Digital Commons Network^™

Isoflurane Conditioning Improves Functional Outcomes After Peripheral Nerve Injury In A Sciatic Cut Repair Murine Model, Yameng Xu, Ying Yan, Gregory J Zipfel, Matthew Macewan, Wilson Z Ray, Umeshkumar Athiraman

2020-Current year OA Pubs

INTRODUCTION: Anesthetic conditioning has been shown to provide neuroprotection in several neurological disorders. Whether anesthetic conditioning provides protection against peripheral nerve injuries remains unknown. The aim of our current study is to investigate the impact of isoflurane conditioning on the functional outcomes after peripheral nerve injury (PNI) in a rodent sciatic nerve injury model.

METHODS: Adult male Lewis rats underwent sciatic nerve cut and repair and exposed to none (Group 1, sham), single isoflurane exposure (Group 2), three-time isoflurane exposure (Group 3), and six-time isoflurane exposure (Group 4). Isoflurane conditioning was established by administration of 2% isoflurane for 1 hour, …

Unraveling The Role Of Hif And Epigenetic Regulation In Pulmonary Arterial Hypertension: Implications For Clinical Research And Its Therapeutic Approach, Ankita Mitra, Dan Yi, Zhiyu Dai, Vinicio De Jesus Perez

2020-Current year OA Pubs

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective …

The Role Of Mek Inhibition In Pediatric Low-Grade Gliomas, Shehryar R Sheikh, Laura J Klesse, Ross Mangum, Ashley Bui, Benjamin I Siegel, Mohamed S Abdelbaki, Neha J Patel

2020-Current year OA Pubs

Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children. Many patients with unresectable tumors experience recurrence or long-term sequelae from standard chemotherapeutics. This mini-review explores the emerging role of MEK inhibitors in the management of pLGGs, highlighting their potential to transform current treatment paradigms. We review the molecular basis for therapeutic MEK inhibition in the context of pLGG, provide an evidence base for the use of the major MEK inhibitors currently available in the market for pLGG, and review the challenges in the use of MEKi inhibitors in this population.

Perspectives Of Traditional Herbal Medicines In Treating Retinitis Pigmentosa, Shihui Liu, Toshihiko Matsuo, Chie Matsuo, Takumi Abe, Jinghua Chen, Chi Sun, Qing Zhao

2020-Current year OA Pubs

Medicinal plants, also known as herbs, have been discovered and utilized in traditional medical practice since prehistoric times. Medicinal plants have been proven rich in thousands of natural products that hold great potential for the development of new drugs. Previously, we reviewed the types of Chinese traditional medicines that a Tang Dynasty monk Jianzhen (Japanese: Ganjin) brought to Japan from China in 742. This article aims to review the origin of Kampo (Japanese traditional medicine), and to present the overview of neurodegenerative diseases and retinitis pigmentosa as well as medicinal plants in some depth. Through the study of medical history …

Case Report: Targeted Treatment By Fluoxetine/Norfluoxetine Of A Kcnc2 Variant Causing Developmental And Epileptic Encephalopathy, Ping Li, Alice Butler, Yu Zhou, Karl L Magleby, Christina A Gurnett, Lawrence Salkoff

2020-Current year OA Pubs

The Kv3.2 subfamily of voltage activated potassium channels encoded by the

Campylobacter Colonization And Undernutrition In Infants In Rural Eastern Ethiopia — A Longitudinal Community-Based Birth Cohort Study, Dehao Chen, Nurmohammad Shaik, Mark J Manary, Et Al.

2020-Current year OA Pubs

BACKGROUND:

METHODS: We followed a birth cohort of 106 infants in rural smallholder households in eastern Ethiopia up to 13 months of age. We measured anthropometry, surveyed sociodemographic determinants, and collected stool and urine samples. A short survey was conducted during monthly visits, infant stool samples were collected, and

RESULTS: The

CONCLUSION: This study found that most determinants associated with increased

Ddr2-Regulated Arginase Activity In Ovarian Cancer-Associated Fibroblasts Promotes Collagen Production And Tumor Progression, Favour A Akinjiyan, Zainab Ibitoye, Peinan Zhao, Leah P Shriver, Gary J Patti, Gregory D Longmore, Katherine C Fuh

2020-Current year OA Pubs

Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, …

The Forkhead Transcription Factor Foxj1 Controls Vertebrate Olfactory Cilia Biogenesis And Sensory Neuron Differentiation, Dheeraj Rayamajhi, Steven L. Brody, Et Al.

2020-Current year OA Pubs

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the …

Transcription Factor Interactions Explain The Context-Dependent Activity Of Crx Binding Sites, Kaiser J. Loell, Ryan Z. Friedman, Connie A. Myers, Joseph C. Corbo, Barak A. Cohen, Michael A. White

2020-Current year OA Pubs

The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while …

A Neural Mechanism For Conserved Value Computations Integrating Information And Rewards, Ethan S Bromberg-Martin, Yang-Yang Feng, Takaya Ogasawara, J Kael White, Kaining Zhang, Ilya E Monosov

2020-Current year OA Pubs

Behavioral and economic theory dictate that we decide between options based on their values. However, humans and animals eagerly seek information about uncertain future rewards, even when this does not provide any objective value. This implies that decisions are made by endowing information with subjective value and integrating it with the value of extrinsic rewards, but the mechanism is unknown. Here, we show that human and monkey value judgements obey strikingly conserved computational principles during multi-attribute decisions trading off information and extrinsic reward. We then identify a neural substrate in a highly conserved ancient structure, the lateral habenula (LHb). LHb …

Neurosteroids: Mechanistic Considerations And Clinical Prospects, Jamie L Maguire, Steven Mennerick

2020-Current year OA Pubs

Like other classes of treatments described in this issue's section, neuroactive steroids have been studied for decades but have risen as a new class of rapid-acting, durable antidepressants with a distinct mechanism of action from previous antidepressant treatments and from other compounds covered in this issue. Neuroactive steroids are natural derivatives of progesterone but are proving effective as exogenous treatments. The best understood mechanism is that of positive allosteric modulation of GABA

Cep120 Is Essential For Kidney Stromal Progenitor Cell Growth And Differentiation, Ewa Langner, Tao Cheng, Eirini Kefaloyianni, Charles Gluck, Baolin Wang, Moe R Mahjoub

2020-Current year OA Pubs

Mutations in genes that disrupt centrosome structure or function can cause congenital kidney developmental defects and lead to fibrocystic pathologies. Yet, it is unclear how defective centrosome biogenesis impacts renal progenitor cell physiology. Here, we examined the consequences of impaired centrosome duplication on kidney stromal progenitor cell growth, differentiation, and fate. Conditional deletion of the ciliopathy gene Cep120, which is essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of interstitial lineages including pericytes, fibroblasts and mesangial cells. These phenotypes were caused by a combination of delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, …

Chemotherapy-Induced Neutropenia Management In A Patient With Metastatic Breast Cancer And Shwachman-Diamond Syndrome (Sds): A Case Report, Renee Morecroft, Constantine N. Logothetics, Stefan P. Tarnawsky, Andrew A. Davis

2020-Current year OA Pubs

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome associated with cytopenia and the development of hematologic malignancies. Solid tumor occurrence is rare and, historically, these patients have had poor outcomes due to chemotherapy-induced myelosuppression and increased susceptibility to infections. We report the administration of cytotoxic systemic therapy with granulocyte colony-stimulating factor (G-CSF) in a patient with SDS and metastatic breast cancer. We describe the risk-benefit profile of utilizing G-CSF in managing this patient to improve her therapeutic outcome and review the prior literature.

CASE DESCRIPTION: A 41-year-old Caucasian female with SDS developed stage IV triple-positive [estrogen …

Characterization Of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels In Oligodendrocytes., Kyle A Lyman, Ye Han, Andrew P Robinson, Samuel E Weinberg, Daniel W Fisher, Robert J Heuermann, Reagan E Lyman, Dong Kyu Kim, Andreas Ludwig, Navdeep S Chandel, Mark D Does, Stephen D Miller, Dane M Chetkovich

2020-Current year OA Pubs

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (I

A Structure-Function Analysis Of Hepatocyte Arginase 2 Reveals Mitochondrial Ureahydrolysis As A Determinant Of Glucose Oxidation, Yiming Zhang, Jiameng Sun, Henry D Wasserman, Joshua A Adams, Cassandra B Higgins, Shannon C Kelly, Louise Lantier, Brian J Debosch

2020-Current year OA Pubs

BACKGROUND & AIMS: Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation.

METHODS: To do this, we generated mice expressing wild-type murine Arg2, enzymatically inactive Arg2 (Arg2

RESULTS: We show …

The Response Of Dual-Leucine Zipper Kinase (Dlk) To Nocodazole: Evidence For A Homeostatic Cytoskeletal Repair Mechanism, Laura Devault, Chase Mateusiak, John Palucki, Michael Brent, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNA-seq. This signature includes genes likely …

Targeting Of Oncogenic Aaa-Atpase Trip13 Reduces Progression Of Pancreatic Ductal Adenocarcinoma, Farrukh Afaq, Sumit Agarwal, Prachi Bajpai, Sameer Al Diffalha, Hyung-Gyoon Kim, Shajan Peter, Moh'd Khushman, Subhash C Chauhan, Priyabrata Mukherjee, Sooryanarayana Varambally, Upender Manne

2020-Current year OA Pubs

Thyroid hormone receptor-interacting protein 13 (TRIP13) is involved in cancer progression, but its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. Thus, we assessed the expression, functional role, and mechanism of action of TRIP13 in PDAC. We further examined the efficacy of TRIP13 inhibitor, DCZ0415, alone or in combination with gemcitabine on malignant phenotypes, tumor progression, and immune response. We found that TRIP13 was overexpressed in human PDACs relative to corresponding normal pancreatic tissues. TRIP13 knockdown or treatment of PDAC cells with DCZ0415 reduced proliferation and colony formation, and induced G2/M cell cycle arrest and apoptosis. Additionally, TRIP13 knockdown or …

Neurosteroids Mediate And Modulate The Effects Of Pro-Inflammatory Stimulation And Toll-Like Receptors On Hippocampal Plasticity And Learning, Yukitoshi Izumi, Kazuko A. O'Dell, Anil G. Cashikar, Steven M. Paul, Douglas F. Covey, Steven J. Mennerick, Charles F. Zorumski

2020-Current year OA Pubs

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (μg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low …

Control Of Acute Myeloid Leukemia And Generation Of Immune Memory In Vivo Using Amv564, A Bivalent Bispecific Cd33 X Cd3 T Cell Engager, Linda G. Eissenberg, Julie K. Ritchey, Michael P. Rettig, Dilan A. Patel, Kiran Vij, Feng Gao, Victoria Smith, Tae H Han, John F. Dipersio

2020-Current year OA Pubs

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, …

Buffered Lugol's Iodine Preserves Dna Fragment Lengths, P M Gignac, D Valdez, A C Morhardt, L M Lynch

2020-Current year OA Pubs

Museum collections play a pivotal role in the advancement of biological science by preserving phenotypic and genotypic history and variation. Recently, contrast-enhanced X-ray computed tomography (CT) has aided these advances by allowing improved visualization of internal soft tissues. However, vouchered specimens could be at risk if staining techniques are destructive. For instance, the pH of unbuffered Lugol's iodine (I

Arid1a Loss Is Associated With Increased Nrf2 Signaling In Human Head And Neck Squamous Cell Carcinomas, Vinh Nguyen, Travis P. Schrank, Michael B. Major, Bernard E. Weissman

2020-Current year OA Pubs

Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional …

Reference Ranges For Left Modified Myocardial Performance Index: Systematic Review And Meta-Analysis, Katherine H Bligard, Michelle Doering, Shay Porat, Joshua I Rosenbloom

2020-Current year OA Pubs

INTRODUCTION: The modified myocardial performance index (mod-MPI) is a noninvasive Doppler-derived metric used to evaluate fetal cardiac function. However, the reference ranges for mod-MPI in normal fetuses are not clearly defined, which limits the use of this technology in fetuses with potential cardiac compromise. Thus, we aimed to perform a systematic review and meta-analysis of published mod-MPI reference ranges across gestation.

METHODS: The published literature was systematically searched, and all published articles in any language that provided values for the left ventricular mod-MPI obtained in low-risk, singleton fetuses were considered eligible for further review. All retrieved titles and abstracts were …

Proceedings Of The 11th Annual Deep Brain Stimulation Think Tank: Pushing The Forefront Of Neuromodulation With Functional Network Mapping, Biomarkers For Adaptive Dbs, Bioethical Dilemmas, Ai-Guided Neuromodulation, And Translational Advancements, Kara A Johnson, Nico U F Dosenbach, Evan M Gordon, Et Al.

2020-Current year OA Pubs

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and …

Lung Lymphatic Endothelial Cells Undergo Inflammatory And Prothrombotic Changes In A Model Of Chronic Obstructive Pulmonary Disease, Anjali Trivedi, Tyler M Lu, Barbara Summers, Kihwan Kim, Alexander J Rhee, Sean Houghton, Derek E Byers, Raphaël Lis, Hasina Outtz Reed

2020-Current year OA Pubs

The lymphatic vasculature regulates lung homeostasis through drainage of fluid and trafficking of immune cells and plays a key role in the response to lung injury in several disease states. We have previously shown that lymphatic dysfunction occurs early in the pathogenesis of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) and that this is associated with increased thrombin and fibrin clots in lung lymph. However, the direct effects of CS and thrombin on lymphatic endothelial cells (LECs) in COPD are not entirely clear. Studies of the blood vasculature have shown that COPD is associated with increased thrombin …

A Critical Evaluation Of "Leakage" At The Cochlear Blood-Stria-Barrier And Its Functional Significance, Kevin K Ohlemiller, Noël Dwyer, Veronica Henson, Kaela Fasman, Keiko Hirose

2020-Current year OA Pubs

The blood-labyrinth-barrier (BLB) is a semipermeable boundary between the vasculature and three separate fluid spaces of the inner ear, the perilymph, the endolymph and the intrastrial space. An important component of the BLB is the blood-stria-barrier, which shepherds the passage of ions and metabolites from strial capillaries into the intrastrial space. Some investigators have reported increased "leakage" from these capillaries following certain experimental interventions, or in the presence of inflammation or genetic variants. This leakage is generally thought to be harmful to cochlear function, principally by lowering the endocochlear potential (EP). Here, we examine evidence for this dogma. We find …

Modular Horizontal Network Within Mouse Primary Visual Cortex, Andreas Burkhalter, Weiqing Ji, Andrew M Meier, Rinaldo D D'Souza

2020-Current year OA Pubs

Interactions between feedback connections from higher cortical areas and local horizontal connections within primary visual cortex (V1) were shown to play a role in contextual processing in different behavioral states. Layer 1 (L1) is an important part of the underlying network. This cell-sparse layer is a target of feedback and local inputs, and nexus for contacts onto apical dendrites of projection neurons in the layers below. Importantly, L1 is a site for coupling inputs from the outside world with internal information. To determine whether all of these circuit elements overlap in L1, we labeled the horizontal network within mouse V1 …

Membrane Potential Hyperpolarization: A Critical Factor In Acrosomal Exocytosis And Fertilization In Sperm Within The Female Reproductive Tract, Paula A Balestrini, Valeria Sulzyk, Martina Jabloñski, Liza J Schiavi-Ehrenhaus, Soledad N González, Juan J Ferreira, Matías D Gómez-Elías, Pablo Pomata, Guillermina M Luque, Dario Krapf, Patricia S Cuasnicu, Celia M Santi, Mariano G Buffone

2020-Current year OA Pubs

Hyperpolarization of the membrane potential (Em), a phenomenon regulated by SLO3 channels, stands as a central feature in sperm capacitation-a crucial process conferring upon sperm the ability to fertilize the oocyte.

Systematic Computer-Aided Disulfide Design As A General Strategy To Stabilize Prefusion Class I Fusion Proteins, Karen J Gonzalez, Kevin C Yim, Jorge C G Blanco, Marina S Boukhvalova, Eva-Maria Strauch

2020-Current year OA Pubs

Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricate task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric …

Sexual Dimorphism In Hepatic Ppar Alpha And Cyp4a12a Expression Is Associated With Reduced Development Of Drug-Induced Non-Alcoholic Steatohepatitis In Female Il-33-/- Mice, Chloe Thomas, Dolores B Njoku

2020-Current year OA Pubs

Males are at higher risk for developing metabolic dysfunction-associated steatohepatitis (MASH) than females; however, mechanisms mediating sexual dimorphism in MASH development are not completely understood. Nutrition-based mouse models suggest that dysregulated fatty acid biosynthesis promotes MASH. Drugs recapitulate MASH without diet variabilities. This brief report investigates associations of sexual dimorphism with male susceptibility to MASH utilizing a drug-induced MASH model and focuses on very-long-chain fatty acid biosynthesis pathways. We assessed male and female mouse livers at 5 and 15 weeks following MASH induction by immunizations and age-matched un-immunized controls utilizing Western blot. Our results suggest that PPAR alpha and CYP4a12a …

Recarving The Future: Bridging Car T-Cell Therapy Gaps With Synthetic Biology, Engineering, And Economic Insights, Alaa Ali, John F Dipersio

2020-Current year OA Pubs

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy in solid tumors, safety concerns related to toxicity, and logistical challenges in manufacturing and scalability. This review critically examines the latest advancements aimed at overcoming these obstacles, highlighting innovations in CAR T-cell engineering, novel antigen targeting strategies, and improvements in delivery and persistence within the tumor microenvironment. We also discuss the development of allogeneic CAR T cells as off-the-shelf therapies, strategies to mitigate adverse effects, and …