Medical Specialties Commons^™

Rescue Of Male Infertility By Human Prss55 In Transgenic Mice Establishes A Contraceptive Research Model, Courtney M Sutton, Kohei Umezu, Daisuke Mashiko, Masahito Ikawa, Irina V Larina, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility phenotypes of their respective knockout mouse lines. We generated transgenic mouse lines expressing human PRSS55 with either an extracellularly or intracellularly positioned C-terminal 3xFLAG tag (RES GPI or RES TM), and a line expressing human TMPRSS12 with a C-terminal 3xFLAG tag (T12 RES), all on their respective mouse null backgrounds. Fertility was assessed through continuous mating trials, and sperm parameters were evaluated. Both …

Grade Concept Paper 9: Rationale And Process For Creating A Grade Ontology, Paul Whaley, Brian Alper, Joanne Dehnbostel, Carlos Alva-Diaz, Stavros Antoniou, Antonio Bognanni, Javier Bracchiglione, Therese Kristine Dalsbø, Sean Grant, Jennifer Hunter, Alfonso Iorio, Malgorzata Lagisz, Harold Lehmann, Sheyu Li, Joerg Meerpohl, Saphia Mokrane, Cauê Monaco, Ignacio Neumann, Kevin Pottie, Shahab Sayfi, Nigar Sekercioglu, Jasvinder Singh, Bernardo Sousa-Pinto, Janice Tufte, Lenny Thinagaran Vasanthan, Li Wang, Jun Xia, Xiaomei Yao, Holger Schünemann

Faculty, Staff and Students Publications

Context: As the rate of research production accelerates, the ability to efficiently and unambiguously communicate judgments relating to the synthesis, evaluation, and use of scientific information becomes paramount.

Perspective: Scientific information can be viewed as a "layered infrastructure" of data, evidence, knowledge, and use. The GRADE approach serves as a de facto data standard for this infrastructure, supporting movement between layers by reducing ambiguity in claims to knowledge (in the form of judgements of certainty in the evidence when answering research questions) and level of commitment to possible solutions to problems (in the form of strength of recommendations for interventions). …

Three Things We Can Do Now To Reduce The Risk Of Avian Influenza Spillovers, Kenneth B Yeh, William P Bahnfleth, Elaine Bradford, Carol Cardona, Kristen K Coleman, Peter J Hudson, Bernadeta Dadonaite, Rebecca J Hutchins, Anthony Maresso, C Raina Macintyre, Matthew Scotch

Faculty, Staff and Students Publications

No abstract provided.

Development And Validation Of Venous Thromboembolism-Bidirectional Encoder Representations From Transformers (Vte-Bert) Natural Language Processing Model, Omid Jafari, Shengling Ma, Barbara D Lam, Jun Y Jiang, Emily Zhou, Mrinal Ranjan, Justine Ryu, Raka Bandyo, Arash Maghsoudi, Bo Peng, Christopher I Amos, Abiodun Oluyomi, Nathanael R Fillmore, Jennifer La, Ang Li

Faculty, Staff and Students Publications

Background: Accurate and rapid phenotyping of venous thromboembolism (VTE) in longitudinal studies is important. A natural language processing (NLP) tool externally validated in representative patients is lacking.

Objectives: To train and validate an efficient NLP model to detect incident VTE event.

Methods: We designed a novel NLP platform, NLPMed, to assist thrombosis researchers with data preprocessing, phenotype annotation, language model finetuning, and NLP application. Using clinical notes, discharge summaries, and radiology reports from patients with cancer at 2 healthcare institutions, we finetuned Bio_Clinical Bidirectional Encoder Representations from Transformers (BERT) to develop VTE-BERT. The new model was trained to detect acute …

Integrating Ctdna Analysis And Radiomics For Dynamic Risk Assessment In Localized Lung Cancer, Everett J Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B Hui, Barzin Y Nabet, Yufei Liu, Jacob J Chabon, Michael S Binkley, David M Kurtz, Emily G Hamilton, Aadel A Chaudhuri, Chih Long Liu, Zhe Li, Rene F Bonilla, Alice L Jiang, Brianna C Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J Ramchandran, Sukhmani K Padda, Joel W Neal, Heather A Wakelee, Michael F Gensheimer, Billy W Loo, Ruijiang Li, Steven H Lin, Ash A Alizadeh, Maximilian Diehn

Faculty, Staff and Student Publications

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. Circulating tumor DNA (ctDNA) minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. Here, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration …

Car-Macrophage Cell Therapy: A New Era Of Hope For Pancreatic Cancer, Daoyan Wei, Liang Wang, Yi Liu, Xiangsheng Zuo, Xiling Shen, Robert S Bresalier

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by late diagnosis, early metastasis, and resistance to conventional therapies. A major barrier to effective treatment is its desmoplastic and immunosuppressive tumor microenvironment (TME), which restricts T cell infiltration and dampens responses to immune checkpoint inhibitors (ICIs). These features highlight the urgent need for innovative immunotherapeutic strategies capable of overcoming PDAC's immunologic and physical barriers. Chimeric antigen receptor (CAR)-macrophage (CAR-M) therapy has emerged as a promising approach to address these challenges. Unlike CAR-T or CAR-NK cells, CAR-Ms can efficiently infiltrate tumors, remodel the TME, phagocytose tumor cells, and stimulate …

Depletion Of Effector Regulatory T Cells Associates With Major Response To Induction Dual Immune Checkpoint Blockade, Xianli Jiang, Nils-Petter Rudqvist, Bo Jiang, Shengbin Ye, Shan He, Qingnan Liang, Jinzhuang Dou, Michelle D Williams, Joe Dan Dunn, Jason M Johnson, Keiko Akagi, Weihong Xiao, Shaoheng Liang, Satvik Elayavalli, Baohua Sun, Edwin R Parra, Renata Ferrarotto, Adam S Garden, Clifton David Fuller, Jay Reddy, Neil D Gross, Miriam N Lango, Cheuk Hong Leung, Suyu Liu, Diane D Liu, Meng Li, J Jack Lee, Michael A Curran, Jack Phan, Ken Chen, Maura L Gillison

Faculty, Staff and Student Publications

In a phase II trial, patients with local-regionally advanced human papillomavirus-positive oropharyngeal carcinoma (n = 35) received ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Coprimary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. …

Hemispherotomy For Drug-Resistant Epilepsy In Bilateral Sturge-Weber Syndrome: Illustrative Cases, Eveline Teresa Hidalgo, Eric A Grin, Yosef Dastagirzada, Nealen Laxpati, Judith Bluvstein, Julia R Schneider, Daniel Miles, Michal Tzadok, James Riviello, Howard L Weiner

Faculty, Staff and Students Publications

Background: Sturge-Weber syndrome (SWS) is a congenital neurocutaneous disorder characterized by angiomas of the face, choroid, and leptomeninges. Seizures in these children often present within the first 2 years of life. SWS is typically unilateral, but bilateral SWS occurs in approximately 15% of cases. Bilateral SWS is associated with earlier seizure onset and poorer cognitive, developmental, and functional outcomes. More than half of children with SWS develop drug-resistant epilepsy requiring surgical intervention. Hemispherotomy has been established as a successful treatment for unilateral SWS, but resective surgery has traditionally not been considered a treatment option for patients with bilateral disease.

Observations: …

Partial Cystectomy For Muscle-Invasive Bladder Cancer, Peter S Palencia, Nethusan Sivanesan, Syed Rahman, Fady Ghali, David Hesse, John Colberg, Ashwin Sridhar, John D Kelly, Byron H Lee, Ashish M Kamat, Wei-Shen Tan

Faculty, Staff and Student Publications

Partial cystectomy is a surgical bladder-sparing option for selected patients with muscle-invasive bladder cancer (MIBC), urachal adenocarcinoma and diverticular bladder tumors. Partial cystectomy hold several advantages. It allows for definite pathology and accurate staging while avoiding side effects from radiation therapy and preserves the option for salvage radical therapy (radical cystectomy or radical radiotherapy). Patients should have a CT urogram, prostatic urethral biopsy and mapping biopsies or blue light cystoscopy to rule out multifocal disease or CIS. Small solitary MIBC patients without carcinoma in situ in an area of the bladder where resection can be performed with negative margin would …

Bcl-2/Bcl-Xl Dual Inhibition Triggers Gasdermin D-Mediated Pyroptosis In Mantle Cell Lymphoma, Yijing Li, Joseph Mcintosh, Vivian Jiang, Fangfang Yan, Jovanny Vargas, Yuxuan Che, Wei Wang, Ching-Fei Li, Yue Fei, Celeste Lee, Lei Nie, Yixin Yao, Michael Wang, Heng-Huan Lee, Yang Liu

Faculty, Staff and Student Publications

No abstract provided.

Rna Sequencing And Immunohistochemistry Jointly Improve Tumor Biomarker Interpretation, Vladimir Kushnarev, Danil Stupichev, Suren Davitavyan, Kirill Kriukov, Basavaraja U Shanthappa, Anna Butusova, Sofia Menshikova, Anna Belozerova, Anastasia Shvyrkova, Arina Tkachuk, Olga Khatenkova, Linda Balabanian, Ekaterina Postovalova, Jochen K Lennerz, Funda Meric-Bernstam, Alexander Bagaev

Faculty, Staff and Student Publications

This study aimed to assess the correlation between RNA sequencing (RNA-seq) and immunohistochemistry (IHC) in detecting key cancer biomarkers across solid tumors, and then, to establish RNA-seq thresholds that accurately reflect clinical IHC classifications. Expression levels of nine biomarkers-ESR1, PGR, AR, MKI67, ERBB2, CD274, CDX2, KRT7, and KRT20-were analyzed in 365 formalin-fixed, paraffin-embedded samples from breast, lung, gastrointestinal, and other solid carcinomas. Correlations between RNA-seq data and IHC scores were determined using Spearman's correlation coefficients, with RNA-seq cut-offs established to distinguish positive from negative IHC scores. The results revealed strong correlations for most biomarkers, with coefficients ranging from 0.53 to …

Limosilactobacillus Reuteri Enables Oral-To-Systemic Absorption Of Iberiotoxin For Treatment Of Collagen-Induced Arthritis In Rats, Mohamed R Kady, R Nicholas Elston, Lauren J Snyder, Jorie D Fleischman, Madilyn J Brandt, Duolong Zhu, Robert A Britton, Christine Beeton

Faculty, Staff and Students Publications

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and damage in which fibroblast-like synoviocytes (FLS) play a central role. Invasiveness and proliferation of FLS in RA is dependent on activity of the KCa1.1 potassium channel. Peptide blockers of KCa1.1, such as iberiotoxin (IbTX), can be delivered subcutaneously to treat animal models of RA. We tested whether an engineered probiotic oral delivery platform could effectively deliver IbTX systemically in a rat model of RA.

Results: A plasmid for inducible secretion of IbTX was constructed and transformed into probiotic Limosilactobacillus reuteri ATCC PTA-6475 to generate LrIbTX. No differences …

A 65-Year-Old Man With Cough, Hypercalcemia, And Diffuse Opacities, Philip K Angelides, Oriana Salamo, Sujith V Cherian, Eduardo Yepez Guevara, Carlos A Jimenez, Saadia A Faiz

Faculty, Staff and Student Publications

Respiratory infections in patients with cancer are common. A low threshold for bronchoscopy with bronchoalveolar lavage (BAL) should be maintained in immunocompromised patients with pulmonary opacities on chest imaging to evaluate for opportunistic infections. In those with unresolving symptoms, transbronchial biopsies may add significant diagnostic value. Concomitant hypercalcemia in patients with cancer is typically related to underlying malignant disease. However, in those with persistent respiratory symptoms or atypical infiltrates then granulomatous inflammatory diseases should be considered. Diagnosing histoplasmosis in immunocompromised patients can be difficult. Antigen testing is often more sensitive, but tissue biopsy or culture may be needed. We describe …

Multicenter Span Trial Of Fasudil In Ischemic Stroke, Takahiko Imai, Andreia Lopes De Morais, Xuyan Jin, Tao Qin, Jessica Lamb, Karisma A Nagarkatti, Mu-Hsun Chen, Ligia S B Boisserand, Rakesh B Patel, Mariia Kumskova, Anjali Chauhan, Krishnan M Dhandapani, Mohammad B Khan, Pradip K Kamat, Yanrong Shi, Suyi Cao, Basavaraju G Sanganahalli, Joseph B Mandeville, Patrick D Lyden, David C Hess, Enrique C Leira, Anil K Chauhan, Jaroslaw Aronowski, Louise D Mccullough, Raymond C Koehler, Lauren H Sansing, Márcio A Diniz, Cenk Ayata

Children’s Nutrition Research Center Staff Publications

Background: The SPAN (Stroke Preclinical Assessment Network) is a confirmatory multicenter trial network to test cerebroprotective interventions in experimental acute stroke. In a first-of-its-kind trial, SPAN tested 6 interventions in a rodent model of transient focal ischemic stroke. Here, we report the efficacy of fasudil, an isoform-nonselective rho-associated kinase inhibitor, on primary and secondary outcomes in the SPAN trial.

Methods: Fasudil was administered at 10 mg/kg intraperitoneally every 12 hours for 6 doses starting 5 minutes before reperfusion in a 60-minute endovascular filament middle cerebral artery occlusion model. The active treatment arm (n=345) was compared with the pooled intraperitoneal and …

Family-Level Factors That Influence Physical Activity Among Hispanic Adolescents At Risk For Type 2 Diabetes, Sandra Mihail, Ayleen A Hernandez, Erica G Soltero

Children’s Nutrition Research Center Staff Publications

Objective: Family-based health promotion and disease prevention strategies are recommended as best practice; however, there is limited knowledge regarding the family-level factors that influence modifiable behavior risk factors like physical activity (PA) among Latinx adolescents. This study addressed this knowledge gap by using qualitative methods to identify perceptions of family-level factors that influence PA among Hispanic youth.

Methods: We conducted semistructured, open-ended interviews with 20 Latinx adolescents (14-16 years) with obesity (body mass index ≥95th percentile) to identify their perceptions of how family influences PA. Content analysis was used to identify emergent themes, which were then compared across demographic factors, …

Microbial Metabolite Regulation Of Microglial Ahr Signaling In Alzheimer’S Disease, Ghalya E. Alrousan

Dissertations and Theses (Open Access)

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, neuroinflammation, and cognitive decline. Recent evidence suggests that systemic factors, particularly the gut microbiota and its metabolites, play a significant role in shaping brain immune responses, including microglial activation. However, the mechanisms linking gut dysbiosis to microglial dysfunction in AD are poorly understood. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsive to tryptophan metabolites, has recently gained attention as a key regulator of neuroinflammation and microglial function. I hypothesize that the loss of beneficial microbial AHR ligands, specifically indole derivatives, during aging and AD …

Genome-Wide Approaches To Bacterial Strain Typing: A History And Review Of Recent Methodological Advances, William C Shropshire, Blake M Hanson, Samuel A Shelburne

Faculty, Staff and Student Publications

Purpose of review: Whole genome sequencing (WGS) has transformed bacterial strain typing, an essential tool for outbreak detection, antimicrobial resistance surveillance, and tracking clonal emergence across clinical, research, and public health settings. Herein, we will review recent advances in WGS-based bacterial strain typing methods for purposes of comparison and classification with a focus on improvements in variant identification, strain classification, and transmission assessment.

Recent findings: Advances in sequencing technologies as well as variant calling methodologies and parameter optimization have enhanced the precision and accuracy of single nucleotide variant identification. Hierarchical clustering of gene-by-gene strain typing, combined with novel data management …

Bridging Psychiatry And Rare Genetic Diseases: A Scoping Review Of Therapeutic Strategies And Diagnostic Delay Paired With Healthcare Economic Burden Analysis, Sheldon R Garrison, Isaac J Siegel, Christopher R Takala, Sarah L Vaithilingam, Gene W Yang, Anthony W Zoghbi, Madeline M Hartig, Sreya Vadapalli, Margaret E Anderson

Duncan NRI Faculty and Staff Publications

Rare genetic diseases (RDs) with primary neuropsychiatric symptoms pose unique challenges for diagnosis and management. While the majority of these RDs have neuropsychiatric symptoms that are secondary to the RD, a subset presents with primary neuropsychiatric symptoms directly linked to their underlying pathophysiology. This subset has significant unmet medical need with delayed diagnoses leading to prolonged delays in treatment optimization and the trialing of medications that fail to target the underlying pathophysiology. This comprehensive review identifies 108 RDs with central neuropsychiatric symptoms that have a 7.7-year average diagnostic delay. Optimal management strategies for these RDs typically includes non-psychotropic medications, dietary …

Rapid Dissection And Dissociation Of The Mouse Olfactory Epithelium For Single-Nucleus Suspensions, Benjamin D W Belfort, Anthony M Insalaco, Claude C Chew, Johnathan D Jia, Julia Younis, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

The murine olfactory epithelium is the initial entry point of the olfactory system, housing various cell types that include olfactory sensory neurons, their regenerating progenitors, and support cells. Olfactory sensory neurons transduce chemical odorants into neural signals, yet the mechanisms underlying how these cells develop and turnover, create synapses with the olfactory bulb, and regulate their odorant receptors remain areas of intense study. Located on the dorsal aspect of the nasal cavity, the olfactory epithelium adheres to intricate bony structures known as turbinates. This anatomy poses unique challenges for its extraction and dissociation, especially in the context of preparing viable …

De Novo And Inherited Variants In Ddx39b Cause A Novel Neurodevelopmental Syndrome, Kevin T A Booth, Sharayu V Jangam, Martin M C Chui, Kayla Treat, Lorenzo Graziani, Alessia Soldano, Yao Ruan, Jeffrey Wan-Hei Hui, Kerry White, Celanie K Christensen, Ty Lynnes, Shinya Yamamoto, Oguz Kanca, Mandy H Y Tsang, Sally A Lynch, Sureni V Mullegama, Julia Baptista, Daniela Iancu, Shelagh K Joss, Sandra Y Y Wong, Christopher C Y Mak, Anna K Y Kwong, Hugo J Bellen, Erin Conboy, Remo Sanges, Anskar Yu-Hung Leung, Michael F Wangler, Brian H Y Chung, Francesco Vetrini

Duncan NRI Faculty and Staff Publications

DDX39B is a conserved member of the DEAD-box family of ATP-dependent RNA helicases, critical in mRNA metabolism across eukaryotes. DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, and recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four harbouring de novo missense variants in DDX39B and one with an inherited splicing variant, presenting with variable developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities, dysmorphic features and microcephaly in three patients.

3D molecular modelling predicts these variants would alter protein structure. In vitro …

Folliculin Depletion Results In Liver Cell Damage And Cholangiocarcinoma Through Mit/Tfe Activation, Bruno Maria Custode, Francesco Annunziata, Felipe Dos Santos Matos, Valentina Schiano, Veronica Maffia, Milena Lillo, Rita Colonna, Rossella De Cegli, Andrea Ballabio, Nunzia Pastore

Duncan NRI Faculty and Staff Publications

Mutations in the tumor suppressor gene Folliculin (FLCN) are responsible for Birt-Hogg-Dube’ (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis. While previous studies showed that Flcn liver-specific conditional knockout (FlcnLiKO) mice are protected from developing liver fibrosis and damage upon high-fat diet exposure, the potential role of FLCN loss in liver carcinogenesis …

Isolation And Functional Properties Of Highly-Purified N-Terminal Domain Of Human Napi2b By Scalable “Resin Overload” Technique, Daria Savenkova, Irina Makarenko, Daria Nedorezova, Ramziya Kiyamova, Mikhail Bogdanov

Faculty, Staff and Student Publications

Despite the enthusiasm and advances in the purification of native and engineered full-length membrane proteins, little attention has been paid to their fragments which could serve as attractive inspiration for function, regulation, or targeting of full-length membrane protein with therapeutic antibodies (Abs). Production of recombinant fragments of "therapeutic" membrane proteins for early-stage discovery research requires their purification to near homogeneity. It is important not only for the production of biotherapeutic antibodies but also for structural and functional studies of competitive protein-Abs, protein-protein, and lipid-protein interactions which heavily rely on the purity and quality of the isolated protein fragment of interest. …

2025 European Leukemianet Recommendations For The Management Of Chronic Myeloid Leukemia, Jane F Apperley, Dragana Milojkovic, Nicholas C P Cross, Henrik Hjorth-Hansen, Andreas Hochhaus, Hagop Kantarjian, Jeffrey H Lipton, Hemant Malhotra, Dietger Niederwieser, Jerald Radich, Philippe Rousselot, Susanne Saussele, Charles A Schiffer, Richard Silver, Simona Soverini, Leif Stenke, Anna Turkina, Luis Felipe Casado, Fausto Castagnetti, Francisco Cervantes, Richard E Clark, Jorge Cortes, Michael Deininger, Timothy P Hughes, Jeroen Janssen, Qian Jiang, Dong-Wook Kim, Richard A Larson, Francois X Mahon, Michael Mauro, Jiri Mayer, Franck E Nicolini, Fabrizio Pane, Delphine Rea, Johan Richter, Gianantonio Rosti, Giuseppe Saglio, Rüdiger Hehlmann

Faculty, Staff and Student Publications

In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate …

Addressing Challenges In Developing Treatments For Inherited Retinal Diseases: Recommendations From The Third Monaciano Symposium, Debra A Thompson, K Thiran Jayasundera, Oleg Alekseev, Robin R Ali, Alessia Amato, Vadim Y Arshavsky, Isabelle S Audo, Alberto Auricchio, James W B Bainbridge, Eyal Banin, Cagri G Besirli, David G Birch, Kari E Branham, Artur V Cideciyan, Stephen P Daiger, Jacque L Duncan, Abigail T Fahim, John G Flannery, Roberto Gattegna, John R Heckenlively, Elise Héon, Alessandro Iannaccone, Naheed W Khan, Samer Khateb, Henry J Klassen, Bart P Leroy, Dario Marangoni, Michel Michaelides, David C Musch, Mark E Pennesi, Simon M Petersen-Jones, Eric A Pierce, Rajesh C Rao, José-Alain Sahel, Paul A Sieving, Enrica Strettoi, Cameron R Strong, Thomas J Wubben, Paul Yang, David N Zacks

Faculty, Staff and Student Publications

Over the past decade, efforts focused on developing genetic therapies for inherited retinal diseases have advanced steadily to clinical trials and the development of a treatment, fueling optimism for the potential of precision medicines to provide safe and effective therapies for these rare conditions. Although several ongoing programs remain poised for success, numerous challenges have negatively impacted the ability to obtain regulatory approvals. The present position paper briefly summarizes recent advances and challenges in developing therapeutics for inherited retinal diseases, and presents a set of recommendations for moving the field forward. The priorities identified are discussed in terms of progress …

Transcriptomic Analysis Of Localized High-Risk Prostate Cancer Improves Prognostication And Identifies Benefit From Adding Docetaxel To Definitive Radiotherapy With Androgen Suppression In The Nrg Oncology/Rtog 0521 Phase 3 Trial, Ryan M Phillips, James A Proudfoot, Elai Davicioni, Yang Liu, Daniel E Spratt, Jeff M Simko, Robert B Den, Alan Pollack, Seth A Rosenthal, A Oliver Sartor, Christopher J Sweeney, Gerhardt Attard, Leslie Longoria, Samir Patel, Michael W Straza, Jason A Efstathiou, Amit B Shah, Karen E Hoffman, Joseph P Rodgers, Howard M Sandler, Felix Y Feng, Phuoc T Tran

Faculty, Staff and Student Publications

Background and objective: NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response.

Methods: Decipher GC scores and basal-luminal cellular subtypes were generated for specimens from …

Efficacy And Safety Of Oral Decitabine/Cedazuridine In The Chronic Myelomonocytic Leukaemia Subpopulations From Phase 2 And 3 Studies, Michael R Savona, Olatoyosi Odenike, Gail J Roboz, Harshad Amin, Amy E Dezern, Elizabeth A Griffiths, Kim-Hien Dao, Amer M Zeidan, Bhavana Bhatnagar, Rena Buckstein, Brian Leber, Mary-Margaret Keating, Somedeb Ball, Aram Oganesian, Yuri Sano, Harold N Keer, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

DNA methyltransferase inhibitors (DNMTis) are commonly used in treating chronic myelomonocytic leukaemia (CMML); however, data from prospective studies of DNMTis in CMML are limited. The present analysis evaluated the efficacy, safety and pharmacodynamics of the oral DNMTi decitabine/cedazuridine in the subset of patients with CMML from the phase 2 and 3 trials, which led to the approval of this agent for myelodysplastic syndromes and CMML in the United States and Canada. Potential prognostic factors also were analysed. In all, 34 patients with CMML were screened and 33 were treated. Most patients (76% [n = 25]) had myelodysplastic type-CMML and 77% …

Bayesian Counterfactual Machine Learning Individualizes Radiation Modality Selection To Mitigate Immunosuppression, Duo Yu, Michael J Kane, Yiqing Chen, Steven H Lin, Radhe Mohan, Brian P Hobbs

Faculty, Staff and Student Publications

Purpose: Lymphocytes play critical roles in cancer immunity and tumor surveillance. Radiation-induced lymphopenia (RIL) is a common side effect observed in patients with cancer undergoing chemoradiation therapy (CRT), leading to impaired immunity and worse clinical outcomes. Although proton beam therapy (PBT) has been suggested to reduce RIL risk compared with intensity-modulated radiation therapy (IMRT), this study used Bayesian counterfactual machine learning to identify distinct patient profiles and inform personalized radiation modality choice.

Methods: A novel Bayesian causal inferential technique is introduced and applied to a matched retrospective cohort of 510 patients with esophageal cancer undergoing CRT to identify patient profiles …

Celebrating The Fifth Edition Of The International Symposium On Fungal Stress – Isfus, A Decade After Its 2014 Debut, Alene Alder-Rangel, Amanda E A Rangel, Arturo Casadevall, Asiya Gusa, Chaoyang Xue, Charles M Boone, Chris Todd Hittinger, Claudio A Masuda, Consuelo Olivares-Yañez, Deborah Bell-Pedersen, Erica J Washington, Gerhard Braus, Guilhem Janbon, István Pócsi, Jason E Stajich, Jay C Dunlap, Joan W Bennett, Joseph Heitman, Ling Lu, Lucia Landi, Mari L Shinohara, Maurizio Del Poeta, Mavis A Acheampong, Mia R Maltz, Michael C Lorenz, Minou Nowrousian, N Louise Glass, Nichole A Broderick, Nicolás Pedrini, Nir Osherov, R Blake Billmyre, Sabrina Sarrocco, Salomé Leibundgut-Landmann, Vânia Aparecida Vicente, Xiaorong Lin, Xin-Qing Zhao, Yong-Sun Bahn, Zachary A Lewis, Drauzio E N Rangel

Faculty, Staff and Student Publications

The Fifth International Symposium on Fungal Stress (ISFUS) brought together in Brazil many of the leaders in the field of fungal stress responses, from fourteen countries, for four days of outstanding science ranging from basic research to studies with agricultural, medical, industrial, and environmental significance. In addition to the excellent oral and poster presentations, the Symposium organisers ensured that all participants had ample opportunity to engage, socialise, and network to exchange ideas and share research. The conference was enhanced by the world-class venue near Iguazu Falls, probably the greatest natural phenomenon in South America.

12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction And Microthrombi After Subarachnoid Hemorrhage In Mice, Ari Dienel, Sung Ha Hong, Hussein A Zeineddine, Sithara Thomas, Shafeeque C M, Dania A Jose, Kiara Torres, Jose Guzman, Andrew Dunn, P Kumar T, Gadiparthi N Rao, Spiros L Blackburn, Devin W Mcbride

Faculty, Staff and Student Publications

Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus, 12/15-LOX is an important target to prevent delayed cerebral ischemia. SAH was induced in C57BL/6 and 12/15-LOX−/− mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed …

Development Of A Multi-Institutional Dataset To Validate A Novel Inflammatory Breast Cancer Diagnostic Score, Filipa Lynce, Samuel M Niman, Megumi Kai, Sean Ryan, Elizabeth Troll, Li Li, Kathy D Miller, Reshma Jagsi, Ginny Mason, Beth A Overmoyer, H T Carisa Le-Petross, Faina Nakhlis, Savitri Krishnamurthy, Beth T Harrison, Susie X Sun, Eren D Yeh, Jennifer R Bellon, Laura E Warren, Michael C Stauder, Meredith M Regan, Wendy A Woodward

Faculty, Staff and Student Publications

Background: Susan G. Komen, the Inflammatory Breast Cancer (IBC) Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to propose novel quantitative scoring rubrics for IBC diagnosis. In this study, we developed a multi-institutional clinical dataset to test and validate the proposed scoring system.

Methods: IBC (N = 988) and non-IBC (N = 332) cases were identified at 2 institutions with dedicated multidisciplinary IBC programs. The non-IBC cohort included consecutive cT4b and cT4c patients. Standard operating procedures (SOPs) were developed for all ambiguous findings and languages. Three different methods were used for the imputation of missing data, …