Digital Commons Network^™

Perspectives On The Clinical Use Of Anti-Amyloid Therapy For The Treatment Of Alzheimer's Disease: Insights From The Fields Of Cancer, Rheumatology, And Neurology, Gregory Jicha, Erin Abner, Elif Pinar Coskun, Mark Huffmyer, Thomas Tucker, Peter T. Nelson

Neurology Faculty Publications

Introduction: The advent of disease-modifying therapies for Alzheimer’s disease (AD) has raised many questions and debates in the field as to the clinical benefits, risks, and costs of such therapies. The controversies have resulted in the perception that many clinicians are apprehensive about prescribing these medications to their patient populations. There also remains widespread uncertainty as to the economic impact, cost benefit ratio, and safety oversight for use of these medications in standard clinical care settings.

Methods: To contextualize such issues, the present study compared anti-amyloid biologic therapy (lecanemab) to four commonly used biologic agents in other fields, including trastuzumab …

Hereditary Spherocytosis Due To A Novel Variant, P.Q1034x, In The Beta Subunit Of The Spectrin Gene: A Case Report, Emmalee M. Kugler, Akash Patel, Faraz Afridi, Maria I. Scarano, Rafat Ahmed

Department of Emergency Medicine Faculty Papers

Background: Heterozygous pathogenic variants of SPTB cause hereditary spherocytosis (HS) in a quarter of cases. Case report: A 14-day-old male presenting with persistent anemia and hyperbilirubinemia was diagnosed with HS by increased red blood cell osmotic fragility and decreased fluorescence on the eosin-5′-maleimide binding test. For his failure to thrive and hypotonia, genetic sequencing revealed a de novo variant of the SPTB gene (p.Q1034X) on exon 15. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. A variant of uncertain significance (p.R438W) in the chondroitin sulfate synthase 1 (CHSY1) gene …

Infertility’S Impact On Couples’ Functioning, Elizabeth Sanders

Dissertations

Historically, infertility has been a taboo topic of discussion and is often avoided in conversation because of the stigmatization of the diagnosis. According to the World Health Organization (2022), infertility affects 186 million individuals globally. However, there seems to be a gap in the research as it pertains to the psychological well-being and treatment of men and women diagnosed with this condition. While it has become less of a feared topic, it still is not discussed or researched enough, thus further exacerbating the gap in research on mental health and treatment options. The following dissertation completed a critical review of …

Ataxia Telangiectasia And Rad3-Related (Atr) Inhibitor Camonsertib Dose Optimization In Patients With Biomarker-Selected Advanced Solid Tumors (Tresr Study), Elisa Fontana, Ezra Rosen, Elizabeth K Lee, Martin Højgaard, Niharika B Mettu, Stephanie Lheureux, Benedito A Carneiro, Gregory M Cote, Louise Carter, Ruth Plummer, Devalingam Mahalingam, Adrian J Fretland, Joseph D Schonhoft, Ian M Silverman, Marisa Wainszelbaum, Yi Xu, Danielle Ulanet, Maria Koehler, Timothy A Yap

Faculty, Staff and Student Publications

BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects.

METHODS: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of …

Identification Of Hypoxia-Alcamhigh Macrophage- Exhausted T Cell Axis In Tumor Microenvironment Remodeling For Immunotherapy Resistance, Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han

Faculty, Staff and Student Publications

Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM

Target Engagement And Immunogenicity Of An Active Immunotherapeutic Targeting Pathological Α-Synuclein: A Phase 1 Placebo-Controlled Trial, Pepijn Eijsvogel, Pinaki Misra, Luis Concha-Marambio, Justin D Boyd, Shuang Ding, Lauren Fedor, Yueh-Ting Hsieh, Yu Shuang Sun, Madeline M Vroom, Carly M Farris, Yihua Ma, Marieke L De Kam, Igor Radanovic, Maurits F J M Vissers, Dario Mirski, Ghazal Shareghi, Mohammad Shahnawaz, Wolfgang Singer, Philip Kremer, Geert Jan Groeneveld, Hui Jing Yu, Jean-Cosme Dodart

Faculty, Staff and Student Publications

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks …

Mechanistic Insights Into Metabolic Function Of Dynamin-Related Protein 1, Xin Li, Katherine Pham, Jazmin Ysaguirre, Iqbal Mahmud, Lin Tan, Bo Wei, Long J Shao, Maryam Elizondo, Rabie Habib, Fathima Elizondo, Hiromi Sesaki, Philip L Lorenzi, Kai Sun

Faculty, Staff and Student Publications

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, …

An Analysis Of Suspected Microplastics In The Muscle And Gastrointestinal Tissues Of Fish From Sarasota Bay, Fl: Exposure And Implications For Apex Predators And Seafood Consumers, Eric Conger, Miranda Dziobak, Elizabeth J Berens Mccabe, Tita Curtin, Ayushi Gaur, Randall S Wells, John E Weinstein, Leslie B Hart

Faculty, Staff and Student Publications

Microplastics have been found in the gastrointestinal (GI) fluid of bottlenose dolphins (Tursiops truncatus), inhabiting Sarasota Bay, FL, suggesting exposure by ingestion, possibly via contaminated fish. To better understand the potential for trophic transfer, muscle and GI tissues from 11 species of dolphin prey fish collected from Sarasota Bay were screened for microplastics (particles <5 mm diameter). Suspected microplastics were found in 82% of muscle samples (n=89), and 97% of GI samples (n=86). Particle abundance and shapes varied by species (p<0.05) and foraging habit (omnivore vs. carnivore, p<0.05). Pinfish (Lagodon rhomboides) had the highest particle abundance for both tissue types (muscle: 0.38 …

Chemical Screening By Time-Resolved X-Ray Scattering To Discover Allosteric Probes, Chris A Brosey, Todd M Link, Runze Shen, Davide Moiani, Kathryn Burnett, Greg L Hura, Darin E Jones, John A Tainer

Faculty, Staff and Student Publications

Drug discovery relies on efficient identification of small-molecule leads and their interactions with macromolecular targets. However, understanding how chemotypes impact mechanistically important conformational states often remains secondary among high-throughput discovery methods. Here, we present a conformational discovery pipeline integrating time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS) and classic fragment screening applied to allosteric states of the mitochondrial import oxidoreductase apoptosis-inducing factor (AIF). By monitoring oxidized and X-ray-reduced AIF states, TR-HT-SAXS leverages structure and kinetics to generate a multidimensional screening dataset that identifies fragment chemotypes allosterically stimulating AIF dimerization. Fragment-induced dimerization rates, quantified with time-resolved SAXS similarity analysis (k

Dopaminergic Neurons In Zona Incerta Drives Appetitive Self-Grooming, Zhiying Jiang, Michelle He, Claire Young, Jing Cai, Yuanzhong Xu, Yanyan Jiang, Hongli Li, Maojie Yang, Qingchun Tong

Faculty, Staff and Student Publications

Dopaminergic (DA) neurons are known to play a key role in controlling behaviors. While DA neurons in other brain regions are extensively characterized, those in zona incerta (ZITH or A13) receive much less attention and their function remains to be defined. Here it is shown that optogenetic stimulation of these neurons elicited intensive self‐grooming behaviors and promoted place preference, which can be enhanced by training but cannot be converted into contextual memory. Interestingly, the same stimulation increased DA release to periaqueductal grey (PAG) neurons and local PAG antagonism of DA action reduced the elicited self‐grooming. In addition, A13 neurons increased …

Premalignant Progression In The Lung: Knowledge Gaps And Novel Opportunities For Interception Of Non-Small Cell Lung Cancer An Official American Thoracic Society Research Statement, Seyed Javad Moghaddam, Rajkumar Savai, Ramin Salehi-Rad, Shreoshi Sengupta, Michael N Kammer, Pierre Massion, Jennifer E Beane, Edwin J Ostrin, Carmen Priolo, Meredith A Tennis, Laura P Stabile, Alison K Bauer, Catherine R Sears, Eva Szabo, M Patricia Rivera, Charles A Powell, Humam Kadara, Brendan J Jenkins, Steven M Dubinett, A Mcgarry Houghton, Carla F Kim, Robert L Keith

Faculty, Staff and Student Publications

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the …

A Pilot Study Of The Cd38 Antagonist Daratumumab In Patients With Metastatic Renal Cell Carcinoma Or Muscle-Invasive Bladder Cancer, Matthew T Campbell, Amishi Y Shah, Pavlos Msaouel, Nizar M Tannir, Arlene O Siefker-Radtke, Ashish M Kamat, Neema Navai, Colin P N Dinney, Priya Rao, Charles C Guo, Rahul A Sheth, Aradhana M Venkatesan, Rebecca S Tidwell, Shalini S Yadav, Aidi Gu, Hong Chen, Marc Macaluso, Fei Duan, Sreyashi Basu, Sonali Jindal, Padmanee Sharma

Faculty, Staff and Student Publications

PURPOSE: We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC).

EXPERIMENTAL DESIGN: Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring …

Mechanisms That Clear Mutations Drive Field Cancerization In Mammary Tissue, Marta Ciwinska, Hendrik A Messal, Hristina R Hristova, Catrin Lutz, Laura Bornes, Theofilos Chalkiadakis, Rolf Harkes, Nathalia S M Langedijk, Stefan J Hutten, Renée X Menezes, Jos Jonkers, Stefan Prekovic, Grand Challenge Precision Consortium, Benjamin D Simons, Colinda L G J Scheele, Jacco Van Rheenen

Faculty, Staff and Student Publications

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1-3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1-/-;Trp53-/- cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to …

Novel Psychoplastogen Dm506 Reduces Cue-Induced Heroin-Seeking And Inhibits Tonic Gaba Currents In The Prelimbic Cortex, Kassandra Looschen, Shailesh N. Khatri, Malabika Maulik, Colin Salisbury, Alaina F. Carman, Katilyn Corriveau, Colton Smith, Dina Manetti, Maria Novella Romanelli, Hugo R. Arias, Cassandra D. Gipson, Swarup Mitra

Markey Cancer Center Faculty Publications

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior …

Complete Genome Sequence Of An Indian Outbreak Strain Of Chikungunya Virus, Eshna Laha, Deepak Jena, Viplov K. Biswas, Sharad Singh, Sunil K. Raghav, Asit K. Pattnaik, Soma Chattopadhyay

Nebraska Center for Virology: Faculty Publications

Here, we report the complete genome sequence of an Indian strain of chikungunya virus isolated from an infected patient from Hyderabad, Andhra Pradesh, India, during a massive outbreak in 2005–2006. The genome length spans 11,811 nucleotides and has a poly(A) tail of 29 residues at the 3′ end.

Long-Term Trajectories Of Sleep Duration Are Associated With Incident Diabetes In Middle-To-Older-Aged Black And White Americans, Qian Xiao, Kelsie M Full, Martin K Rutter, Loren Lipworth

Faculty, Staff and Student Publications

AIMS/HYPOTHESIS: Both short and long sleep durations have been linked to higher diabetes risk. However, sleep duration may vary over time, and there has been limited research focusing on individual sleep trajectories and diabetes risk. There are substantial racial disparities in both sleep health and diabetes risk in the USA. Thus, it is important to understand the role of suboptimal sleep patterns in diabetes risk in different racial groups.

METHODS: We assessed long-term trajectories of sleep duration and incident diabetes in 22,285 Black adults (mean age ± SD, 51.1 ± 8.2 years; 64.8% women) and 13,737 White adults (mean age …

Proton Therapy Toxicity Outcomes For Localized Prostate Cancer: Long-Term Results At A Comprehensive Cancer Center, Alan J Sosa, Michael K Rooney, Howard D Thames, Jeremiah W Sanders, David M Swanson, Seungtaek L Choi, Quynh-Nhu Nguyen, Henry Mok, Deborah A Kuban, X Ron Zhu, Shalin Shah, Lauren L Mayo, Karen E Hoffman, Chad Tang, Sean E Mcguire, Narayan Sahoo, Xiaodong Zhang, Andrew K Lee, Thomas J Pugh, Usama Mahmood, John W Davis, Brian F Chapin, Paul Corn, Reena Kudchadker, Noveen Ausat, Steven J Frank

Faculty, Staff and Student Publications

BACKGROUND: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database.

METHODS: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high …

Lifr Regulates Cholesterol-Driven Bidirectional Hepatocyte-Neutrophil Cross-Talk To Promote Liver Regeneration, Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, Yutong Sun, Fan Yao, Michael A Curran, Hao Zhu, Li Ma

Faculty, Staff and Student Publications

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 …

Panel Stacking Is A Threat To Consensus Statement Validity, Kasper P Kepp, Preben Aavitsland, Marcel Ballin, Francois Balloux, Stefan Baral, Kevin Bardosh, Howard Bauchner, Eran Bendavid, Raj Bhopal, Daniel T Blumstein, Paolo Boffetta, Florence Bourgeois, Adam Brufsky, Peter J Collignon, Sally Cripps, Ioana A Cristea, Nigel Curtis, Benjamin Djulbegovic, Oliver Faude, Maria Elena Flacco, Gordon H Guyatt, George Hajishengallis, Lars G Hemkens, Tammy Hoffmann, Ari R Joffe, Terry P Klassen, Despina Koletsi, Dimitrios P Kontoyiannis, Ellen Kuhl, Carlo La Vecchia, Tea Lallukka, John Lambris, Michael Levitt, Spyros Makridakis, Helena C Maltezou, Lamberto Manzoli, Ana Marusic, Clio Mavragani, David Moher, Ben W Mol, Taulant Muka, Florian Naudet, Paul W Noble, Anna Nordström, Peter Nordström, Nikolaos Pandis, Stefania Papatheodorou, Chirag J Patel, Irene Petersen, Stefan Pilz, Nikolaus Plesnila, Anne-Louise Ponsonby, Manuel A Rivas, Andrea Saltelli, Manuel Schabus, Michaéla C Schippers, Holger Schünemann, Marco Solmi, Andreas Stang, Hendrik Streeck, Joachim P Sturmberg, Lehana Thabane, Brett D Thombs, Athanasios Tsakris, Simon N Wood, John P A Ioannidis

Faculty, Staff and Student Publications

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a …

Metabolic Cell Death In Cancer: Ferroptosis, Cuproptosis, Disulfidptosis, And Beyond, Chao Mao, Min Wang, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

Radiation Therapy Quality Assurance Analysis Of Alliance A021501: Preoperative Mfolfirinox Or Mfolfirinox Plus Hypofractionated Radiation Therapy For Borderline Resectable Adenocarcinoma Of The Pancreas, Leila T Tchelebi, Diana Segovia, Koren Smith, Qian Shi, T J Fitzgerald, Michael D Chuong, Tyler J Zemla, Eileen M O'Reilly, Jeffrey A Meyerhardt, Eugene J Koay, Jessica Lowenstein, Ardaman Shergill, Matthew H G Katz, Joseph M Herman

Faculty, Staff and Student Publications

Purpose: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered.

Methods and materials: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable …

Strategies For The Development Of Metalloimmunotherapies, Xiaoqi Sun, Xingwu Zhou, Xiaoyue Shi, Omar A Abed, Xinran An, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host-microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases.

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by …

Lessons Learnt From Broad-Spectrum Coronavirus Antiviral Drug Discovery, Andrew A Bolinger, Jun Li, Xuping Xie, Hongmin Li, Jia Zhou

Faculty, Staff and Student Publications

Introduction: Highly pathogenic coronaviruses (CoVs), such as severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and the most recent SARS-CoV-2 responsible for the COVID-19 pandemic, pose significant threats to human populations over the past two decades. These CoVs have caused a broad spectrum of clinical manifestations ranging from asymptomatic to severe distress syndromes (ARDS), resulting in high morbidity and mortality.

Areas covered: The accelerated advancements in antiviral drug discovery, spurred by the COVID-19 pandemic, have shed new light on the imperative to develop treatments effective against a broad spectrum of CoVs. This perspective discusses strategies and …

Ketamine’S Mechanism Of Action With An Emphasis On Neuroimmune Regulation: Can The Complement System Complement Ketamine’S Antidepressant Effects?, Brandi Quintanilla, Carlos A Zarate, Anilkumar Pillai

Faculty, Staff and Student Publications

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital …

Racialized Inequities In Live Birth After Cancer: A Population-Based Study Of 63,000 Female Adolescents And Young Adults With Cancer, Andrea C Betts, Michael E Roth, Karen Albritton, Sandi L Pruitt, Philip J Lupo, Jennifer S Wang, L Aubree Shay, Marlyn A Allicock, Caitlin C Murphy

Faculty, Staff and Student Publications

Introduction: Fertility after cancer is a top concern for adolescents and young adults with cancer (AYAs) (15-39 years old at diagnosis). The authors characterized live births after cancer by race and ethnicity ("race/ethnicity") in a population-based sample of female AYAs.

Methods: This study used Texas Cancer Registry data linked to birth certificates (1995-2016) to estimate cumulative incidence of live birth, based on first live birth after cancer, and compared differences by race/ethnicity. Proportional subdistribution hazards models were used to estimate associations between race/ethnicity and live birth, adjusted for diagnosis age, cancer type, stage, year, and prior live birth, overall and …

Early And Enduring: Targeting The Endothelium For Blood-Brain Barrier Protection, Silin Wu, Xuefang Sophie Ren, Yejie Shi

Faculty, Staff and Student Publications

The disruption of the blood-brain barrier marks a pivotal early pathological event in ischemic stroke that significantly contributes to subsequent permanent damage. Here we delve into the ramifications of a study conducted by Xu and colleagues, which underscores the essential role of the protein peroxiredoxin-4 in cerebrovascular endothelial cells. Peroxiredoxin-4 was shown to preserve blood-brain barrier integrity during the early stages after cerebral ischemia and reperfusion, ultimately leading to improved long-term outcomes.

Immunoprevention Strategies For Colorectal Cancer In Lynch Syndrome Carriers, Charles M Bowen, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce …

Inferring Super-Resolution Tissue Architecture By Integrating Spatial Transcriptomics With Histology, Daiwei Zhang, Amelia Schroeder, Hanying Yan, Haochen Yang, Jian Hu, Michelle Y Y Lee, Kyung S Cho, Katalin Susztak, George X Xu, Michael D Feldman, Edward B Lee, Emma E Furth, Linghua Wang, Mingyao Li

Faculty, Staff and Student Publications

Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.

Small Molecules Targeting Micrornas: New Opportunities And Challenges In Precision Cancer Therapy, Ancuta Jurj, Beatrice Fontana, Gabriele Varani, George A Calin

Faculty, Staff and Student Publications

Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential …