Medical Specialties Commons^™

Global Impact Of Aging On The Hemodynamic Response Function In The Gray Matter Of Human Cerebral Cortex, Nooshin J Fesharaki, Amanda Taylor, Keisjon Mosby, Ruosha Li, Jung Hwan Kim, David Ress

Faculty, Staff and Students Publications

In functional magnetic resonance imaging, the hemodynamic response function (HRF) is a stereotypical response to local changes in cerebral hemodynamics and oxygen metabolism due to briefly (< 4 s) evoked neural activity. Accordingly, the HRF is often used as an impulse response with the assumption of linearity in data analysis. In cognitive aging studies, it has been very common to interpret differences in brain activation as age-related changes in neural activity. Contrary to this assumption, however, evidence has accrued that normal aging may also significantly affect the vasculature, thereby affecting cerebral hemodynamics and metabolism, confounding interpretation of fMRI cognitive aging studies. In this study, use was made of a multisensory task to evoke the HRF in ~87% of cerebral cortex in cognitively intact adults with ages ranging from 22 to 75 years. This widespread activation enabled us to investigate age trends in the spatial distributions of HRF characteristics within the majority of cortical gray matter, which we termed as global age trends. The task evoked both positive and negative HRFs, which were characterized using model-free parameters in native-space coordinates. We found significant global age trends in the distributions of HRF parameters in terms of both amplitudes (e.g., peak amplitude and contrast-to-noise ratio) and temporal dynamics (e.g., full-width-at-half-maximum). Our findings offer insight into how age-dependent changes affect neurovascular coupling and show promise for use of HRF parameters as non-invasive indicators for age-related pathology.

A Practical Clinical Approach To Navigate Pulmonary Embolism Management: A Primer And Narrative Review Of The Evolving Landscape, Kevin Benavente, Bradley Fujiuchi, Hafeez Ul Hassan Virk, Pavan K Kavali, Walter Ageno, Geoffrey D Barnes, Marc Righini, Mahboob Alam, Rachel P Rosovsky, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Advances in imaging, pharmacological, and procedural technologies have rapidly expanded the care of pulmonary embolism. Earlier, more accurate identification and quantification has enhanced risk stratification across the spectrum of the disease process, with a number of clinical tools available to prognosticate outcomes and guide treatment. Direct oral anticoagulants have enabled a consistent and more convenient long-term therapeutic option, with a greater shift toward outpatient treatment for a select group of low-risk patients. The array of catheter-directed therapies now available has contributed to a more versatile and nuanced armamentarium of treatment options, including ultrasound-facilitated thrombolysis and mechanical thrombectomy. Research into supportive …

Preoperative Detection Of Extraprostatic Tumor Extension In Patients With Primary Prostate Cancer Utilizing [68ga]Ga-Psma-11 Pet/Mri, Clemens P Spielvogel, Jing Ning, Kilian Kluge, David Haberl, Gabriel Wasinger, Josef Yu, Holger Einspieler, Laszlo Papp, Bernhard Grubmüller, Shahrokh F Shariat, Pascal A T Baltzer, Paola Clauser, Markus Hartenbach, Lukas Kenner, Marcus Hacker, Alexander R Haug, Sazan Rasul

Faculty, Staff and Student Publications

Objectives: Radical prostatectomy (RP) is a common intervention in patients with localized prostate cancer (PCa), with nerve-sparing RP recommended to reduce adverse effects on patient quality of life. Accurate pre-operative detection of extraprostatic extension (EPE) remains challenging, often leading to the application of suboptimal treatment. The aim of this study was to enhance pre-operative EPE detection through multimodal data integration using explainable machine learning (ML).

Methods: Patients with newly diagnosed PCa who underwent [68Ga]Ga-PSMA-11 PET/MRI and subsequent RP were recruited retrospectively from two time ranges for training, cross-validation, and independent validation. The presence of EPE was measured from post-surgical histopathology …

The 2024 Nobel Prize In Physiology Or Medicine: Microrna Takes Center Stage, George A Calin, Florent Hubé, Michael R Ladomery, Nicholas Delihas, Manuela Ferracin, Laura Poliseno, Luca Agnelli, Suresh K Alahari, Ai-Ming Yu, Xiao-Bo Zhong

Faculty, Staff and Student Publications

The Non-coding Journal Editorial Board Members would like to congratulate Victor Ambros and Gary Ruvkun, who were jointly awarded the 2024 Nobel Prize in Physiology or Medicine for their groundbreaking discovery of microRNAs and the role of microRNAs in post-transcriptional gene regulation, uncovering a previously unknown layer of gene control in eukaryotes [...].

The Rise, Fall, And Resurgence Of Phage Therapy For Urinary Tract Infection, Jacob J Zulk, Kathryn A Patras, Anthony W Maresso

Faculty, Staff and Students Publications

In the face of rising antimicrobial resistance, bacteriophage therapy, also known as phage therapy, is seeing a resurgence as a potential treatment for bacterial infections including urinary tract infection (UTI). Primarily caused by uropathogenic Escherichia coli, the 400 million UTI cases annually are major global healthcare burdens and a primary cause of antibiotic prescriptions in the outpatient setting. Phage therapy has several potential advantages over antibiotics including the ability to disrupt bacterial biofilms and synergize with antimicrobial treatments with minimal side effects or impacts on the microbiota. Phage therapy for UTI treatment has shown generally favorable results in recent …

Ire1Α Silences Dsrna To Prevent Taxane-Induced Pyroptosis In Triple-Negative Breast Cancer, Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E Dobrolecki, Weijie Zhang, Dong Han, Na Zhao, Eric Jaehnig, Jingyi Wang, Weiche Wu, Davis A Graham, Yumei Li, Rui Chen, Weiyi Peng, Yiwen Chen, Andre Catic, Zhibin Zhang, Bing Zhang, Anthony M Mustoe, Albert C Koong, George Miles, Michael T Lewis, Meng C Wang, Susan M Rosenberg, Bert W O'Malley, Thomas F Westbrook, Han Xu, Xiang H-F Zhang, C Kent Osborne, Jin Billy Li, Matthew J Ellis, Mothaffar F Rimawi, Jeffrey M Rosen, Xi Chen

Faculty, Staff and Students Publications

Chemotherapy is often combined with immune checkpoint inhibitor (ICI) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane-chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced dsRNA through RIDD (Regulated IRE1-Dependent Decay) to prevent NLRP3 inflammasome–dependent pyroptosis. Inhibition of IRE1α in Trp53−/− TNBC allows taxane to induce extensive dsRNAs that are sensed …

An Orphan Kinesin In Trypanosoma Brucei Regulates Hook Complex Assembly And Golgi Biogenesis, Qing Zhou, Yasuhiro Kurasawa, Huiqing Hu, Thiago Souza Onofre, Ziyin Li

Faculty, Staff and Student Publications

Kinesins are microtubule-based motor proteins that play diverse cellular functions by regulating microtubule dynamics and intracellular transport in eukaryotes. The early branching kinetoplastid protozoan Trypanosoma brucei has an expanded repertoire of kinetoplastid-specific kinesins and orphan kinesins, many of which have unknown functions. We report here the identification of an orphan kinesin named KIN-G that plays an essential role in maintaining hook complex integrity and promoting Golgi biogenesis in T. brucei. KIN-G localizes to the distal portion of the centrin arm of the flagellum-associated hook complex through association with the centrin arm protein TbCentrin4. Knockdown of KIN-G in T. brucei …

Nomenclature For Human And Animal Fungal Pathogens And Diseases: A Proposal For Standardized Terminology, Sybren De Hoog, Thomas J Walsh, Sarah A Ahmed, Ana Alastruey-Izquierdo, Maiken Cavling Arendrup, Andrew Borman, Sharon Chen, Anuradha Chowdhary, Robert C Colgrove, Oliver A Cornely, David W Denning, Philippe J Dufresne, Laura Filkins, Jean-Pierre Gangneux, Josepa Gené, Andreas H Groll, Jaques Guillot, Gerhard Haase, Catriona Halliday, David L Hawksworth, Roderick Hay, Martin Hoenigl, Vit Hubka, Tomasz Jagielski, Hazal Kandemir, Sarah E Kidd, Julianne V Kus, June Kwon-Chung, Shawn R Lockhart, Jacques F Meis, Leonel Mendoza, Wieland Meyer, M Hong Nguyen, Yinggai Song, Tania C Sorrell, J Benjamin Stielow, Rachel Vilela, Roxana G Vitale, Nancy L Wengenack, P Lewis White, Luis Ostrosky-Zeichner, Sean X Zhang

Faculty, Staff and Student Publications

Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host's immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately …

Staphylococcus Epidermidis St2 Strains Associated With Bloodstream Infections Contain A Unique Mobile Genetic Element Encoding A Plasmin Inhibitor, Amy A Gomez, Clara Kjerfve, Minseo Choi, Wen Liu, Kelly Churion, Sheila Thomas, Holger Rohde, Sam Shelburne, Jon T Skare, Magnus Hook, Srishtee Arora

Faculty, Staff and Student Publications

Staphylococcus epidermidis, a common commensal bacterium, is a leading cause of nosocomial catheter-associated bloodstream infections. S. epidermidis sequence type 2 (ST2) is specifically recognized globally for causing invasive disease. In this study, we identified a novel putative integrated conjugative element, pICE-Sepi-ST2, unique to the genomes of S. epidermidis ST2. Our investigation identified pICE-Sepi-ST2 in all ST2 isolates from bloodstream infections. Meanwhile, ST2 isolates from other infection sources, such as catheters, prosthetic joints, and fracture fixations, showed variable pICE-Sepi-ST2 prevalence. pICE-Sepi-ST2 encodes two putative cell wall anchored proteins that we have designated SesX and SesY. Biochemical characterization of SesY revealed …

Micrornas: Where Brilliance, Perseverance, And Ambition Converged, Rares Drula, George A Calin

Faculty, Staff and Student Publications

Victor Ambros at the University of Massachusetts Medical School and Gary Ruvkun at Harvard University were awarded the 2024 Nobel Prize in Medicine and Physiology for the discovery of microRNAs. This “groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans” (1). This is a well-deserved and highly anticipated recognition for a seminal discovery published 31 years ago in back-to-back Cell publications (2, 3). This landmark finding changed the way we understand gene expression regulation among most multicellular organisms (4) and had …

An Empirical Model Of Carbon-Ion Relative Biological Effectiveness Based On The Linear Correlation Between Radiosensitivity To Photons And Carbon Ions, David B Flint, Scott J Bright, Conor Mcfadden, Teruaki Konishi, David K J Martinus, Mandira Manandhar, Mariam Ben Kacem, Lawrence Bronk, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Objective.To develop an empirical model to predict carbon ion (C-ion) relative biological effectiveness (RBE).Approach.We used published cell survival data comprising 360 cell line/energy combinations to characterize the linear energy transfer (LET) dependence of cell radiosensitivity parameters describing the dose required to achieve a given survival level, e.g. 5% (D5%), which are linearly correlated between photon and C-ion radiations. Based on the LET response of the metrics D5%and D37%, we constructed a model containing four free parameters that predicts cells' linear quadratic model (LQM) survival curve parameters for C-ions,αCandβC, from the reference LQM parameters …

Impact Of Prior Inotuzumab Ozogamicin Treatment On Brexucabtagene Autoleucel Outcomes In Adults With B-Cell All, Ibrahim Aldoss, Gregory W Roloff, Rawan Faramand, Noam E Kopmar, Chenyu Lin, Anjali S Advani, Simone E Dekker, Vishal K Gupta, Timothy E O'Connor, Nikeshan Jeyakumar, Ibrahim N Muhsen, Yannis Valtis, Amy Zhang, Katharine Miller, Katherine Sutherland, Kaitlyn C Dykes, Mohamed Ahmed, Evan Chen, Hector Zambrano, Danielle Bradshaw, Santiago Mercadal, Marc Schwartz, Sean Tracy, Bhagirathbhai Dholaria, Michal Kubiak, Akash Mukherjee, Navneet Majhail, Minoo Battiwalla, Luke Mountjoy, Shahbaz A Malik, John Mathews, Paul Shaughnessy, Aaron C Logan, Abdullah Ladha, Maryann Stefan, Caitlin Guzowski, Rasmus T Hoeg, Talal Hilal, Jozal Moore, Matthew Connor, Kristen M O'Dwyer, Laquisa C Hill, Stephanie B Tsai, Joshua Sasine, Melhem M Solh, Catherine J Lee, Vamsi K Kota, Divya Koura, Muthu Veeraputhiran, Betsy Blunk, Caspian Oliai, Jessica T Leonard, Noelle V Frey, Jae H Park, Marlise R Luskin, Veronika Bachanova, Ahmed Galal, Michael R Bishop, Wendy Stock, Ryan D Cassaday, Vinod Pullarkat, Bijal D Shah, Lori S Muffly

Faculty, Staff and Students Publications

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). …

Resident & Fellow Section: Commemorating 20 Years Of Innovation And Growth, Skyler M Kane, Ariel M Lyons-Warren, Katrina Hannah D Ignacio, Kathleen M Pieper, Katherine A Fu

Faculty, Staff and Students Publications

No abstract provided.

Multidisciplinary Travel Health Education: Current Status And Rationale For Standardized Competencies, Karl M Hess, Sheila M Seed, Eva H Clark, Tara Lombardo, Francesca F Norman, Gerard Flaherty

Faculty, Staff and Students Publications

This perspective highlights the inconsistent integration of travel health education across medical, nursing and pharmacy educational programmes globally and calls for standardized travel health competencies based on the International Society of Travel Medicine’s (ISTM) Body of Knowledge to help improve patient care outcomes as global travel returns to pre-pandemic levels.

Simple Improvements In Vector Design Afford Substantial Gains In Aav Delivery Of Aggregation-Slowing Aβ Variants, Ella Borgenheimer, Cameron Trueblood, Bryan L Nguyen, William R Lagor, Joanna L Jankowsky

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that …

A Rare Case Of A Malignant Proliferating Trichilemmal Tumor: A Molecular Study Harboring Potential Therapeutic Significance And A Review Of Literature, Mokhtar H Abdelhammed, Hanna Siatecka, A Hafeez Diwan, Christie J Finch, Angela D Haskins, David J Hernandez, Ya Xu

Faculty, Staff and Students Publications

Malignant proliferating trichilemmal tumors (MPTTs), arising from the external root sheath of hair follicles, are exceptionally rare, with limited documentation of their genetic alterations. We present a case of a 64-year-old African American woman who initially presented with a gradually enlarging nodule on her posterior scalp. An initial biopsy at an outside hospital suggested metastatic adenocarcinoma or squamous cell carcinoma (SCC) of an uncertain origin. A subsequent wide local excision revealed a 2.0 cm tumor demonstrating characteristic trichilemmal keratinization, characterized by an abrupt transition from the nucleated epithelium to a laminated keratinized layer, confirming MPTT. Immunohistochemistry demonstrated diffuse p53 expression, …

Oncologic Outcomes In Patients With Localized, Primary Head And Neck Synovial Sarcoma, Riddhi R Patel, Vancheswaran Gopalakrishnan, Behrang Amini, Alexander J Lazar, Patrick P Lin, Robert S Benjamin, Andrew J Bishop, Ryan P Goepfert, Dejka M Araujo

Faculty, Staff and Student Publications

Background: this study aims to evaluate the survival outcomes of patients suffering from head and neck synovial sarcoma (HNSS), especially in relation to patients with a localized disease at diagnosis.

Methods: this retrospective chart review includes 57 patients diagnosed with primary HNSS between 1981 and 2020 who presented with a localized disease at diagnosis. Overall survival (OS) from diagnosis, local recurrence-free survival (LRFS), and metastasis-free survival (MFS) from the end of the primary tumor treatment are estimated. The Kaplan-Meier method, the log-rank test, and the Cox proportional hazards regression are used.

Results: the 5-year OS, LRFS, and MFS are estimated …

Automated Segmentation Of Mri White Matter Hyperintensities In 8421 Patients With Acute Ischemic Stroke, Hosung Kim, Wi-Sun Ryu, Dawid Schellingerhout, Jonghyeok Park, Jinyong Chung, Sang-Wuk Jeong, Dong-Seok Gwak, Beom Joon Kim, Joon-Tae Kim, Keun-Sik Hong, Kyung Bok Lee, Tai Hwan Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Man Seok Park, Hee-Joon Bae, Dong-Eog Kim

Faculty, Staff and Student Publications

Background and purpose: To date, only a few small studies have attempted deep learning-based automatic segmentation of white matter hyperintensity (WMH) lesions in patients with cerebral infarction; this issue is complicated because stroke-related lesions can obscure WMH borders. We developed and validated deep learning algorithms to segment WMH lesions accurately in patients with cerebral infarction using multisite data sets involving 8421 patients with acute ischemic stroke.

Materials and methods: We included 8421 patients with stroke from 9 centers in Korea. 2D UNet and squeeze-and-excitation (SE)-UNet models were trained using 2408 FLAIR MRIs from 3 hospitals and validated using 6013 FLAIR …

Additional Expression Of T-Cell Engager In Clinically Tested Oncolytic Adeno-Immunotherapy Redirects Tumor-Infiltrated, Irrelevant T Cells Against Cancer Cells To Enhance Antitumor Immunity, Daisuke Morita, Amanda Rosewell Shaw, Greyson Biegert, Caroline Porter, Mae Woods, Spyridoula Vasileiou, Bora Lim, Masataka Suzuki

Faculty, Staff and Student Publications

Background: Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested "Armed" OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T …

Clinical And Radiologic Findings In Children With Anomalous Pontine Cranial Nerves, Karen K Moeller, Brandon H Tran, Thierry A G M Huisman, Nilesh K Desai, Marcia K Kukreja, Rajan P Patel, Uma S Ramaswamy, Carol Liu, Stephen F Kralik

Faculty, Staff and Students Publications

We retrospectively reviewed the clinical and radiologic findings in 17 children with an aberrant cisternal cranial nerve 7 (CN7), and found that these patients had additional anomalies involving other pontine cranial nerves (CNs). The hallmark imaging feature identified in all patients was an aberrant cisternal segment of an enlarged-appearing CN7. The abnormal nerve coursed anteriorly toward the Gasserian ganglion, where it fanned out toward the internal auditory canal, Meckel cave, or both. This finding was accompanied by a small cisternal CN5, which often had a lateral bowed appearance. CN5 and CN7 were abnormally close to each other. Meckel's cave appeared …

Mutation- And Mrd-Informed Treatments For Transplant-Ineligible Patients, Curtis A Lachowiez, Courtney D Dinardo

Faculty, Staff and Student Publications

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups. Furthermore, the simultaneous discovery of resistance mechanisms to targeted therapies and AZA-VEN has enabled the identification of patient subgroups with inferior outcomes, …

Transplant-Associated Tma: The Conundrum Of Diagnosis And Treatment, Ang Li, Sarah E Sartain

Faculty, Staff and Students Publications

Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic cell transplantation is characterized by microangiopathic hemolytic anemia (MAHA) with persistent schistocytosis, elevated markers of hemolysis, thrombocytopenia, and microvascular thrombosis leading to ischemic injuries in the kidneys and other organs. The initial evaluation of the disease requires confirmation of non-immune MAHA and careful examination of known secondary causes of TMA. Due to increased likelihood of long-term renal failure and overall mortality, a rapid diagnosis and treatment of the underlying trigger is needed. However, the diagnostic criteria proposed to define TA-TMA remain insufficient. sC5b9, the soluble form of the membrane attack complex of the terminal …

Spino-Plastic Surgery: Addressing Spinal Tumors With New Techniques, Casey Martinez, Isra Abdulwadood, Sebastian Winocour, Alexander E Ropper, Marco Innocenti, Michael Bohl, Maziyar Kalani, Edward M Reece

Faculty, Staff and Students Publications

Background/Objectives: Spino-plastic surgery describes a specialized, multidisciplinary approach to addressing various spinal pathologies. The field is the innovative product of a multidisciplinary collaboration between plastic and reconstructive, orthopedic, and neurosurgery. Over the last few decades, this collaboration has borne promising surgical techniques and treatment plans geared toward restoring form, function, and aesthetics in patients with a variety of spinal conditions, including failed fusions, pseudoarthrosis, and the need for oncologic reconstruction. This paper explores the application of spino-plastic surgery in the context of post-sarcoma resection reconstructions, focusing on the efficacy in addressing the unique challenges posed by extensive tissue loss and …

Ai-Enabled Wearable Cameras For Assisting Dietary Assessment In African Populations, Frank P-W Lo, Jianing Qiu, Modou L Jobarteh, Yingnan Sun, Zeyu Wang, Shuo Jiang, Tom Baranowski, Alex K Anderson, Megan A Mccrory, Edward Sazonov, Wenyan Jia, Mingui Sun, Matilda Steiner-Asiedu, Gary Frost, Benny Lo

Children’s Nutrition Research Center Staff Publications

We have developed a population-level method for dietary assessment using low-cost wearable cameras. Our approach, EgoDiet, employs an egocentric vision-based pipeline to learn portion sizes, addressing the shortcomings of traditional self-reported dietary methods. To evaluate the functionality of this method, field studies were conducted in London (Study A) and Ghana (Study B) among populations of Ghanaian and Kenyan origin. In Study A, EgoDiet's estimations were contrasted with dietitians' assessments, revealing a performance with a Mean Absolute Percentage Error (MAPE) of 31.9% for portion size estimation, compared to 40.1% for estimates made by dietitians. We further evaluated our approach in Study …

Integrative Multi-Omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes In Ovarian Cancer, Spencer R Rosario, Mark D Long, Shanmuga Chilakapati, Eduardo Cortes Gomez, Sebastiano Battaglia, Prashant K Singh, Jianmin Wang, Katy Wang, Kristopher Attwood, Suzanne M Hess, A J Robert Mcgray, Kunle Odunsi, Brahm H Segal, Gyorgy Paragh, Song Liu, Jennifer A Wargo, Emese Zsiros

Faculty, Staff and Student Publications

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We …

Clonal Landscape And Clinical Outcomes Of Telomere Biology Disorders: Somatic Rescue And Cancer Mutations, Fernanda Gutierrez-Rodrigues, Emma M Groarke, Natthakan Thongon, Juan Jose Rodriguez-Sevilla, Luiz Fernando B Catto, Marena R Niewisch, Ruba Shalhoub, Lisa J Mcreynolds, Diego V Clé, Bhavisha A Patel, Xiaoyang Ma, Dalton Hironaka, Flávia S Donaires, Nina Spitofsky, Barbara A Santana, Tsung-Po Lai, Lemlem Alemu, Sachiko Kajigaya, Ivana Darden, Weiyin Zhou, Paul V Browne, Subrata Paul, Justin Lack, David J Young, Courtney D Dinardo, Abraham Aviv, Feiyang Ma, Michel Michels De Oliveira, Ana Paula De Azambuja, Cynthia E Dunbar, Malgorzata Olszewska, Emmanuel Olivier, Eirini P Papapetrou, Neelam Giri, Blanche P Alter, Carmem Bonfim, Colin O Wu, Guillermo Garcia-Manero, Sharon A Savage, Neal S Young, Simona Colla, Rodrigo T Calado

Faculty, Staff and Student Publications

Telomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, …

Immune Landscape Of Isocitrate Dehydrogenase-Stratified Primary And Recurrent Human Gliomas, Pravesh Gupta, Minghao Dang, Shivangi Oberai, Simona Migliozzi, Rakesh Trivedi, Gayatri Kumar, Mekenzie Peshoff, Nancy Milam, Aml Ahmed, Krishna Bojja, Tuan M Tran, Joy Gumin, Carlos Kamiya-Matsuoka, Jason Huse, Kathryn Cox, Jianzhuo Li, Huma Shehwana, Sameer A Sheth, Rodriguez Saxon, Sun Baohua, Brittany Parker Kerrigan, Atul Maheshwari, Edwin Roger Parra Cuentas, Nicholas E Navin, Amy B Heimberger, Frederick F Lang, Antonio Iavarone, Karen Clise-Dwyer, Linghua Wang, Krishna P Bhat

Faculty, Staff and Student Publications

Background: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear.

Methods: In this study, we used sequential single-cell transcriptomics on 144 678 and spectral cytometry on over 2 million immune cells encompassing 48 human gliomas to decipher their immune landscape.

Results: We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild type-associated patterns, such as an abundance …

Amniotic Fluid-Derived Stem Cells: Potential Factories Of Natural And Mimetic Strategies For Congenital Malformations, Cristiane S R Fonteles, Julia Enterria-Rosales, Ying Lin, John W Steele, Ramiro A Villarreal-Leal, Jing Xiao, Daniel I Idowu, Beck Burgelin, Bogdan J Wlodarczyk, Richard H Finnell, Bruna Corradetti

Faculty, Staff and Students Publications

BACKGROUND: Mesenchymal stem cells (MSCs) derived from gestational tissues offer a promising avenue for prenatal intervention in congenital malformations although their application is hampered by concerns related to cellular plasticity and the need for invasive, high-risk surgical procedures. Here, we present naturally occurring exosomes (EXOs) isolated from amniotic fluid-derived MSCs (AF-MSCs) and their mimetic analogs (MIMs) as viable, reproducible, and stable alternatives. These nanovesicles present a minimally invasive therapeutic option, addressing the limitations of MSC-based treatments while retaining therapeutic efficacy.

METHODS: MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion …

Integrating Drug Target Information In Deep Learning Models To Predict The Risk Of Adverse Events In Patients With Comorbid Post-Traumatic Stress Disorder And Alcohol Use Disorder, Oshin Miranda, Xiguang Qi, M Daniel Brannock, Ryan Whitworth, Thomas R Kosten, Neal David Ryan, Gretchen L Haas, Levent Kirisci, Lirong Wang

Faculty, Staff and Students Publications

Background/Objectives: Comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) patients are at a significantly higher risk of adverse outcomes, including opioid use disorder, depression, suicidal behaviors, and death, yet limited treatment options exist for this population. This study aimed to build on previous research by incorporating drug target information into a novel deep learning model, T-DeepBiomarker, to predict adverse outcomes and identify potential therapeutic medications.

Methods: We utilized electronic medical record (EMR) data from the University of Pittsburgh Medical Center (UPMC), analyzing 5565 PTSD + AUD patients. T-DeepBiomarker was developed by integrating multimodal data, including lab results, drug …

Exploration Of The Tunability Of Brd4 Degradation By Dcaf16 Trans-Labelling Covalent Glues, Muhammad Murtaza Hassan, Yen-Der Li, Michelle W Ma, Mingxing Teng, Woong Sub Byun, Kedar Puvar, Ryan Lumpkin, Brittany Sandoval, Justine C Rutter, Cyrus Y Jin, Michelle Y Wang, Shawn Xu, Anna M Schmoker, Hakyung Cheong, Brian J Groendyke, Jun Qi, Eric S Fischer, Benjamin L Ebert, Nathanael S Gray

Faculty, Staff and Students Publications

Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.g. glutarimide ligands for CUL4CRBN), offer the potential to target undruggable proteins. Yet, their rational design is largely unattainable due to the unpredictability of the ‘gain-of-function’ nature of the glue interaction upon chemical modification of ligands. We recently reported a covalent trans-labelling glue mechanism which we named ‘Template-assisted covalent modification’, where an electrophile decorated BRD4 inhibitor was effectively delivered to …