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Dopamine Signaling in Substantia Nigra and Its Impact on Locomotor Function-Not a New Concept, but Neglected Reality
Get PDFThe mechanistic influences of dopamine (DA) signaling and impact on motor function are nearly always interpreted from changes in nigrostriatal neuron terminals in striatum. This is a standard practice in studies of human Parkinson's disease (PD) and aging and related animal models of PD and aging-related parkinsonism. However, despite dozens of studies indicating an ambiguous relationship between changes in striatal DA signaling and motor phenotype, this perseverating focus on striatum continues. Although DA release in substantia nigra (SN) was first reported almost 50 years ago, assessment of nigral DA signaling changes in relation to motor function is rarely considered. Whereas DA signaling has been well-characterized in striatum at all five steps of neurotransmission (biosynthesis and turnover, storage, release, reuptake, and post-synaptic binding) in the nigrostriatal pathway, the depth of such interrogations in the SN, outside of cell counts, is sparse. However, there is sufficient evidence that these steps in DA neurotransmission in the SN are operational and regulated autonomously from striatum and are present in human PD and aging and related animal models. To complete our understanding of how nigrostriatal DA signaling affects motor function, it is past time to include interrogation of nigral DA signaling. This brief review highlights evidence that changes in nigral DA signaling at each step in DA neurotransmission are autonomous from those in striatum and changes in the SN alone can influence locomotor function. Accordingly, for full characterization of how nigrostriatal DA signaling affects locomotor activity, interrogation of DA signaling in SN is essential.This research was funded by US Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Program (grant number W81XWH19-1-0757), the National Institute on Aging (grant number AG040261), and the American Federation for Aging Research (grant number 110301090A). The APC was funded by W81XWH-19-1-0757
Expression of CD155 on LN-18 Glioblastoma Multiforme Cancer Cell Line
No full textPurpose: Glioblastoma multiforme (GBM) stands as the most common form of primary brain cancer among adults, it has a five-year survival rate of 5% - 10%. Traditional treatment options include surgical intervention, chemotherapy, and radiation therapy. Recently, immunotherapy has emerged as a promising treatment paradigm for cancer. These immunotherapies often rely on targeting molecular antigens unique to cancer cells. Surface antigens such as CD155 (PVR), previously thought to be expressed almost exclusively by stem cells, can also be expressed on the surface of certain cancer cells. CD-155, in the context of cancer survival, acts to downregulate cancer killing mechanisms of Natural Killer (NK) cells, making it a promising target for immunotherapy. To treat GBM tumors lacking expression of established antigens, our laboratory has embarked on the quest to uncover novel antigens specific to GBM, envisioned as candidates for Natural Killer (NK) cell-mediated immunotherapy. Methods: This experiment investigated the potential expression of cell surface CD155 on the LN-18 glioblastoma cell line utilizing flow cytometry, employing PE-labeled antibodies designed for CD155 detection. To ensure accuracy, we employed two negative control groups for this cell line: 1) unstained LN-18 cells and 2) LN-18 cells stained with PE-mIgG2a isotype control antibodies. Our hypothesis posited that LN-18 cells would exhibit a heightened fluorescence signal from anti-CD155 antibodies compared to the fluorescence levels observed in the negative control groups (unstained and isotype control-stained cells). Results and Conclusions: Based on the detection of increased fluorescence signal versus negative controls, CD155 was identified to be expressed on LN-18 cells
In-Vitro Assessment of Cortical Repair Induced by Branched-chain Amino Acid Treatment
No full textPurpose: Traumatic Brain Injury (TBI) refers to a constellation of pathologies resulting from mechanical damage to cortical tissue. The neurological sequala of such injuries can be devastating, and definitive treatment does not exist at this time. Branched-chain Amino Acid (BCAA) treatment has demonstrated neuroprotective effects in clinical literature and in various animal models of TBI. However, there is a lack of in-vitro literature referencing the repair capacity of BCAA administration after neuronal injury, particularly in the context of TBI. To fill this gap in knowledge, a scratch assay was repurposed for use in cortical culture, to assess the repair capacity of BCAA treatment.
Methods: Mouse-derived Mixed Cortical Culture (MCC) cells were extracted and seeded in 24 well plates. A scratch assay was performed, where a vertical scratch was drawn across each well in a reproducible manner with a 200 uL pipette tip. This procedure is meant to recapitulate aspects of mechanical damage induced by TBI on cortical tissue. Subsequently, images were taken immediately post-injury (0 hour time point), at 24 hour, and at 48 hour time points post-scratch to quantify the area of scratch unfilled by cells. Various dose concentrations of BCAA were tested in comparison to control (media only) and vehicle control (water). Test conditions included the customary BCAA ratio, which is a 2:1:1 mix of leucine, isoleucine, and valine; additionally, a 1:1:1 ratio of leucine, isoleucine, and valine was also tested.
Results: At 48 hours post-scratch, significant differences were found in open wound area when comparing the media only control to 10 uM (p < 0.01), 30 uM (p < 0.01), 300 uM (p < 0.001), and 1000 uM (p < 0.01) of the 2:1:1 BCAA dose. Significant differences were also found in the wound area when comparing the water vehicle control to 10 uM (p < 0.05), 30 uM (p < 0.01), 300 uM (p < 0.01), and 1000 uM (p < 0.01) of the 2:1:1 BCAA dose. No significant differences were found in the open wound area when comparing the controls and BCAA doses, at the 24 hour time point. Of note, no significant differences were found between control and treatment with the 1:1:1 ratio of leucine, isoleucine, and valine at any time point.
Conclusion: BCAA treatment at the 2:1:1 ratio was seen to accelerate injury recovery at various dose concentrations, as quantified by open wound area after scratch injury was induced. This cell culture model demonstrates the importance of BCAA ratios. While this aligns with animal models and clinical literature, this is the first in-vitro assessment of BCAA repair capacity, in the context of cortical culture. Future studies will be undertaken to further elucidate the constituents of the repair mechanism
Impact of Screening on Mortality for Patients Diagnosed with Hepatocellular Carcinoma in a Safety-Net Healthcare System: An Opportunity for Addressing Disparities
Get PDFPurpose: We describe the impact of screening on outcomes of patients diagnosed with hepatocellular carcinoma (HCC) in an urban safety-net healthcare system compared to a non-screened cohort diagnosed with HCC. Methods: Patients diagnosed with HCC at John Peter Smith Health Network were identified by querying the hospital tumor registry and allocated to the screened cohort if they had undergone any liver imaging within one year prior to HCC diagnosis, while the remainder were allocated to the non-screened cohort. Kaplan-Meier methods and log-rank tests were used to compare 3-year survival curves from an index date of HCC diagnosis. Cox proportional hazard models were used to calculate unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The Duffy adjustment was used to address lead-time bias. Results: A total of 158 patients were included (n = 53 screened, n = 105 non-screened). The median overall survival (OS) for the screened cohort was 19.0 months (95% CI: 9.9-NA) and that for the non-screened cohort was 5.4 months (95% CI: 3.7-8.5) [HR death (non-screened vs. screened) = 2.4, 95% CI: 1.6-3.6; log rank p < 0.0001]. The benefit of screening remained after adjusting for lead-time bias (HR 2.19, 95% CI 1.4-3.3, p = 0.0002). Conclusions: In an urban safety-net population, screening for HCC was associated with improved outcomes compared to patients diagnosed with HCC outside of a screening protocol.This study is supported in part by a Cancer Prevention and Research Institute of Texas (CPRIT) Clinical Trials Network Award (RP220542) to D.E.G., NIH/NCI L30CA274783 to T.J.B. and NIH/NIMHD (S21MD012472) to R.B
Anomalous Blood Supply of the Superficial Face: A Case Report and Cadaveric Study of Facial and Transverse Facial Artery Variations
Get PDFThe facial and transverse facial arteries supply blood to the superficial structures of the face. Understanding these arterial variations is essential for optimizing surgical planning and outcomes, especially in invasive facial procedures. A 78-year-old male cadaveric dissection documented variations in facial and transverse facial arteries. A hypoplastic facial artery arose from the external carotid artery between the lingual and occipital arteries and terminated below the oral fissure, supplying only the lower face. The transverse facial artery, originating from the superficial temporal artery, took an atypical path, running deep to the parotid gland and following the nasolabial sulcus to supply the upper face, areas typically served by the facial artery. The variations observed in the facial and transverse facial arteries highlight the diversity in facial vascular anatomy. Preoperative identification of such anomalies can help minimize surgical risks and improve outcomes, making detailed anatomical knowledge critical for tailoring surgical approaches.All authors have declared that no financial support was received from any organization for the submitted work
Obesity and leptin in breast cancer angiogenesis
No full textAt the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm(3) in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded in part through a Tulane Center for Aging COBRE Pilot Award (P30GM145498 (JSF)), a Louisiana Cancer Research Center (LCRC) New Investigator Award (M1-CR1305A6 (JSF)), and a Carol Lavin Bernick Faculty award from the Tulane Provost's Office (JSF). This work was also funded by USDA Project #6054-41000-112-000D (MEB)
Sex estimation using metrics of the innominate: A test of the DSP2 method
No full textSex estimation is a critical component of the biological profile, and forensic anthropologists may use a variety of sex estimation methods depending upon the degree of completeness and state of preservation of the skeletal remains being analyzed. The innominate is widely accepted to be the most sexually dimorphic skeletal element. The Diagnose Sexuelle Probabiliste (DSP) method, which uses 10 measurements of the innominate, was introduced in 2005 and updated as DSP2 in 2017. While DSP2 has been reported to have high classification accuracy rates in studies of South American and European populations, the method has not been widely tested in US samples, and few US practitioners incorporate this method into their casework. The goal of this study was to test the reliability and accuracy of DSP2 using a large, modern sample from the US (n = 174). Two observers, blinded from demographic information associated with each specimen, collected the DSP2 metrics. Intra- and interobserver error analyses showed acceptable levels of agreement for all measurements, except for IIMT. Classification accuracies exceeded 95%, with minimal sex bias, for both observers and using various measurement combinations; however, an inclusivity sex bias occurred with more males reaching the 0.95 posterior probability threshold required by DSP2 to provide a sex classification estimate. Based on its high accuracy, forensic anthropologists in the US may consider incorporating DSP2 into their casework, although we recommend excluding IIMT and using SPU with caution. Additional methods will continue to be needed when the posterior probability threshold is not reached.This research was funded by the National Science Foundation Grant No. 2214747 (co-funded by the National Institute of Justice DOJ- NIJ-22-RO- 0007)
Histological Examination of Ectopic Thyroid Tissue in an 88-year-old Caucasian Female: A Case Report
No full textBackground: Ectopic thyroid tissue (ETT) is a rare developmental abnormality that accounts for 1% of all mediastinal tumors and has a higher prevalence in females. ETT classically presents as an encapsulated mass separate from the normal subhyoid thyroid gland present on the anterior neck. Case studies have reported that ETT can arise in the mouth, oropharynx, subclavicular area, or mediastinum. Unless large enough to compress the surrounding tissues, individuals with ETT are typically asymptomatic. Therefore, ETT is often an incidental finding during imaging studies, surgery, or at autopsy. Histologically, ETT usually appears identical to "normal" thyroid tissue.
Case Information: During routine dissection, an 88-year-old Caucasian female with a cause of death of renal cancer presented with an encapsulated, solitary nodule located at the intersection between the thoracic cavity and superior mediastinum (2.0 x 1.0 x 1.5 cm). The nodule was densely adherent to the medial aspect of the right lung's apex, leaving behind a notable impression following extraction. No attachments to the thyroid proper were noted. Tan-brown, glassy, and multinodular cut surfaces were grossly appreciated following sectioning. Histological examination demonstrated the nodule was entirely composed of benign thyroid tissue with variable sized colloid follicles. No suspicious foci were identified. It is indeterminate if this nodule influenced the donor’s thyroid hormone levels due to the lack of access to a thyroid panel. Next, the thyroid proper was examined to reveal an enlarged, asymmetric gland with disconnected lobes. No obvious isthmus was present. The total gland weighed 85 grams. The external surface of the thyroid proper was tan-brown, bosselated, and featured an intact capsule. The left lobe (5.0 x 3.4 x 1.7 cm; 9 grams) was markedly smaller when compared to the enlarged right lobe (8.6 x 5.2 x 3.4 cm; 76 grams). Sectioning of the left lobe revealed tan, homogenous, and grossly unremarkable cut surfaces; the right lobe revealed tan-brown to maroon, firm, and multinodular cut surfaces. Additionally, a white, soft, and ill-defined area, with intervening colorless gelatinous material, was noted at roughly mid-pole of the right lobe.
Conclusion: This report describes a rare case of ETT and other relevant anatomical findings in an 88-year-old Caucasian female. These findings will further contribute to a scarcely documented developmental abnormality in the literature
Phenotypic and transcriptomic comparison of genetically distinct mouse strains for susceptibility to glucocorticoid-induced ocular hypertension (GC-OHT)
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Postdoctoral Poster Presentation AwardPurpose: Anti-inflammatory and immunosuppressive glucocorticoids (GCs) are widely prescribed for a variety of conditions and diseases. Unfortunately, a significant number of people experience negative side-effects associated with long term GC therapy and develop GC-induced ocular hypertension (GC-OHT) leading to secondary glaucoma. GC-OHT shares clinical and molecular signatures with primary open angle glaucoma (POAG) making this an appropriate model to study POAG. However, not all humans develop GC-OHT when treated with GCs. The ones that develop GC-OHT are called ‘responders’ whereas the ones that do not respond to GCs are called ‘non-responders’. The purpose of our study is to: (1) determine whether there are mouse strain differences in the development of GC-OHT, (2) whether resistance to develop GC-OHT is correlated with endogenous TM tissue gene expression using transcriptomic analysis.
Methods: After measurement of baseline IOP, various mouse strains (B6, D2.gpnmb⁺, BALB/cJ, 129P3/J, C3H/HeJ) were treated with weekly periocular injections of potent GC dexamethasone (DEX; n=5-10) or vehicle (n=5-10) in both eyes for 4-5 weeks. IOPs were measured weekly using a TonoLab rebound tonometer in isoflurane anesthetized mice. “TM ring” tissue and underlying sclera was carefully collected, and mRNA libraries were prepared for sequencing. Differential expression analysis was performed to identify DEX-induced changes within each strain. Furthermore, Ingenuity Pathway Analysis (IPA) was used to identify DEX-altered pathways in each strain and compare differences between responder and non-responder strains.
Results: B6 and C3H/HeJ mice robustly and reproducibly develop DEX-OHT with ΔIOP of 5-8 mmHg (P<0.0001). In contrast, D2.gpnmb⁺, 129P3/J, and BALB/cJ mice were resistant to the development of DEX-OHT. Differential analysis of gene expression between mouse strains showed novel DEX-responsive genes in all strains. Moreover, comparison of mouse strains using IPA showed similarities in the pathway and networks of the responder strains (B6 and C3H/HeJ).
Conclusions: As observed in humans, we find that there are differences in GC responsiveness and the ability to develop GC-OHT among mouse strains. Transcriptomics evidence suggests that responder strains share common pathways that contribute towards development of GC-OHT. These studies will reveal the molecular mechanisms responsible for GC-OHT as well as provide insights into the pathogenesis of POAG.NEI grant EY030967 to AF
Enhanced Protection of Retinal Ganglion Cells against Ischemia/Reperfusion Injury and Neurotrophic Factor Deprivation with Compound SA-10
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Oral Presentation Award - 1st PlacePurpose: Glaucoma is one of the leading causes of irreversible blindness worldwide. In glaucoma, the retinal ganglion cells (RGCs), which transmit visual signals to the brain, undergo neurodegeneration, leading to a gradual loss of vision. Oxidative stress is the imbalance between antioxidant activity and free radical production, which has been shown to be associated with glaucomatous RGC degeneration. In this study, we investigated the potential of SA-10, a hybrid nitric oxide donating and sulfone reactive oxygen species (ROS) scavenging molecule, to promote the survival of RGCs against glaucomatous damage. We investigated its neuroprotective effects following retinal ischemia/reperfusion (I/R) injury in mice and ex vivo following neurotrophic factor (NF) deprivation in human retinal explants (HREs).
Methods: Acute I/R injury was induced in C57BL/6J mice (n=2-3 mice/group/sex) through intracameral pressure elevation to 120 mmHg for 1 hour. The mice were pre-treated topically with a PLGA nanosuspension of SA-10 (1% SA-10-NPs) and treated for 14 days (7 doses) after I/R injury. The obtained retinal sections were stained with anti-heme oxygenase-1 antibody (Hmox1, a marker of protective response to oxidative stress) to quantify its expression levels. H&E sections were used to measure retinal thickness.
In another set of experiments, biopsy punches from HREs (n=3 donors) were isolated and treated with either SA-10 [10 µM] or vehicle and maintained without NF for 7 days ex vivo (DEV). Four control punches were collected on day 0 (0 DEV). After 7 days, HREs were immunostained with RBPMS (RGC-specific marker), and cell survival was analyzed. Analysis of Variance (ANOVA) was performed for all experiments.
Results: In the nerve fiber and ganglion cell layers (ganglion cell complex, GCC), I/R injury caused a significant reduction in Hmox1 expression in female (79.8%, p<0.05) and male (54.5%, p<0.05) mice, compared to the sham control. Additionally, I/R injury led to a decline in GCC thickness by 27.5% (p=0.23) in females and 32.7% (n=2) in males. However, treatment with SA-10-NPs increased Hmox1 expression by 4.2-fold (p<0.05) in females and by 0.5-fold (p=0.43) in males. SA-10-NPs also preserved GCC thickness by 17.6% (p=0.68) in females and 27.1% in males. In human retinal explants, the 7 DEV vehicle-treated group had a significant loss in RGCs by 45.2% (p<0.01) compared to 0 DEV. In contrast, SA-10 treatment enhanced RGC survival at 7 days with an 83.1% (p<0.01) higher RGC counts than the vehicle group.
Conclusions: SA-10 and its nanosuspension exhibited significant neuroprotective effects by enhancing Hmox1 expression, preserving retinal thickness, and promoting RGC survival, highlighting its potential as a therapeutic candidate for glaucoma and ischemic stroke.NEI Grant EY02982