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Immunotherapy in Pediatrics
No full textBackground: Immunotherapy has emerged as a promising treatment approach, specifically designed to boost the response of the immune system to target tumor cells while sparing nontumor tissue. This treatment not only holds the potential for enhanced efficacy but also translates into reduced adverse effects on patients while improving outcomes. Despite its early success, the application of immunotherapy has largely been confined to adults, with slow adoption noted in the treatment of pediatric malignancies. Case Information: Here the objective is to demonstrate a single institution’s experience with immunotherapy in pediatric oncology, to further the exploration of these treatment modalities in the treatment of children with cancer. In our review, we studied a database of 48 pediatric patients out of 226, expressing programmed death ligand 1 (PD-L1), of which 7 have undergone immunotherapy. In this project, we studied various tumor types in which immunotherapy found its utilization. We also noted adverse effects associated with this particular therapy as well as efficacy. We believe immunotherapy is poised to deliver a positive impact in the realm of pediatric patients. 7 pediatric patients with positive expression of PD-L1 received immunotherapy, involving nivolumab alone or in combination with ipilimumab or brentuximab. Hodgkin lymphoma (n=2), metastatic melanoma (n=2), histiocytic sarcoma (n=1), rectal carcinoma in the context of constitutional mismatch repair deficiency (cMMRD) (n=1), epithelioid and spindle cell hemangioma (n=1) comprised the diagnoses. Patients received between 4 and 18 cycles of immunotherapy. Out of all patients who had completed their immunotherapy regimens (n=5) or remained on treatment (n=2), 6 achieved remission or had stabilized disease. The diagnoses responding to treatment included Hodgkin lymphoma (n=2), metastatic melanoma (n=2), rectal carcinoma due to cMMRD (n=1), and epithelioid and spindle cell hemangioma (n=1). Unfortunately, after 13 months in remission, the patient suffering from histiocytic sarcoma experienced reoccurrence in the duodenum. Immune-related adverse events included mild allergic reactions, prodromal symptoms, anemia, neutropenia, transaminitis, endocrinopathies, and self-limiting neuritis. Conclusions: This report highlights the positive impact immunotherapy can have in the realm of pediatric malignancies, with the possibility of tumor regression or stabilizing disease. Further research is needed to accurately identify pediatric oncology patients that could benefit from immunotherapy
Diurnal and Nocturnal Regulation of Intraocular Pressure and Aqueous Humor Outflow Facility in Mice
Get PDFIntraocular pressure (IOP) is known to fluctuate according to a circadian rhythm. While this phenomenon has been quite extensively studied and reported in a number of species, including mice, to date, there have been few studies on the circadian effect upon total aqueous humor outflow facility (Ctot). In this study, we measured IOP in living anesthetized C57BL/6J mice every 3h over a 24h period, using a TonoLab impact tonometer. We also measured daytime (10:00 pm to 12:00 pm) and nighttime (02:00am to 04:00am) Ctot in anesthetized living mice using a constant flow infusion method. We report that over a 24h period, IOP is highest at midnight (18.34 ± 2.79 mmHg, mean ± St Dev mean) and lowest at midday (12.71 ± 1.42 mmHg), ΔIOP = 5.63 mmHg or 44.3% increase at night, P = 0.005. We also report that Ctot at nighttime (13.66 ± 1.12 nL/min/mmHg ± SEM) is lower than corresponding measurements made during the day time (24.58 ± 2.42 nL/min/mmHg ± SEM), ΔCtot = 10.92 nL/min/mmHg, or 44.4% reduction at night, P = 0.004. In living C57BL/6J mice, IOP and Ctot exhibit circadian variation and appear to be inversely related.The authors would like to acknowledge the generous support the National Eye Institute provided through grant NEI R01 EY026177
Assessment of WIN 55,212-2 Loaded Reconstituted High-Density Lipoprotein Nanoparticles for Ocular Delivery
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 North Texas Eye Research Institute Graduate Student Award - 2nd PlacePurpose:
Overcoming challenges in glaucoma therapy, such as biological barriers and retina delivery, led us to develop innovative reconstituted high-density lipoprotein nanoparticles (rHDL NPs) for effective drug delivery. Optic nerve head astrocytes (ONHAs) are vital in maintaining retinal ganglion cell (RGC) axon integrity. This study describes the encapsulation of WIN 55,212-2 (WIN) in rHDL NPs and investigates the delivery mechanism of these nanoparticles in ONHAs.
Methods:
Using a novel preparation method, a stable rHDL-payload complex was created by combining lipophilic fluorescent dye IR780 or therapeutic agent WIN with phosphatidylcholine and apolipoprotein A-I (Apo A-I). Fluorescent rHDL (rHDL-IR780) was used to assess cellular uptake in human primary ONHAs in vitro. Scavenger receptor class B1 (SR-B1) expression was confirmed in retinal cell lysates by SDS-PAGE followed by western blot analysis. Receptor-mediated payload release through SR-B1 was confirmed by receptor blocking using BLT-1 as a specific SR-B1 receptor-blocking agent.
Results:
Fluorescent rHDL NPs exhibited an IR780 encapsulation efficiency of 68.7% (103 M), a polydispersity index (PDI) of 0.287 ± 0.013, a size of 14.01 ± 4.36 nm, and a zeta potential of -7.44 ± 0.90 mV. Additionally, drug-loaded rHDL-WIN NPs displayed a WIN encapsulation efficiency of 44.6% (341.4 M), a PDI of 0.280 ± 0.011, a size of 62.04 ± 25.06 nm, and a zeta potential of -20.13 ± 0.86 mV. Western blot analysis on human retinal lysates, ONHA lysates, and RGC lysates indicated the expression of SR-B1 (57/82 kDa (unmodified/glycosylated)). Cellular uptake studies confirmed the ability of rHDL to deliver payloads to ONHAs and RGCs. Receptor blocking with 10 nM BLT-1 highlighted the role of SR-B1 in specific cellular uptake from rHDL to ONHAs (p < 0.01).
Conclusions:
Our study highlights the role of SR-B1 in facilitating the delivery of rHDL payloads to ONHAs, offering the potential for targeted drug delivery in glaucoma. We anticipate that the cellular uptake by RGCs will follow the same SR-B1-mediated pathway. Successful WIN encapsulation in rHDL NPs suggests a potential avenue for targeting therapies to treat and prevent glaucomatous damage. Further studies are needed to determine the neuroprotective effects of rHDL-WIN and develop the potential of rHDL NPs to be used as an agent to target therapies in glaucoma.5T32AG020494-2
Examining the Impact of Multiple Clinical Profiles on Recovery Time in Pediatric Patients with Sports-related Concussion
No full textPurpose: The primary objective is to identify potential relationships between primary clinical profiles (cognitive/fatigue, vestibular, ocular, migraine, anxiety/mood) and secondary clinical profiles, exploring how these interactions influence the duration of recovery in pediatric (SRC) patients. This study aims to provide valuable insights that can be used to create tailored and more effective treatment strategies, ultimately enhancing recovery outcomes. Hypothesis: There is a positive association between primary clinical profile and secondary clinical profile in pediatric patients with SRC (sports related concussion), which is related to patient recovery time. Methods: The study employs a retrospective design, utilizing data from the Concussion Registry at Baylor Scott & White Sports Concussion program to explore associations between variables. Statistical analyses, including chi-squared tests, odds ratio, t-test, ANOVA, and negative binomial regression models, will be conducted. The population consists of pediatric patients aged 12-18 diagnosed with SRC at the BSW Concussion Clinic. Results: We found significant associations between primary and secondary clinical profiles, particularly between cognitive/fatigue and migraine, migraine and ocular, migraine and vestibular, ocular and cognitive/fatigue, and ocular and migraine profiles. However, no substantial correlation was observed between these profile combinations and recovery time. Conclusion: This study emphasizes the need for a multidimensional approach to assessment and management of SRC in pediatric patients. While clinical profiles are associated, they do not significantly impact recovery time. Personalized care plans and treatment strategies can be developed by considering both primary and secondary clinical profiles to enhance recovery outcomes. Further research is required to better understand SRC in this population and address the study's limitations
A Rapid Systematic Literature Review: Barriers to Health Services in Pediatric Refugee Populations
No full textPurpose: Pediatric refugee populations in the United States have lower rates of immunization, difficulty accessing health care, decreased access to health insurance, and lower preventative visit attendance. This systematic review seeks to analyze the existing literature on health services for refugee children in the United States and to understand the socio-demographic, cultural, and systemic factors that contribute to these challenges. Two research questions were investigated: 1) what barriers are identified in the literature to the provision of adequate healthcare among refugee children in the United States, 2) does evidence suggest there are existing services and solutions that are accessible to refugee communities? Methods: A systematic search of electronic databases, including PubMed, CINAHL, and SCOPUS, was conducted to identify relevant peer-reviewed articles published. PRISMA guidelines for rapid reviews were followed, keywords were defined, and Covidence was used to structure content. The initial search produced 547 studies, and after 34 duplicates were removed, 513 studies remained. Title and abstracts were screened based on inclusion criteria, specifically, studies published in the last 10 years that referenced health services for pediatric refugee populations. Studies were excluded based on incorrect participant age and population specifications. Editorials and non-peer-reviewed articles were also excluded. 79 articles received a full-text review, with 13 articles meeting all inclusion criteria. These articles (n=13) were analyzed, content related to the research questions was classified using a data extraction tool, and common themes and patterns were identified. Results: Nine common themes isolated among the articles were linguistic differences, trauma-related mental health issues, lack of insurance coverage, cultural differences, limited health literacy, transportation difficulties, stigma, social isolation, and insufficient housing. The most prevalent theme isolated was linguistic differences with 11 out of the 13 studies that met inclusion criteria including it as a barrier to accessing healthcare. While these are listed as distinct themes and patterns, it is important to note that many of these barriers are interrelated. Our review revealed a lack of coherent and consistent services designed to meet the complex needs of this high-risk population. Conclusion: This rapid systematic review highlights the need for targeted interventions and policies that address the complex and interrelated barriers refugee populations face in accessing health care services. There does not appear to be consistent services that target this population specifically. In prior studies, refugee children were shown to have lower rate of immunizations, emphasizing the need for improved vaccination outreach strategies and health education. The isolated nine barriers serve as a foundational starting point to build targeted interventions to better serve this vulnerable population. Since linguistic differences were the most prevalent barrier to care, targeted interventions should include translators, either in-person or virtual, to be made available at clinics to provide care to this population. Ultimately, a more comprehensive understanding of these barriers through further research and policy development can improve health equity and outcomes for pediatric refugee populations in the United States
Intraoperative Osteopathic Manipulative Therapy Used to Manage Acute Cervical Somatic Dysfunction During Deep Brain Stimulator Implantation for Parkinson’s Disease: A Case Report
No full textResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2024 Medical Student Government Association Best in Third Year ClassResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2024 Student Research Award - Best Case StudyResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2024 OMM-I.M. Korr, Ph.D. Memorial Research AwardBackground: Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms such as bradykinesia, resting tremors, and cognitive changes. Deep brain stimulation (DBS) is a surgical procedure used to control the motor symptoms of PD, where electrodes are placed inside the patient’s basal ganglia under conscious sedation. Of the documented complications directly attributable to DBS, intraoperative and postoperative musculoskeletal pain is currently not well reported on, and management of this pain is also not well established. In this case report, we describe the intraoperative osteopathic assessment and management with osteopathic manipulative treatment (OMT) of acute cervical and occipital somatic dysfunctions in a patient with PD who underwent a DBS implant.
Case Information: A 72-year-old female with a five-year history of PD presented with worsening bradykinesia, dyskinesia, rigidity, balance issues, and bilateral lower extremity pain. The patient’s carbidopa/levodopa dosage effectively controlled her motor symptoms for 2 hours before symptoms returned. Her physical exam was unremarkable except for aspects of her neurological exam, which revealed resting tremors throughout her bilateral upper and lower extremities, a very unsteady, shuffling gait, and an inability to do tandem gait, heel, or toe walking. She could not squat or rise independently. DBS implantation was recommended as a palliative option. Preoperative brain magnetic resonance images revealed an arachnoid cyst on one side and multiple small vessels surrounding the target for her DBS lead positions, necessitating more planning and increased surgery duration than expected. During the procedure, she developed severe musculoskeletal neck pain, a rating of 8/10, that gradually worsened to involve her posterior occiput and right shoulder. An osteopathic examination of the neck region showed acute tissue texture changes in her cervical paravertebral, suboccipital, trapezius, and sternocleidomastoid (SCM) musculature with hypertonicity, bogginess to palpation, and multiple myofascial trigger points. OMT was used intraoperatively in an attempt to control the musculoskeletal pain after the implementation of traditional methods of warm compresses and extra support failed to alleviate the severity. OMT used included longitudinal soft tissue of the paravertebral, direct inhibition of myofascial trigger points, and indirect myofascial release of the suboccipital musculature and SCM, reducing pain to a reported 2/10 by the patient. OMT was well-tolerated and did not give rise to any adverse events as the DBS implant procedure proceeded and was completed successfully.
Conclusions: This case illustrates how indirect and soft tissue techniques can effectively be used in close proximity to an area of operation without compromising the sterile field or displacing the patient with augmenting positional pain tolerance. Future studies should evaluate the safety and effectiveness of OMT under conscious sedation, intraoperatively, and its application as a treatment modality to augment patient tolerance of surgical procedures
Longitudinal microRNA profiling of neuronal-enriched exosomes associated with cognitive function and decline
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Microbiology, Immunology & Genetics (Genetics) Award - 1st PlaceBackground. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that disproportionately affects several racial/ethnic groups, including Mexican Americans (MAs). Evidence suggests that early alterations in the AD brain can propagate to local and distal cells through small biological packages called exosomes. Exosomes secreted by neurons are capable of mediating cell-to-cell communication through their bioactive cargo, leading to metabolic and epigenetic reprogramming in target cells. Exosomes derived from neurons have been detected in plasma and isolated from other subpopulations using the neural cell adhesion molecule CD171. These neuronal-enriched exosomes (NEEs) cross the blood-brain barrier and thus represent an easily accessible derivative of otherwise inaccessible brain tissue in living humans. Small, non-coding RNAs called microRNAs (miRNA) are transcribed from nuclear DNA and function as strong intracellular expression regulators. miRNAs, which can be selectively packaged and transported by exosomes, have been shown to significantly alter the expression patterns of target cells. This project aims to identify the aberrant miRNA profiles that correlate with disease progression and key comorbidities (e.g., type 2 diabetes (T2D), hyperlipidemia, hypertension) in NEEs of plasma from MAs and Non-Hispanic Whites (NHWs). Hypothesis. We hypothesize that population-specific differences in NEE miRNA cargo will reflect cognitive function and decline. Methods. Longitudinal plasma samples (two time points, 2 years apart) received from the Texas Alzheimer’s Research and Care Consortium (TARCC) were processed using a two-step method that involves precipitation of total exosomes followed by NEE capture with a biotinylated antibody against the neuronal surface marker, CD171. After isolating RNA from NEEs, miRNAs were then profiled using next-generation sequencing. These profiles were then analyzed for differential miRNA expression in individuals with cognitive impairment compared to the normal control group. Results. Our preliminary quality control and sequencing data confirmed the successful isolation of miRNA from NEEs. We identified specific miRNA candidates that were differentially expressed in NEEs from cognitively impaired subjects compared to healthy controls. These miRNAs target gene networks that have been implicated in AD pathophysiology. Conclusion. This innovative workflow along with the unique sample type provides novel insight into the role of exosomal miRNA cargo in AD pathogenesis, identifying novel, population-specific targets for biomarker/diagnosis as well as therapeutic design. Further, this approach provides a conceptual framework for blood-based exosomal profiling in other complex diseases characterized by epigenetic dysregulation and systemic inflammation.Texas Alzheimer’s Research and Care Consortium under the direction of the Texas Council on AD and Related Disorders and the Neurobiology of Aging and Alzheimer's Disease Training Grant (NIH-T32 AG 020494)
Interactions Between Carotid Arterial Stiffness, Amplitude of Cerebral Blood Flow Oscillations, and Cerebral Tissue Oxygenation During Simulated Hemorrhage in Humans
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Physiology & Anatomy (Integrative Physiology) Award - 1st PlaceIntroduction: Inducing 0.1 Hz (10-s cycle) oscillations in cerebral blood flow attenuates the reduction in cerebral tissue oxygenation during simulated hemorrhage in humans. It is unknown, however, how stiffness of the cerebral feed arteries influences the magnitude of cerebral blood flow oscillations, and/or the protection of cerebral tissue oxygenation. When 0.1 Hz oscillations are induced during simulated hemorrhage, we hypothesize that: 1) arterial stiffness of the internal carotid artery (ICA) will increase from rest; 2) the amplitude of 0.1 Hz oscillations in cerebral blood flow will be higher in individuals with stiffer arteries, and; 3) the reduction in cerebral tissue oxygenation will be smaller with higher amplitude of cerebral blood flow oscillations.
Methods: 8 healthy human participants (age: 30.1±7.6 y) underwent a 10-min hypovolemic oscillatory lower body negative pressure (OLBNP) protocol, where chamber pressure oscillated every 5-s between -30 mmHg and -90 mmHg (i.e., 0.1 Hz). ICA beta stiffness index was calculated from measurements of ICA diameter (via ultrasound imaging), and arterial pressure (via finger photoplethysmography). Middle cerebral artery velocity (MCAv) was measured using transcranial doppler ultrasound, and cerebral tissue oxygenation (ScO2) was measured with near infrared spectroscopy. Fast Fourier transformation was used to quantify oscillations in mean MCAv at ~0.1 Hz.
Results: While Mean MCAv 0.1 Hz oscillations increased from baseline to OLBNP (N=8, 34.0±33.9 (cm/s)2vs. 104.7±58.1(cm/s)2, p=0.01), ICA beta stiffness did not increase (N=5, 6.1±0.7 au vs. 8.2±2.7 au, p=0.21). There was no relationship between baseline ICA beta stiffness and the percent change in mean MCAv 0.1 Hz oscillations (N=5; r=0.44, p=0.46). ScO2 decreased from baseline to OLBNP (N=8, 66.5±2.9 % vs. 64.8±2.9%,p=0.03), but there was also no relationship between the percent change in mean MCAv 0.1 Hz oscillations and the decrease in ScO2(r=0.28, p=0.50).
Conclusions: Based on these data, 0.1 Hz OLBNP does not affect ICA stiffness, and there is no relationship between ICA stiffness, amplitude of induced 0.1 Hz cerebral blood flow oscillations, and the reduction in cerebral tissue oxygenation during simulated hemorrhage. However, as this analysis was performed retrospectively, and arterial stiffness was not initially an outcome measure, there was limited data available for analysis. This limitation will be addressed in a project currently in progress in our laboratory.American Heart Association Grant in Ai
Assessing Changes to the Lower GI Tract Microbiome in Response to Neglect-related Early Life Stress Exposure
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Microbiology, Immunology & Genetics (Cell Biology, Immunology & Microbiology) Award - 1st PlaceResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2024 Medical Student Government Association Best of DO/PhD Dual Degree StudentsGrowing evidence supports exposure to early life stress (ELS) is associated with alterations in the developing immune system and increases the risk for chronic health conditions. It is widely understood that alterations to the gut microbiome can occur from exposure to various environmental factors, including diet and stress. Early life malnutrition is a form of neglect-related ELS that refers to states of both under- and over-nutrition in which a child may have insufficient intake of one or more nutrients due to an imbalanced diet. Malnutrition during childhood is a public health concern with significant health ramifications. Recent research shows the gut microbiome is intimately involved with immune system development—especially during early life when the immune system is being trained. In the present study, we use a modified version of the maternal separation with early weaning (MSEW) model to study the impact of physical neglect and malnutrition on the gut microbiome in mice. Conditions of neglect-related stress were simulated based on scheduled dam-pup separation (physical neglect) and a high carbohydrate early-wean diet (malnutrition). C57BL/6J mice were bred in-house and ELS pups were subjected to: (1) daily dam-pup separation on postnatal days (PD) 2-13 and/or (2) early weaning (EW) to a high carbohydrate diet on PD14-21. All tissues and stool samples were collected on PD21 for analysis. Pups exposed to MSEW or EW alone were assessed separately. 16S rRNA gene sequencing revealed the neglect-related ELS condition, as described under the present model, led to significant shifts in the predominate species in the lower GI tract microbial community. ELS-mediated shifts included increased Bacteroides and Enterococcus and were accompanied by decreased Lachnospiraceae. RTqPCR of bilateral adrenal glands revealed gene expression changes in key enzymes for stress response pathways, namely those implicated in the synthesis of adrenal glucocorticoids. These results demonstrate ELS-mediated dysbiosis can be observed at PD21 under the present model. Our findings at the PD21 timepoint reveal acute changes to the gut microbiome in the context of ELS and characterizes the baseline microbial community in the lower GI tract.National Institutes of Health/National Institute on Aging (NIA) T32 AG020494; National Institute on Minority Health and Health Disparities (NIMHD) 5U54MD006882-1
CREB Activation by Mini-Chaperone CPP-P1 Enhances Retinal Ganglion Cell Survival in an Acute Glaucoma Model
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 North Texas Eye Research Institute Graduate Student Award - 1st PlacePurpose: Alpha-B crystallin is a heat shock protein that has been found to have anti-apoptotic properties and was used to design the novel mini-chaperone called peptain-1 (P1) conjugated with a cell-penetrating peptide (CPP), named CPP-P1. Transcriptomics of primary retinal ganglion cells (RGCs) isolated from adult rats subjected to ocular hypertension and treated with CPP-P1 revealed the activation of CREB signaling as a major pathway activated by the drug. Creb activation by phosphorylation (p-Creb) was previously confirmed in primary RGCs and tested here in a rat model of ocular hypertension.
Methods: Adult male Brown Norway rats (N=15, 5 per group) were grouped into naïve, IOP-Vehicle, and IOP-CPP-P1 experimental groups. Silicone oil (20µl) was injected into the anterior chamber, and 2µl of either PBS (vehicle) or CPP-P1 (2µg/µl) was injected intravitreally. On day 7 of elevated IOP, rats were euthanized. Retinal sections obtained were stained with Creb, p-Creb, and DAPI and imaged at 4X for cell counts and at 20X for integrated density measurements. Unpaired t-tests or Mann-Whitney tests in GraphPad Prism were used to calculate statistical significance. Retinal punches from post-mortem human eyes (N=3) were cultured with PBS or CPP-P1 (12.5µg/ml) for 48 hours, and tissue RNA was collected for qPCR.
Results: Ganglion cell layer counts obtained from rat retinal sections showed that the silicone oil injury group with no intervention (IOP-Veh) had a 51% decrease in ganglion cells compared to the naïve group (p<0.0001), and the silicone injury with CPP-P1 intervention group (IOP-CPP-P1) showed only a 23% decrease compared to the naïve group (p=0.0016). Integrated density measurements of Creb expression in IOP-Veh was 17% (p=0.615) higher than the naïve group, while in IOP-CPP-P1, it was 136% (p=0.092) higher than the naïve group. Expression of p-Creb showed a decrease in IOP-Veh by 50% (p=0.056) in comparison to the naïve group, while the IOP-CPP-P1 group was significantly higher than the IOP-Veh group (p=0.036). RNA expression of Creb1 in human retinal tissue was increased by 1.7-fold with CPP-P1 treatment.
Discussion: IOP-mediated RGC damage was mitigated by CPP-P1 treatment, demonstrating neuroprotective effects when compared to vehicle-treated rats. CREB signaling contributes to CPP-P1-mediated neuroprotection during glaucomatous insults.Gates Grubstake Award and R01EY02982