034 cases over 35-years at a single ocular oncology referral center evaluated the primary endpoint of cumulative incidence of metastasis at 5-, 10-, 15-, 20-, 25- and 30-years using non-conditional and conditional analysis at 3-years, 5-years, and 10-years of metastasis-free survival.

RESULTS: The mean thicknesses for small, medium, and large UMs were 2.5 mm, 5.0 mm, …

Colorectal Cancer And The Risk Of Mortality Among Individuals With Suicidal Ideation, Srikanta Banerjee, Jagdish Khubchandani, Stanley Nkemjika

Department of Psychiatry and Human Behavior Faculty Papers

Suicide is a major public health problem that has grown at alarming rates in the last two decades. Colorectal cancer (CRC) is one of the most common causes of cancer deaths in the United States in both males and females. However, the influence of suicidal ideation (SI) on the association between CRC and risk of mortality has not been well examined.

METHODS: For this study, the 2005-2018 National Health and Nutrition Examination Survey (NHANES), a nationally representative survey of United States adults aged 20 years or older, was utilized. CRC survivorship was determined from self-reported data on CRC, and mortality …

A Smart Pill Bottle And Text Messaging Intervention For Promoting Medication Adherence In Patients With Chronic Myeloid Leukemia: A Pilot Study Of Txt4 Tki, Kuang-Yi Wen, Neil Palmisiano, Rita Smith, Rachel Slamon, Gina Keiffer, Christian Fidler, Margaret Kasner, Lindsay Wilde, Md

Department of Medical Oncology Faculty Papers

BACKGROUND: Patients undergoing tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) often face challenges with adherence, despite the efficacy of the treatment. Theory-guided and evidence-informed interventions addressing psychosocial and adherence barriers are critical for promoting adherence. Using a mixed-method approach, the pilot study developed and evaluated the feasibility and potential impact of an intervention "txt4TKI," to support medication and symptom management among CML patients undergoing TKI therapy.

METHODS: Guided by the Necessity and Concerns framework, the study comprised two phases: Phase 1 involved qualitative patient needs assessment interviews informing intervention design. Phase 2 was a single-arm pilot study …

Tacrolimus Dosing In Liver Transplant Recipients Using Phenotypic Personalized Medicine: A Phase 2 Randomized Clinical Trial, Jeffrey Khong, Megan Lee, Curtis Warren, Un Kim, Sergio Duarte, Kenneth Andreoni, Sunaina Shrestha, Mark Johnson, Narendra Battula, Danielle Mckimmy, Thiago Beduschi, Ji-Hyun Lee, Derek Li, Chih-Ming Ho, Ali Zarrinpar

Department of Surgery Faculty Papers

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large …

Causes Of Death Among Us Medical Residents, Nicholas A. Yaghmour, William E. Bynum, Frederic W. Hafferty, Karen D. Könings, Thomas Richter, Timothy P. Brigham, Thomas J. Nasca

Division of Nephrology Faculty Papers

IMPORTANCE: From 2000 to 2014, the leading causes of medical resident death in the United States were neoplastic diseases and suicide.

OBJECTIVE: To examine whether US medical resident rates of death have changed since 2014 and whether causes of resident death differ by specialty.

DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, residents and fellows who were enrolled in Accreditation Council for Graduate Medical Education (ACGME)-accredited training programs and who died from January 2015 to December 2021 were submitted to the National Death Index to obtain causes of death. These decedents were compared with residents and fellows who died between …

How Reliable Is The Assessment Of Fusion Status Following Acdf Using Dynamic Flexion-Extension Radiographs?, Christopher T. Martin, Sangwook Tim Yoon, Ram Kiran Alluri, Edward C. Benzel, Chris M. Bono, Samuel K. Cho, Dean Chou, Xiaolong Chen, Jason P. Y. Cheung, Juan P. Cabrera, Stipe Ćorluka, Andreas K. Demetriades, Matthew F. Gary, Zoher Ghogawala, Waeel Hamouda, Inbo Han, Dimitri Hauri, Patrick C. Hsieh, Amit Jain, Jun S. Kim, Hai V. Le, Philip K. Louie, Zhuojing Luo, Hans-Jörg Meisel, Sathish Muthu, Dal-Sung Ryu, Charles A. Sansur, Andrew J. Schoenfeld, Laura Scaramuzzo, Gregory D. Schroeder, Shanmuganathan Rajasekaran, Veranis Sotiris, Gianluca Vadalà, Pieter-Paul A. Vergroesen, Jeffrey C. Wang, Yabin Wu, K. Daniel Riew

Rothman Institute Papers

Study DesignReliability study.ObjectivesThe radiographic diagnosis of non-union is not standardized. Prior authors have suggested using a cutoff of < 1 mm interspinous process motion (ISPM) on flexion-extension radiographs, but the ability of practicing surgeons to make these measurements reliably is not clear.Methods29 practicing spine surgeons measured ISPM on 19 levels of ACDF from 9 patients. Surgeons relied on these measurements to report on fusion status. Inter-observer correlation co-efficients (ICC), standard error (SEM) and the minimum detectable difference (MD) of these measurements were calculated. We screened for clerical errors by checking measurements more than one standard deviation from the group mean.ResultsThe ICC for ISPM was .76 (.64; .88) with a SEM of 1 mm and a MD of 2.76 mm. Agreement on fusion status was moderate, with an ICC of .6 (.44; .76). After screening for and removing clerical errors, the ICC improved to .82 (.71; .91), SEM improved to .83 mm, and MD improved to 2.29 mm. Six reviewers had an ICC >.9. The ICC from these high performing reviewers was .94 (.9; .97), SEM was .45 mm, and MD was 1.26 mm.ConclusionsThe MD of 2.29 mm in our study group was not precise enough to support a cutoff of < 1 mm ISPM as the sole measurement technique in screening for non-union after ACDF, and there was only moderate agreement amongst surgeons on fusion status based on dynamic radiographs. More stringent techniques are necessary to avoid mis-diagnosing non-union in clinical studies. Future studies should consider auditing measurements to identify clerical errors.

Normative Variability In Retinal Nerve Fiber Layer Thickness: Does It Matter Where The Peaks Are?, Sowjanya Gowrisankaran, Ashkan Abbasi, Xubo Song, Joel Schuman, Gadi Wollstein, Bhavna Antony, Hiroshi Ishikawa

Wills Eye Hospital Papers

PURPOSE: Retinal nerve fiber layer thickness (RNFLT), a glaucoma biomarker, has a wide normative range affecting its sensitivity and specificity for abnormality detection. The interindividual RNFLT peak location variability contribution to this wide normative range has not been directly evaluated. The purpose of this study is to assess the effect of RNFLT peak normalization (PN) on normative variability.

METHODS: Circumpapillary RNFLT profiles at 1.7 mm radius from the optic nerve head (ONH) were re-sampled from optical coherence tomography (OCT) volumes (Cirrus HD-OCT, 200 × 200) obtained from one eye of 83 healthy individuals. Fovea-ONH axis (FOA) was calculated from corresponding …

Leveraging Lower Body Negative Pressure For Enhanced Outcomes In Orthopedic Arthroplasty—Insights From Nasa’S Bone Health Research, Phani Paladugu, Rahul Kumar, Tamer Hage, Swapna Vaja, Tejas Sekhar, Samuel Weisberg, Kyle Sporn, Ethan Waisberg, Joshua Ong, Amar S. Vadhera, Mouayad Masalkhi, Ryung Lee, Chirag Gowda, Ram Jagadeesan, Nasif Zaman, Alireza Tavakkoli

SKMC Student Presentations and Publications

Exposure to microgravity causes rapid bone loss and muscle atrophy, posing serious challenges for long-duration spaceflight. In response, NASA developed countermeasures such as Lower Body Negative Pressure (LBNP) to simulate gravitational loading on astronauts’ lower extremities. LBNP, often combined with exercise, has proven effective in mitigating musculoskeletal degradation during bed rest analogs. This opinion paper argues that LBNP’s success in preserving bone mass and muscle function in microgravity can be translated to improve re- covery after orthopedic arthroplasty on Earth. We draw physiological parallels between microgravity-induced musculoskeletal disuse and the postoperative period following total joint replacement, during which reduced weight-bearing …

Plasma Proteomic Biomarkers Of Physical Frailty In Heart Failure: A Propensity Score Matched Discovery-Based Pilot Study, Quin Denfeld, Noelle Pavlovic, Christopher Lee, Jon Jacobs, Mary Roberts Davis, Samantha Powell, Marina Gritsenko, Susan Joseph, Beth Habecker

Division of Cardiology Faculty Papers

BACKGROUND: Physical frailty is highly prevalent in heart failure (HF), but we lack an understanding of the underlying pathophysiology. Proteomic evaluation of plasma samples may elucidate potential mechanisms and biomarkers of physical frailty in HF.

OBJECTIVES: We aimed to identify plasma proteomic biomarkers that are differentially expressed between physically frail and non-physically frail adults with HF.

METHODS: This was a secondary analysis of a subset of data and plasma samples from a study of frailty among patients with New York Heart Association (NYHA) Functional Classification I-IV HF. Physical frailty was measured using the Frailty Phenotype Criteria. Propensity score matching was …

Hexasodium Fytate (Snf472 Or Csl525) Inhibits Ectopic Calcification In Various Pseudoxanthoma Elasticum And Calcinosis Cutis Animal Models, Miguel Ferrer, Maria Pérez-Ferrer, Marc Blasco, Ida Jacobs, Qiaoli Li, Olivier Vanakker, Lisa Dangreau, Andrea López, Gianluca Malagraba, Firas Bassissi, Joan Perelló, Carolina Salcedo

Department of Biochemistry and Molecular Biology Faculty Papers

Background/Objectives: Ectopic calcification is a pathological condition characterized by the mineralization of soft tissues due to the deposition of calcium phosphate crystals. Hexasodium fytate (CSL525, previously known as SNF472) is a crystallization inhibitor being developed for the treatment of ectopic calcification-related disorders. Our aim was to investigate CSL525 for the treatment of soft-tissue calcification disorders in animal models of pseudoxanthoma elasticum and calcinosis cutis. Methods: In a first study, abcc6^-/- zebrafish larvae were exposed to 1 mM CSL525 for 7 days or kept under the same conditions without CSL525, and spinal mineralization was quantified. In a second study, abcc6 …

Molecular Subtyping Of Hypertensive Disorders Of Pregnancy, Michal Elovitz, Elaine Gee, Nathaniel Delaney-Busch, Alison Moe, Mitsu Reddy, Arkady Khodursky, Johnny La, Ilma Abbas, Kay Mekaru, Hunter Collins, Farooq Siddiqui, Rory Nolan, Rupsa Boelig, Daniel Kiefer, Pamela Simmons, George Saade, Antonio Saad, Ebony Carter, Thomas Mcelrath, Stephen Quake, Mark Depristo, Carrie Haverty, Manfred Lee, Eugeni Namsaraev, Vincenzo Berghella, Ai-Ris Collier, Antonia Frolova, Esther Park-Hwang, Luis Pacheco, Elizabeth Sutton, Maneesh Jain, Kara Rood, William A Grobman, Joseph Biggio, Cynthia Gyamfi-Bannerman, Arun Jeyabalan, Morten Rasmussen

Department of Obstetrics and Gynecology Faculty Papers

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. …

3d-Printed Organ-Realistic Phantoms To Verify Quantitative Spect/Ct Accuracy For 177lu-Psma-617 Treatment Planning, Lydia J. Wilson, Sara Belko, Eric L. Gingold, Shuying Wan, Rachel Monane, Robert S. Pugliese, Firas Mourtada

Department of Radiation Oncology Faculty Papers

Background/Objectives: Accurate patient-specific dosimetry is essential for optimizing radiopharmaceutical therapy (RPT), but current tools lack validation in clinically realistic conditions. This work aimed to develop a workflow for designing and fabricating patient-derived, organ-realistic RPT phantoms and evaluate their feasibility for commissioning patient-specific RPT radioactivity quantification. Methods: We used computed tomographic (CT) and magnetic resonance (MR) imaging of representative patients, computer-aided design, and in-house 3D printing technology to design and fabricate anthropomorphic kidney and parotid phantoms with realistic organ spacing, anatomically correct orientation, and surrounding tissue heterogeneities. We evaluated the fabrication process via geometric verification (i.e., volume comparisons) and leak testing …

Larotrectinib Compared With Real-World Non-Tropomyosin Receptor Kinase Inhibitor Therapies In Patients With Tropomyosin Receptor Kinase Fusion Cancer, Marcia S. Brose, C. Benedikt Westphalen, Xiaoyun Pan, Vadim Bernard-Gauthier, Milena Kurtinecz, Helen Guo, Virginie Aris, Neil R. Brett, Abdelali Majdi, Vivek Subbiah, Nathan A. Pennell, Kenneth L. Kehl, Alexander Drilon

Kimmel Cancer Center Faculty Papers

PURPOSE: Neurotrophic tyrosine receptor kinase gene fusions are oncogenic drivers of various solid tumors. Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor approved for patients with TRK fusion cancer on the basis of single-arm trials. This study was a matched comparative effectiveness study of larotrectinib in clinical trials versus standard of care (SOC) in the real-world (RW) setting.

METHODS: Adult patients with advanced/metastatic TRK fusion non-small cell lung cancer, colorectal cancer, soft tissue sarcoma, thyroid cancer, or salivary gland carcinoma were included. Deduplicated data from RW patients were from US and ex-US data sources. Patients in the larotrectinib …

Vpac Receptor Positivity In Comparison With Mp-Mri In The Diagnosis Of Prostate Cancer: A Preliminary Study, Nishant Setya, Shridhar Ghagane, Rajendra Nerli, Ashwin Bokare, Mathew Thakur, Leonard Gomella

Kimmel Cancer Center Faculty Papers

Objective: The study aimed to prospectively evaluate the feasibility of diagnosing PCa using voided urine samples and by targeting the genomic VPAC (vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide) receptors in comparison with multiparametric magnetic resonance imaging (mp-MRI) in male patients (≥40 years of age) with lower urinary tract symptoms and having a serum PSA of >4 but < 15 ng/ml.

Patients and methods: Male patients attending urological services ≥40 years old, with lower urinary tract symptoms and serum PSA levels of >4 but < 15 ng/ml formed the study group. Voided urine samples were collected to target VPAC receptors on malignant cells. All patients underwent mp-MRI. A 12-core transrectal ultrasound-guided prostate biopsy was performed in all, and the results were compared for the diagnosis of PCa.

Results: A total of 61 patients with a median age of 65.33 ± 8.11 years and with a …

Evaluating Artifact-Free Four-Dimensional Computer Tomography With 16 Cm Detector Array, Inhwan Yeo, Wei Nie, Jiajin Fan, Mindy Joo, Michael Correa, Qianyi Xu

Department of Radiation Oncology Faculty Papers

PURPOSE: To evaluate a 16 cm-array axial four-dimensional computer tomography (4DCT) in comparison with a 4 cm-array 4DCT in the presence of respiration irregularity.

METHOD: Ten traces of lung tumor motion from CyberKnife treatments were imported to move the lung cylinder, containing a spherical target, of a phantom. Images were acquired for the lung that moved to each of the 10-positions/phases (1) step-wisely by nominal helical scan at each movement (ground truth), (2) continuously by 4D scan with the 16 cm array, and (3) the same with the 4 cm array, involving table shift. Irregularities, consisting of baseline shift and/or …

Impact Of Body Mass Index On Stroke In Extracorporeal Cardiopulmonary Resuscitation: Data From The Extracorporeal Life Support Organization Registry, Jin Kook Kang, Shi Nan Feng, Winnie Liu, Jiah Kim, Andrew Kalra, Patricia Brown, Christopher Wilcox, Daniel Brodie, Steven Keller, Bo Soo Kim, Glenn Whitman, Sung-Min Cho

SKMC Student Presentations and Publications

Objective: We aimed to characterize the impact of body mass index (BMI) on stroke in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). Methods: We queried the Extracorporeal Life Support Organization registry for patients receiving ECPR (2020-2024). Patients were categorized into five BMI groups: underweight (< 18.5 kg/m²), normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), class 1 obesity (30-34.9 kg/m²), and class 2 obesity or above (≥35 kg/m²). A generalized additive model (GAM) analysis was used to identify the BMI range with the greatest stroke risk. Multivariable regression was used to compare odds of …

Evaluation Of The Distress Thermometer In Older Patients With Cancer, Charlotte Zuber, Kristine Swartz, Andrew Chapman, Lora Rhodes, Tingting Zhan, Kuang-Yi Wen

Kimmel Cancer Center Faculty Papers

INTRODUCTION: The Geriatric Depression Scale is a useful tool in screening for depression in older adults, a particularly vulnerable population in oncology. The National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) has been validated as a fast and effective screening tool for psychological distress in general oncology populations, and it could possibly be used as a surrogate for the longer Geriatric Depression Scale (GDS) test in older adults with cancer.

MATERIALS AND METHODS: In this retrospective cross-sectional study in older adults prior to starting cancer treatment, we evaluated the relationship between the DT and GDS by comparing 242 older adults …

Characterization Of Novel Arrhythmogenic Patterns Arising Secondary To Heterogeneous Expression And Activation Of Nav1.8, Zhong-He Zhang, Hector Barajas-Martinez, Hong-Yi Duan, Guo-Hua Fan, Hong Jiang, Charles Antzelevitch, Hao Xia, Dan Hu

Department of Medicine Faculty Papers

Background: Previous studies suggested that SCN10A/Nav1.8 may influence cardiac electrophysiology and the susceptibility to cardiac arrhythmias. Notably, the expression of SCN10A is not uniform, showing variable expression in each cardiac chamber. The present study aims to explore the functional significance of Nav1.8 expression among different cell types present in the ventricular myocardium.

Methods: The effect of the specific Nav1.8 blocker, A-803467, on action potential was recorded from epicardial, mid-myocardial (M cells) and Purkinje tissue slices isolated from the canine left ventricle using standard microelectrode techniques and on late sodium current from Purkinje cells using patch-clamp techniques.

Results: A-803467 treatment …

Editorial: Old Drugs: Confronting Recent Advancements And Challenges, Anna Wiktorowska-Owczarek, Diego Iacono, Magdalena Jasińska-Stroschein

Department of Neurology Faculty Papers

No abstract provided.

Effect Of Testosterone Treatment During Puberty In Boys With Klinefelter Syndrome (The Tipy Study): Protocol For A Nationwide Randomised, Double-Blinded, Placebo-Controlled Study, Ida Dyhr Caspersen, Andrés Felipe Østergaard Fritzbøger, Jørgen Holm Petersen, Niels Birkebæk, Ann-Margrethe Rønholt Christensen, Anders Jørgen Schou, Kurt Kristensen, Judith L. Ross, Shanlee Davis, Gary Butler, Sophie Van Rijn, Anders Juul, Lise Aksglaede

Department of Pediatrics Faculty Papers

INTRODUCTION: Klinefelter syndrome (KS) is a genetic condition characterised by the presence of an extra X chromosome in males (47,XXY). KS is associated with various phenotypic characteristics in adult life, including infertility, hypogonadism and increased risk of type II diabetes, cardiovascular disease and osteoporosis. Additionally, individuals with KS often experience mental health challenges and functional impairments that significantly impact their quality of life. Currently, testosterone replacement therapy (TRT) in adolescence is considered the first-line treatment by some physicians for patients with KS and biochemical signs of hypogonadism. However, comprehensive evidence on its effectiveness in preventing typical phenotypic traits associated with …

Prodrug Activation In Malaria Parasites Mediated By An Imported Erythrocyte Esterase, Acylpeptide Hydrolase (Apeh), Sesh A. Sundararaman, Justin J. Miller, Ellora C. Daley, Kelsey A. O'Brien, Paulina Kasak, Abigail M. Daniels, Rachel L. Edwards, Kenneth M. Heidel, Darean A. Bague, Madeleine A. Wilson, Andrew J. Koelper, Elexi C. Kourtoglou, Alex D. White, Sloan A. August, Georgia A. Apple, Regis W. Rouamba, Anthony J. Durand, John J. Esteb, Florian L. Muller, R. Jeremy Johnson, Geoffrey C. Hoops, Cynthia S. Dowd, Audrey R. Odom John

College of Health Professions Faculty Papers

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by undesirable drug-like properties of lead compounds. Prodrug approaches temporarily mask undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher antimalarial potency than their parent compounds [R.L. Edwards et al., Sci. Rep. 7, 8400 (2017)]. However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple …

Vdac2 And Bak Scarcity In Liver Mitochondria Enables Targeting Hepatocarcinoma While Sparing Hepatocytes, Shamim Naghdi, Piyush Mishra, Soumya S. Roy, David Weaver, Ludivine Walter, Erika Davies, Anil N. Antony, Xuena Lin, Gisela Moehren, Mark A. Feitelson, Christopher A. Reed, Tullia Lindsten, Craig B. Thompson, Hien T. Dang, Jan B. Hoek, Erik S. Knudsen, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins …

Condensed Low-Dose Total Skin Electron Beam Therapy For Mycosis Fungoides: An Institutional Retrospective Review And Subgroup Analysis Of Patients With Large Cell Transformation, Louis Cappelli, Megan Cappelli, Nilanjan Haldar, Tiara Paul, Jenna Mandel, Tingting Zhan, Neda Nikbakht, Wenyin Shi

Department of Dermatology and Cutaneous Biology Faculty Papers

Low-dose total skin electron beam therapy (TSEBT) is an effective treatment option for mycosis fungoides (MF) with proven palliative effects and reduced toxicity. Presented is an institutional analysis of survival/response rate and quality of life for MF patients with subgroup analysis of those possessing pathologic large cell transformation (LCT). This is a single institutional retrospective review of patients with mycosis fungicides treated from 2014 to 2023 with low-dose TSEBT. All patients received 12 Gy in 6 fractions every other day with the modified Stanford technique, with boosts to shadowed sites between treatments, completed in 2 weeks. Outcomes evaluated included clinical …

Association Of Inflammatory Biomarkers With New Functional Morbidity At Hospital Discharge In Children Who Survive Severe Sepsis, Mallory Perry-Eaddy, Walter Faig, Martha Curley, Scott Weiss

Department of Pediatrics Faculty Papers

OBJECTIVE: New functional morbidity is common in critically ill children who survive sepsis; yet, the underlying biological mechanisms, particularly the impact of inflammation, remain unknown. We sought to test the hypothesis that increased levels of inflammatory biomarkers during the acute phase of pediatric sepsis are associated with new functional morbidity at hospital discharge.

METHODS: We conducted a post hoc secondary analysis of the MitoPSe clinical study, including N = 119 critically ill children who survived sepsis. Data collected included demographic and clinical variables and 31 inflammatory biomarkers collected at three distinct timepoints (within days 1-2 of PICU admission, days 3-5, …

Predictors Of Perioperative Stroke In Patients With Ischemic-Type Moyamoya Disease Treated With Surgical Revascularization: A Retrospective Multicenter Study, Basel Musmar, Joanna M. Roy, Hammam Abdalrazeq, Elias Atallah, Kareem El Naamani, Ching-Jen Chen, Roland Jabre, Hassan Saad, Jonathan A. Grossberg, Adam A. Dmytriw, Aman B. Patel, Mirhojjat Khorasanizadeh, Christopher S. Ogilvy, Ajith J. Thomas, Andre Monteiro, Adnan Siddiqui, Gustavo M. Cortez, Ricardo A. Hanel, Guilherme Porto, Alejandro M. Spiotta, Anthony J. Piscopo, David M. Hasan, Mohammad Ghorbani, Joshua Weinberg, Shahid M. Nimjee, Kimon Bekelis, Mohamed M. Salem, Jan-Karl Burkhardt, Akli Zetchi, Charles Matouk, Brian M. Howard, Rosalind Lai, Rose Du, Rawad Abbas, Georgios S Sioutas, Abdelaziz Amllay, Alfredo Munoz, Nabeel A Herial, Stavropoula I Tjoumakaris, Michael Reid Gooch, Robert H Rosenwasser, Pascal Jabbour

Department of Neurosurgery Faculty Papers

INTRODUCTION: Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the internal carotid arteries and the development of collateral moyamoya vessels. Surgical revascularization is commonly used to prevent future ischemic events in ischemic-type MMD, but there remains a high rate of stroke perioperatively. This study aims to analyze the predictive factors for perioperative stroke in patients with ischemic-type MMD undergoing surgical revascularization using a large multicenter database.

METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. This study included patients with ischemic-type …

5-Hydroxymethylcytosine Sequencing Of Plasma Cell-Free Dna Identifies Epigenomic Features In Prostate Cancer Patients Receiving Androgen Deprivation Therapies, Qianxia Li, Chiang-Ching Huang, Shane Huang, Yijun Tian, Jinyong Huang, Amirreza Bitaraf, Xiaowei Dong, Marja T. Nevalainen, Manishkumar Patel, Jodie Wong, Jingsong Zhang, Brandon J Manley, Jong Y. Park, Manish Kohli, Elizabeth M. Gore, Deepak Kilari, Liang Wang

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

BACKGROUND: We evaluated whether 5hmC signatures in cell-free DNA (cfDNA) are associated with treatment failure to androgen-deprivation therapies (ADT) among men with hormone-naive prostate cancer.

METHODS: We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at 3 time points including baseline (before initiating ADT, n = 55); 3 months (after initiating ADT, n = 55); and disease progression (n = 15) within 24 months or 24 months if no progression was detected (n = 14). We used selective chemical labeling sequencing to quantify 5hmC abundance across the genome and Kaplan-Meier analysis to assess …

Non-Dre Voided Urine Test To Diagnose Prostate Cancer: Updated Results, Patrick T. Gomella, Joon Yau Leong, Leonard G. Gomella, Vivek S. Tomar, Hector Teran, Edouard J. Trabulsi, Mathew L. Thakur

Department of Urology Faculty Papers

Background: The standard diagnostic approach for prostate cancer (PCa) diagnosis consists of serum prostate-specific antigen (PSA) testing, digital rectal examination (DRE) and image-guided targeted biopsies. Given the invasive nature, potential adverse events and costs associated with these techniques, alternative approaches have been investigated, specifically with serum and urine assays. The work presented here is intended to further validate a novel noninvasive optical technique for PCa detection, targeting the VPAC genomic receptors that are overexpressed on prostate cancer's malignant cells (MC), in non-DRE voided urine. Methods: Patients (N = 62) who had image-guided biopsy and histologically confirmed localized PCa, and …

External Validation Of The Phoenix Sepsis Score In Children With Suspected Community-Acquired Sepsis, Elliot Long, Meredith Borland, Shane George, Shefali Jani, Eunicia Tan, Natalie Phillips, Amit Kochar, Simon Craig, Anna Lithgow, Arjun Rao, Stuart Dalziel, Ed Oakley, Stephen Hearps, Ben Gelbart, Sarah Mcnab, Fran Balamuth, Scott Weiss, Nathan Kuppermann, Charlotte Brad, Amanda Williams, Franz Babl

Department of Medicine Faculty Papers

IMPORTANCE: The novel Phoenix Sepsis Score and sepsis criteria were derived and validated using a multicountry dataset and proposed as a new definition for sepsis in children.

OBJECTIVE: To externally validate the Phoenix Sepsis Score and sepsis criteria in a cohort of children hospitalized with suspected community-acquired sepsis.

DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study used data from the multicenter, multicountry Sepsis Epidemiology in Australian and New Zealand Emergency Departments (SENTINEL) study, collected from 2021 to 2023 and including 90-day follow-up. Children admitted to the hospital through 11 emergency departments in Australia and New Zealand and treated with parenteral antibiotics …